Biology subjects

Jiang, R. H. Y.

Publications and source records attributed to Jiang, R. H. Y..

5 recordsLinked to original sources

bioRxiv2024

Uncovering Porphyrin Accumulation in the Tumor Microenvironment

Heme, an iron-containing tetrapyrrole, is essential in almost all organisms. Heme biosynthesis needs to be exquisitely regulated particularly given the potential cytotoxicity of protoporphyrin IX, the intermediate preceding heme formation. Here, we report on the porphyrin intermediate accumulation within the tumor microenvironment (TME), which we propose to result from dysregulation of heme biosynthesis concomitant with an enhanced cancer survival dependence on mid-step genes, a process we recently termed Porphyrin Overdrive. Specifically, porphyrins build up in both lung cancer cells and stromal cells in the TME. Within the TMEs stromal cells, evidence supports cancer-associated fibroblasts (CAFs) actively producing porphyrins through an imbalanced pathway. Conversely, normal tissues exhibit no porphyrin accumulation, and CAFs deprived of tumor cease porphyrin overproduction, indicating that both cancer and tumor-stromal porphyrin overproduction is confined to the cancer-specific tissue niche. The clinical relevance of our findings is implied by establishing a correlation between imbalanced porphyrin production and overall poorer survival in more aggressive cancers. These findings illuminate the anomalous porphyrin dynamics specifically within the tumor microenvironment, suggesting a potential target for therapeutic intervention.

cancer biology↗

bioRxiv2022

A unique class of Zn2+-binding PBPs underlies cephalosporin resistance and sporogenesis in Clostridioides difficile

{beta}-Lactam antibiotics, particularly cephalosporins, are major risk factors for C. difficile infection (CDI), the most common hospital acquired infection. These broad-spectrum antibiotics irreversibly inhibit penicillin-binding proteins (PBPs), essential enzymes that assemble the bacterial cell wall. Little is known about the C. difficile PBPs, yet they play central roles in the growth, infection, and transmission of this pathogen. In this study we discover that PBP2, essential for vegetative growth, is the primary bactericidal target for {beta}-lactams in C. difficile. We further demonstrate PBP2 is insensitive to cephalosporin inhibition, revealing a key cause of the well-documented, but poorly understood, cephalosporin resistance in C. difficile. For the first time, we determine the crystal structures of C. difficile PBP2, which bears several highly unique features, including significant ligand-induced conformational changes and an active site Zn2+-binding motif that influences {beta}-lactam binding and protein stability. Remarkably, this motif is shared in two other C. difficile PBPs essential for sporulation, PBP3 and SpoVD. While these PBPs are present in a wide range of bacterial taxa, including species in extreme environments and the human gut, they are mostly found in anaerobes, typically Firmicutes. The widespread presence of this convergently evolved thiol-containing motif and its cognate Zn2+ suggests it may function as a redox-sensor to regulate cell wall synthesis for survival in adverse environments. Collectively, our findings address important etiological questions surrounding C. difficile, characterize new elements of PBP structure and function, and lay the groundwork for antibiotic development targeting both C. difficile growth and sporulation.

microbiology↗

bioRxiv2020

The endosymbiotic origins of the apicoplast link fever-survival and artemisinin-resistance in the malaria parasite

BackgroundThe emergence and spread of Plasmodium falciparum parasites resistant to front-line antimalarial artemisinin-combination therapies (ACT) threatens to erase the considerable gains against the disease of the last decade. We developed a new large-scale phenotypic screening pipeline and used it to carry out the first large-scale forward-genetic phenotype screen in P. falciparum to identify genes that allow parasites to survive febrile temperatures. ResultsScreening identified more than 200 P. falciparum mutants with differential responses to increased temperature. These mutants were more likely to be sensitive to artemisinin derivatives as well as to heightened oxidative stress. Major processes critical for P. falciparum tolerance to febrile temperatures and artemisinin included highly essential, conserved pathways associated with protein-folding, heat-shock and proteasome-mediated degradation, and unexpectedly, isoprenoid biosynthesis, which originated from the ancestral genome of the parasites algal endosymbiont-derived plastid, the apicoplast. Apicoplast-targeted genes in general were up-regulated in response to heat shock, as were other Plasmodium genes with orthologs in plant and algal genomes. ConclusionsPlasmodium falciparum parasites appear to exploit their innate febrile-response mechanisms to mediate resistance to artemisinin. Both responses depend on endosymbiotic cynobacterium-related ancestral genes in the parasites genome, suggesting a link to the evolutionary origins of Plasmodium parasites in free-living ancestors.

genomics↗

bioRxiv2020

Epigenetic Potential and DNA Methylation in an Ongoing House Sparrow (Passer domesticus) Range Expansion

During range expansions, epigenetic mechanisms may mediate phenotypic responses to environmental cues, enabling organisms to adjust to novel conditions at novel sites. Here, we predicted that the number of CpG sites within the genome, one form of epigenetic potential, would be important for success during range expansions because DNA methylation can modulate gene expression and hence facilitate adaptive plasticity. Previously, we found that this same form of epigenetic potential was higher in introduced compared to native populations of house sparrows (Passer domesticus) for two immune genes (Toll-like receptors 2A and 4). Here, we took a reduced-representation sequencing approach (ddRadSeq and EpiRadSeq) to investigate how CpG site number, as well as resultant DNA methylation, varied across five sites in the [~]70 year-old Kenyan house sparrow range expansion. We found that the number of CpG sites increased towards the vanguard of the invasion, even when accounting for variation in genetic diversity among sites. This pattern was driven by more losses of CpG sites towards the core of the invasion (the initial site of introduction). Across all sequenced loci, DNA methylation decreased but became more variable towards the range-edge. However, in the subset CpG sites proximal to mutated CpG sites, DNA methylation increased and variation declined. These results indicate that epigenetic potential influenced the Kenyan house sparrow range expansion, likely by providing greater phenotypic plasticity which is genetically assimilated as populations adapt to local conditions. Similar mechanisms might underlie the successes and failures of other natural and anthropogenic range expansions.

evolutionary biology↗

bioRxiv2017

Transmission Expression Signature in Nascent Plasmodium vivax Blood Stage Infection

The lack of a continuous in vitro culture system for Plasmodium vivax severely limits our knowledge of pathophysiology of the most widespread malaria parasite. To gain direct understanding of P. vivax human infections, we used Next Generation Sequencing data mining to unravel parasite in vivo expression profiles for P. vivax, and P. falciparum as comparison. We performed cloud and local computing to extract parasite transcriptomes from publicly available raw data of human blood samples. We developed a Poisson Modelling (PM) method to confidently identify parasite derived transcripts in mixed RNAseq signals of infected host tissues. We successfully retrieved and reconstructed parasite transcriptomes from infected patient blood as early as the first blood stage cycle; and the same methodology did not recover any significant signal from controls. Surprisingly, these first generation blood parasites already show strong signature of transmission, which indicates the commitment from asexual-to-sexual stages. Further, we develop mathematical models for P. vivax and P. falciparum to assess the epidemiological impact of possible 7-day early stage transmission and P. vivax complex life cycle. The study uncovers the earliest onset of P. vivax blood pathogenesis and highlights the challenges of P. vivax eradication programs.\n\nAuthor summaryWe discovered that P. vivax in vivo parasitemia is associated with gametocytogenesis expression signature within the first blood stage cycle, that is, eight days from a mosquito bite. Our results suggest that asexual-to-sexual commitment may happen with first generation merozoite infection. This allows for the possibility of transmission at this early stage, much earlier than for P. falciparum. Our novel mathematical model accounts for multiple unique aspects of P. vivax biology to advance our understanding of expected disease prevalence, and compares the results to those of P. falciparum. We demonstrate that given the presence of asymptotical carriers and the possibility of relapses, earlier parasite transmission is capable of increasing the spread of disease within human populations. In summary, P. vivax gametogenesis has the potential to fast track the transmission cycle, which will drive enhanced propagation of the disease during the transmission season and clinical relapses.

systems biology↗