Biology subjects

Peterson, A.

Publications and source records attributed to Peterson, A..

28 records · Page 2Linked to original sources

bioRxiv2022

ZccE is a Novel P-type ATPase That Protects Streptococcus mutans Against Zinc Intoxication

Zinc is a trace metal that is essential to all forms of life, but that becomes toxic at high concentrations. Because it has both antimicrobial and anti-inflammatory properties and low toxicity to mammalian cells, zinc has been used as a therapeutic agent for centuries to treat a variety of infectious and non-infectious conditions. While the usefulness of zinc-based therapies in caries prevention is controversial, zinc is incorporated into toothpaste and mouthwash formulations to prevent gingivitis and halitosis. Despite this widespread use of zinc in oral healthcare, the mechanisms that allow Streptococcus mutans, a keystone pathogen in dental caries and prevalent etiological agent of infective endocarditis, to overcome zinc toxicity are largely unknown. Here, we discovered that S. mutans is inherently more tolerant to high zinc stress than all other species of streptococci tested, including commensal streptococci associated with oral health. Using a transcriptome approach, we uncovered several potential strategies utilized by S. mutans to overcome zinc toxicity. Among them, we identified a previously uncharacterized P-type ATPase transporter and cognate transcriptional regulator, which we named ZccE and ZccR respectively, as responsible for the remarkable high zinc tolerance of S. mutans. In addition to zinc, we found that ZccE, which was found to be unique to S. mutans strains, mediates tolerance to at least three additional metal ions, namely cadmium, cobalt, and copper. Loss of the ability to maintain zinc homeostasis when exposed to high zinc stress severely disturbed Zinc:Manganese ratios, leading to heightened peroxide sensitivity that was alleviated by manganese supplementation. Finally, we showed that the ability of the {Delta}zccE strain to stably colonize the rat tooth surface after topical zinc treatment was significantly impaired, providing proof of concept that ZccE and ZccR are suitable targets for the development of antimicrobial therapies specifically tailored to kill S. mutans. Author summaryDental caries is an overlooked infectious disease affecting more than 50% of the adult population. While several bacteria that reside in dental plaque have been associated with caries development and progression, Streptococcus mutans is deemed a keystone caries pathogen due to its capacity to modify the dental plaque environment in a way that is conducive with disease development. Zinc is an essential trace metal to life but very toxic when encountered at high concentrations, to the point that it has been used as an antimicrobial for centuries. Despite the widespread use of zinc in oral healthcare products, little is known about the mechanisms utilized by oral bacteria to overcome its toxic effects. In this study, we discovered that S. mutans can tolerate exposure to much higher levels of zinc than closely related streptococcal species, including species that antagonize S. mutans and are associated with oral health. In this study, we identified a new metal transporter, named ZccE, as directly responsible for the inherently high zinc tolerance of S. mutans. Because ZccE is not present in other bacteria, our findings provide a new target for the development of a zinc-based therapy specifically tailored to kill S. mutans.

microbiology↗

bioRxiv2022

Genetic background influences survival of infections with Salmonella enterica serovar Typhimurium in the Collaborative Cross

Salmonella infections typically cause self-limiting gastroenteritis, but in some individuals these bacteria can spread systemically and cause disseminated disease. Salmonella Typhimurium (STm), which causes severe systemic disease in most inbred mice, has been used as a model for disseminated disease. To screen for new infection phenotypes across a range of host genetics, we orally infected 32 Collaborative Cross (CC) mouse strains with STm and monitored their disease progression for seven days by telemetry. Our data revealed a broad range of phenotypes across CC strains in many parameters including survival, bacterial colonization, tissue damage, complete blood counts (CBC), and serum cytokines. Eighteen CC strains survived to day 7, while fourteen susceptible strains succumbed to infection before day 7. Several CC strains had sex differences in survival and colonization. Surviving strains had lower pre-infection baseline temperatures and were less active during their daily active period. Core body temperature disruptions were detected earlier after STm infection than activity disruptions, making temperature a better detector of illness. All CC strains had STm in spleen and liver, but susceptible strains were more highly colonized. Tissue damage was weakly negatively correlated to survival. We identified loci associated with survival on Chromosomes (Chr) 1, 2, 4, 7. Polymorphisms in Ncf2 and Slc11a1, known to reduce survival in mice after STm infections, are located in the Chr 1 interval, and the Chr 7 association overlaps with a previously identified QTL peak called Ses2. We identified two new genetic regions on Chr 2 and 4 associated with susceptibility to STm infection. Our data reveal the diversity of responses to STm infection across a range of host genetics and identified new candidate regions for survival of STm infection. Author SummarySalmonella Typhimurium (STm) infections typically cause self-limiting diarrheal symptoms, but in some individuals, the bacteria can spread throughout the body and cause life-threatening infection. We used a population of genetically different mice (Collaborative Cross) to identify their range of responses to STm infection. We identified a broad range of outcomes across these different mice, including a group of mice susceptible to lethal infection and a group that survived our 7 day study. We found that mice that survived STm infection had a cooler core body temperature before infection than susceptible mice, while remaining active. Thus, body temperature, rather than activity, appears to be a better predictor of poor outcomes after STm infection. We identified several regions of the mouse genome that are associated with outcome after STm infection. One of these regions, mouse Chromosome (Chr) 1 has genes that are already known to influence susceptibility to STm infection. Two other regions that we identified to influence survival after STm infection, located on mouse Chr 2 and 4, are novel and contain numerous genes of interest that may be linked to susceptibility. Our work defines the utility of exploring how host genetic diversity influences infection outcomes with bacterial pathogens.

genetics↗

bioRxiv2021

Species and strain cultivation of skin, oral, and gut microbiota

Genomics-driven discovery of microbial species have provided extraordinary insights into the biodiversity of human microbiota. High resolution genomics to investigate species- and strain-level diversity and mechanistic studies, however, rely on the availability of individual microbes from a complex microbial consortia. Here, we describe and validate a streamlined workflow for cultivating microbes from the skin, oral, and gut microbiota, informed by metagenomic sequencing, mass spectrometry, and strain profiling.

microbiology↗

bioRxiv2020

Genetic and pharmacological evidence for kinetic competition between alternative poly(A) sites in yeast

Most eukaryotic mRNAs accommodate alternative sites of poly(A) addition in the 3 untranslated region in order to regulate mRNA function. Here we present a systematic analysis of 3 end formation factors, which revealed 3UTR lengthening in response to a loss of the core machinery, whereas a loss of the Sen1 helicase resulted in shorter 3UTRs. We show that the anti-cancer drug cordycepin, 3 deoxyadenosine, caused nucleotide accumulation and the usage of distal poly(A) sites. Mycophenolic acid, a drug which reduces GTP levels and impairs RNA polymerase II (RNAP II) transcription elongation, promoted the usage of proximal sites and reversed the effects of cordycepin on alternative polyadenylation. Moreover, cordycepin mediated usage of distal sites was associated with a permissive chromatin template and was suppressed in the presence of an rpb1 mutation, which slows RNAP II elongation rate. We propose that alternative polyadenylation is governed by temporal coordination of RNAP II transcription and 3 end processing and controlled by the availability of 3 end factors, nucleotide levels and chromatin landscape.

cell biology↗

bioRxiv2020

Minimal system for assembly of SARS-CoV-2 virus like particles

SARS-CoV-2 virus is the causative agent of COVID-19. Here we demonstrate that non-infectious SARS-CoV-2 virus like particles (VLPs) can be assembled by co-expressing the viral proteins S, M and E in mammalian cells. The assembled SARS-CoV-2 VLPs possess S protein spikes on particle exterior, making them ideal for vaccine development. The particles range in shape from spherical to elongated with a characteristic size of 129 {+/-} 32 nm. We further show that SARS-CoV-2 VLPs dried in ambient conditions can retain their structural integrity upon repeated scans with Atomic Force Microscopy up to a peak force of 1 nN.

biophysics↗

bioRxiv2018

Incomplete annotation of OMIM genes is likely to be limiting the diagnostic yield of genetic testing, particularly for neurogenetic disorders

Although the increasing use of whole-exome and whole-genome sequencing have improved the yield of genetic testing for Mendelian disorders, an estimated 50% of patients still leave the clinic without a genetic diagnosis. This can be attributed in part to our lack of ability to accurately interpret the genetic variation detected through next-generation sequencing. Variant interpretation is fundamentally reliant on accurate and complete gene annotation, however numerous reports and discrepancies between gene annotation databases reveals that the knowledge of gene annotation remains far from comprehensive. Here, we detect and validate transcription in an annotation-agnostic manner across all 41 different GTEx tissues, then connect novel transcription to known genes, ultimately improving the annotation of 63% of the known OMIM-morbid genes. We find the majority of novel transcription to be tissue-specific in origin, with brain tissues being most susceptible to misannotation. Furthermore, we find that novel transcribed regions tend to be poorly conserved, but are significantly depleted for genetic variation within humans, suggesting they are functionally significant and potentially have human-specific functions. We present our findings through an online platform vizER, which enables individual genes to be visualised and queried for evidence of misannotation. We also release all tissue-specific transcriptomes in a BED format for ease of integration with whole-genome sequencing data. We anticipate that these resources will improve the diagnostic yield for a wide range of Mendelian disorders.

bioinformatics↗

bioRxiv2018

Reduced Salience and Enhanced Central Executive Connectivity Following PTSD Treatment

BACKGROUNDIn soldiers with posttraumatic stress disorder (PTSD), symptom provocation was found to induce increased connectivity within the salience network, as measured by functional magnetic resonance imaging (fMRI) and global brain connectivity with global signal regression (GBCr). However, it is unknown whether these GBCr disturbances would normalize following effective PTSD treatment.\n\nMETHODS69 US Army soldiers with (n = 42) and without PTSD (n = 27) completed fMRI at rest and during symptom provocation using subject-specific script imagery. Then, participants with PTSD received 6 weeks (12 sessions) of group cognitive processing therapy (CPT) or present-centered therapy (PCT). At week 8, all participants repeated the fMRI scans. The primary analysis used a region-of-interest approach to determine the effect of treatment on salience GBCr. A secondary analysis was conducted to explore the pattern of GBCr alterations posttreatment in PTSD participants compared to controls.\n\nRESULTSOver the treatment period, PCT significantly reduced salience GBCr (p = .02). Compared to controls, salience GBCr was high pretreatment (PCT, p = .01; CPT, p = .03) and normalized post-PCT (p = .53), but not post-CPT (p = .006). Whole-brain secondary analysis found high GBCr within the central executive network in PTSD participants compared to controls. Post hoc exploratory analyses showed significant increases in executive GBCr following CPT treatment (p = .01).\n\nCONCLUSIONThe results support previous models relating CPT to central executive network and enhanced cognitive control while unraveling a previously unknown neurobiological mechanism of PCT treatment, demonstrating treatment-specific reduction in salience connectivity during trauma recollection.

neuroscience↗

bioRxiv2018

Salience Network Disruption in US Army Soldiers with PTSD

BACKGROUNDBetter understanding of the neurobiology of posttraumatic stress disorder (PTSD) may be critical to developing novel, effective therapeutics. Here, we conducted a data-driven investigation using a well-established, graph-based topological measure of nodal strength to determine the extent of functional dysconnectivity in a cohort of active duty US Army soldiers with PTSD compared to controls.\n\nMETHODS102 participants with (n=50) or without PTSD (n=52) completed functional magnetic resonance imaging (fMRI) at rest and during symptom provocation using subject-specific script imagery. Vertex/voxel global brain connectivity with global signal regression (GBCr), a measure of nodal strength, was calculated as the average of its functional connectivity with all other vertices/voxels in the brain gray matter.\n\nRESULTSIn contrast to during resting-state, where there were no group differences, we found a significantly higher GBCr, in PTSD participants compared to controls, in areas within the right hemisphere, including anterior insula, caudal-ventrolateral prefrontal, and rostral-ventrolateral parietal cortices. Overall, these clusters overlapped with the ventral and dorsal salience networks. Post hoc analysis showed increased GBCr in these salience clusters during symptom provocation compared to resting-state. In addition, resting-state GBCr in the salience clusters predicted GBCr during symptom provocation in PTSD participants but not in controls.\n\nCONCLUSIONIn PTSD, increased connectivity within the salience network has been previously hypothesized, based primarily on seed-based connectivity findings. The current results strongly support this hypothesis using whole-brain network measure in a fully data-driven approach. It remains to be seen in future studies whether these identified salience disturbances would normalize following treatment.

neuroscience↗

bioRxiv2018

Regional heterogeneity in gene expression, regulation and coherence in hippocampus and dorsolateral prefrontal cortex across development and in schizophrenia

Recent large-scale genomics efforts have better characterized the molecular correlates of schizophrenia in postmortem human neocortex, but not hippocampus which is a brain region prominently implicated in its pathogenesis. Here in the second phase of the BrainSeq Consortium (Phase II), we have generated RiboZero RNA-seq data for 900 samples across both the dorsolateral prefrontal cortex (DLPFC) and the hippocampus (HIPPO) for 551 individuals (286 affected by schizophrenia disorder: SCZD). We identify substantial regional differences in gene expression, in both pre- and post-natal life, and find widespread differences in how genes are regulated across development. By extending quality surrogate variable analysis (qSVA) to multiple brain regions, we identified 48 and 245 differentially expressed genes (DEG) by SCZD diagnosis (FDR<5%) in HIPPO and DLPFC, respectively, with surprisingly minimal overlap in DEG between the two brain regions. We further identified 205,618 brain region-dependent eQTLs (FDR<1%) and found that 124 GWAS risk loci contain eQTLs in at least one of the regions. We also identify potential molecular correlates of in vivo evidence of altered prefrontal-hippocampal functional coherence in schizophrenia. These results underscore the complexity and regional heterogeneity of the transcriptional correlates of schizophrenia, and suggest future schizophrenia therapeutics may need to target molecular pathologies localized to specific brain regions.

neuroscience↗

bioRxiv2017

Stem cell niche signals Wnt, Hedgehog, and Notch distinctively regulate Drosophila follicle precursor cell differentiation

Adult stem cells commonly give rise to transit-amplifying progenitors, whose progeny differentiate into distinct cell types. Signals within the stem cell niche maintain the undifferentiated state. However it is unclear whether or how niche signals might also coordinate fate decisions within the progenitor pool. Here we use quantitative microscopy to elucidate distinct roles for Wnt, Hedgehog (Hh), and Notch signalling in progenitor development in the Drosophila ovary. Follicle stem cells (FSCs) self-renew and produce precursors whose progeny adopt distinct polar, stalk, and main body cell fates. We show that a steep gradient of Wnt signalling maintains a multipotent state in proximally located progenitor cells by inhibiting expression of the cell fate determinant Eyes Absent (Eya). A shallower gradient of Hh signalling controls the proliferation to differentiation transition. The combination of Notch and Wnt signalling specifies polar cells. These findings reveal a mechanism by which multiple niche signals coordinate cell fate diversification of progenitor cells.

developmental biology↗