Biology subjects

Morrison, T.

Publications and source records attributed to Morrison, T..

12 recordsLinked to original sources

bioRxiv2025

Survey of Peristenus spp. (Hymenoptera: Braconidae) parasitoids in the Monterey Bay region of California

Two European parasitoids, Peristenus relictus and Peristenus digoneutis, were introduced into California to improve the management of Lygus hesperus. While P. relictus quickly established, P. digoneutis has only rarely been recovered. After a renewed release effort, a field survey was conducted in an attempt to recover P. digoneutis. Collections of Lygus hesperus nymphs were made from strawberry production areas and associated alfalfa trap crops in the Monterey Bay region in 2023. Parasitoid larvae recovered from dissected nymphs were identified using species-specific molecular markers. All successfully assayed specimens were confirmed as P. relictus. Furthermore, all reared parasitoids from similarly collected Lygus nymphs were identified as P. relictus. This survey corroborates previous findings indicating that P. relictus is the primary nymphal parasitoid in California and fails to provide evidence that P. digoneutis has established on the central coast.

ecology↗

bioRxiv2025

Epithelial-intrinsic nitric oxide synthase 2 sustains host-microbiota dynamics that promote colitis

The microbiota influence disease pathogenesis and treatment, however we have limited ability to assess patient status in relation to the microbiota. Here we find that the nitric oxide generating enzyme, nitric oxide synthase 2 (Nos2), is transcriptionally primed in intestinal epithelial cells (IECs), as opposed to immune cells, in inflammatory bowel disease (IBD) patients. Generation of IEC-specific Nos2 knockout mice revealed that epithelial Nos2 activity promoted susceptibility to intestinal disease and sustained a colitogenic microbiota. Epithelial Nos2 increased levels of nitric oxide-derived nitrates and nitrate-metabolizing bacteria in the intestine. Unexpectedly, extra-intestinal nitrates also reflected IEC-intrinsic Nos2 expression, and systemic nitrate concentrations in patients paralleled intestinal Nos2 activation. In fact, temporally inhibiting epithelial Nos2 was sufficient to alter intestinal nitrate homeostasis and inflammation in mice, as well as restrict nitrate production by human intestinal organoids. These data reveal that epithelial nitric oxide metabolism directs host-microbiota dynamics that can alter disease and that monitoring and targeting this axis may benefit patients with IBD.

immunology↗

bioRxiv2025

Novel Computational Pipeline to Identify Target Sites for Broad Spectrum Antiviral Drugs

Emerging viruses pose an ongoing threat to human health. While certain viral families are common sources of outbreaks, predicting the specific virus within a family that will cause the next outbreak or pandemic is not possible, creating an urgent need for broad spectrum antiviral drugs that are effective against an array of related viral pathogens. However, broad spectrum drug development is hindered by the lack of detailed knowledge of compound binding sites that are structurally and functionally conserved between viral family members and are essential for virus replication. To overcome this limitation, we developed an in silico approach that combines AI-driven protein structure prediction, computational fragment soaking, multiple sequence alignment, and protein stability calculations to identify highly conserved target sites that are both solvent-accessible and conserved. We applied this approach to the Togaviridae family, which includes emerging pandemic disease threats such as chikungunya and Venezuelan equine encephalitis virus for which there are currently no approved antiviral therapies. Our analysis identified multiple solvent accessible and structurally conserved pockets in the alphavirus non-structural protein 2 (nsP2) protease domain, which is essential for processing of the viral replicase proteins. Mutagenesis of key solvent accessible and conserved residues identified novel pockets that are essential for protease activity and the replication of multiple alphaviruses, validating these pockets as potential antiviral target sites for nsP2 inhibitors. These findings highlight the potential of artificial intelligence-informed modeling for revealing functionally conserved, accessible pockets as a means of identifying potential target binding sites for broadly active direct acting antivirals. Significance StatementHere we present a novel integrative computational approach to identify novel target sites for broadly acting antiviral drugs. We used this technique to identify multiple functionally and structurally conserved protein surface pockets within the alphavirus nsP2 protease and methyl-transferase-like domain. Mutagenesis of these pockets identified that they are essential for protease activity and replication of a genetically diverse group of alphaviruses, validating these sites as potential targets for broadly active small molecule alphavirus inhibitors. This integrative AI-driven approach thus provides an important tool in developing antivirals essential for pandemic preparedness.

microbiology↗

bioRxiv2025

Uncovering Heterogeneous Effects via Localized Feature Selection

Identifying features that interact to trigger disease, while accounting for heterogeneity across diverse populations, is essential for the development of precision and targeted medicine. Despite the availability of vast and complex health-related datasets, most existing works focus on identifying disease-associated features at the population level or within a few subpopulations, often overlooking individual-level heterogeneity within these groups. To address this limitation, we propose a novel framework that utilizes localized test statistics to identify disease-associated features tailored to individual profiles. Our method leverages the recently developed knockoffs methodology to control the noise level of the selection set so that the results are replicable. Moreover, it allows for the discovery of hidden heterogeneous effects within the data, as demonstrated in an application to single-cell RNA sequencing data for Alzheimers disease. By aggregating localized feature selection results, our framework also enables powerful population-level feature selection. Our framework provides a powerful tool for exploratory studies of precision medicine, offering the potential to generate novel hypotheses for confirmatory biological experiments.

bioinformatics↗

bioRxiv2024

A specific and portable gene expression program underlies antigen archiving by lymphatic endothelial cells

Antigens from protein subunit vaccination traffic from the tissue to the draining lymph node, either passively via the lymph or carried by dendritic cells at the local injection site. Lymph node (LN) lymphatic endothelial cells (LEC) actively acquire and archive foreign antigens, and archived antigen can be released during subsequent inflammatory stimulus to improve immune responses. Here, we answer questions about how LECs achieve durable antigen archiving and whether there are transcriptional signatures associated with LECs containing high levels of antigen. We used single cell sequencing in dissociated LN tissue to quantify antigen levels in LEC and dendritic cell populations at multiple timepoints after immunization, and used machine learning to define a unique transcriptional program within archiving LECs that can predict LEC archiving capacity in independent data sets. Finally, we validated this modeling, showing we could predict antigen archiving from a transcriptional dataset of CHIKV infected mice and demonstrated in vivo the accuracy of our prediction. Collectively, our findings establish a unique transcriptional program in LECs that promotes antigen archiving that can be translated to other systems.

immunology↗

bioRxiv2024

In silico identification of putative causal genetic variants

Understanding the causal genetic architecture of complex phenotypes will fuel future research into disease mechanisms and potential therapies. Here, we illustrate the power of a novel framework: it detects, starting from summary statistics, and across the entire genome, sets of variants that carry non-redundant information on the phenotypes and are therefore more likely to be causal in a biological sense. The approach, implemented in open-source software, is also computationally efficient, requiring less than 15 minutes on a single CPU to perform genome-wide analysis. Through extensive genome-wide simulation studies, we show that the method can substantially outperform existing methods in false discovery rate control, statistical power and various fine-mapping criteria. In applications to a meta-analysis of ten large-scale genetic studies of Alzheimers disease (AD), we identified 82 loci associated with AD, including 37 additional loci missed by conventional GWAS pipeline. Massively parallel reporter assays and CRISPR-Cas9 experiments have confirmed the functionality of the putative causal variants our method points to. Finally, we retrospectively analyzed summary statistics from 67 large-scale GWAS for a variety of phenotypes. Results reveal the methods capacity to robustly discover additional loci for polygenic traits and pinpoint potential causal variants underpinning each locus beyond conventional GWAS pipeline, contributing to a deeper understanding of complex genetic architectures in post-GWAS analyses.

genetics↗

bioRxiv2023

Temporal Tracking of Plasma Cells in vivo Using J-chain CreERT2 Reporter System.

Plasma cells (PCs) are essential for humoral immunity, as they are responsible for the production of antibodies and contribute to immunological memory. Despite their importance, differentiating between long-lived and short-lived PCs in vivo remains a challenge due to a lack of specific markers to distinguish these populations. Addressing this gap, our study introduces a novel J-chain CreERT2 GFP allele (IgJCreERT2) for precise genetic studies of PCs. This model takes advantage of PC-restricted expression of the J-chain gene, enabling temporal and cell-specific tracking of PCs utilizing a tamoxifen-inducible Cre recombinase. Our in vitro and in vivo validation studies of the inducible Cre allele confirmed the fidelity and utility of this model and demonstrated the models ability to trace the long-lived PC population in vivo following immunization. The IgJCreERT2 model allowed for detailed analysis of surface marker expression on PCs, revealing insights into PC heterogeneity and characteristics. Our findings not only validate the IgJCreERT2 mouse as a reliable tool for studying PCs but also facilitate the investigation of PC dynamics and longevity, particularly in the context of humoral immunity and vaccine responses. This model represents a significant advancement for the in-depth study of PCs in health and disease, offering a new avenue for the exploration of PC biology and immunological memory.

immunology↗

bioRxiv2023

Chikungunya virus infection disrupts lymph node lymphatic endothelial cell composition and function via MARCO

Infection with chikungunya virus (CHIKV) causes disruption of draining lymph node (dLN) organization, including paracortical relocalization of B cells, loss of the B cell-T cell border, and lymphocyte depletion that is associated with infiltration of the LN with inflammatory myeloid cells. Here, we find that during the first 24 h of infection, CHIKV RNA accumulates in MARCO-expressing lymphatic endothelial cells (LECs) in both the floor and medullary LN sinuses. The accumulation of viral RNA in the LN was associated with a switch to an antiviral and inflammatory gene expression program across LN stromal cells, and this inflammatory response, including recruitment of myeloid cells to the LN, was accelerated by CHIKV-MARCO interactions. As CHIKV infection progressed, both floor and medullary LECs diminished in number, suggesting further functional impairment of the LN by infection. Consistent with this idea, we find that antigen acquisition by LECs, a key function of LN LECs during infection and immunization, was reduced during pathogenic CHIKV infection.

immunology↗

bioRxiv2022

Hypoxia shapes the immune landscape in lung injury promoting inflammation persistence

Acute Respiratory Distress Syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, has no cure. Hypoxemia is a defining feature, yet its impact on inflammation is often neglected. Patients with ARDS are monocytopenic early in the onset of the disease. Endotoxin or Streptococcus pneumoniae acute lung injury (ALI) in the context of hypoxia replicates this finding, through hypoxia-driven suppression of type I interferon signalling. This results in failed lung monocyte-derived interstitial macrophages (IM) niche expansion and unchecked neutrophilic inflammation. Administration of colony stimulating factor 1 (CSF1) rescues the monocytopenia, alters the circulating classical monocyte phenotype in hypoxic endotoxin-driven ALI and enables lung IM population expansion, thus limiting lung injury in endotoxin- and virally-induced hypoxic ALI. Hypoxia directly alters immune dynamics to the detriment of the host and manipulation of this aberrant response offers new therapeutic strategies for ARDS.

cell biology↗

bioRxiv2021

Evolution of protection after maternal immunization for respiratory syncytial virus in cotton rats

Maternal anti-respiratory syncytial virus (RSV) antibodies acquired by the fetus through the placenta protect neonates from RSV disease through the first weeks of life. In the cotton rat model of RSV infections, we previously reported that immunization of dams during pregnancy with virus-like particles assembled with mutation stabilized pre-fusion F protein as well as the wild type G protein resulted in robust protection of their offspring from RSV challenge (Blanco, et al Journal of Virology 93: e00914-19, https://doi.org/10.1128/JVI.00914-19). Here we describe the durability of those protective responses in dams, the durability of protection in offspring, and the transfer of that protection to offspring of two consecutive pregnancies without a second boost immunization. We report that four weeks after birth, offspring of the first pregnancy were significantly protected from RSV replication in both lungs and nasal tissues after RSV challenge, but protection was reduced in pups at 6 weeks after birth. However, the overall protection of offspring of the second pregnancy was considerably reduced, even at four weeks of age. This drop in protection occurred even though the levels of total anti-pre-F IgG and neutralizing antibody titers in dams remained at similar, high levels before and after the second pregnancy. The results are consistent with an evolution of antibody properties in dams to populations less efficiently transferred to offspring or the less efficient transfer of antibodies in elderly dams. Author SummaryRespiratory syncytial virus (RSV) is a major cause of acute lower respiratory tract infection of infants. Because there is no licensed vaccine for RSV as well as potential safety issues with any new vaccine, protection of infants from RSV is problematic. A possible safe approach for infant protection is the transfer of maternal anti-RSV antibodies, induced by immunization, across the placenta to the fetus serving to protect the newborn for months after birth. In a cotton rat model, we have previously shown that maternal immunization with virus-like particles assembled with the RSV F and G proteins protects offspring from RSV infection. Here we describe protection of offspring, following a single immunization, through two pregnancies showing that offspring of the first were well protected from RSV challenge. However, offspring of the second pregnancy were very weakly protected although the levels of total anti-pre-F antibodies and neutralizing antibody titers in the dams remained at constant and high levels before and after the second pregnancy. This result is consistent with an evolution of antibody properties in the dams to those less efficiently transferred to offspring and highlights the importance of appropriate strategies for maternal immunization, such as immunization during each pregnancy.

microbiology↗

bioRxiv2021

Deep oncopanel sequencing reveals fixation time- and within block position-dependent quality degradation in FFPE processed samples

Clinical laboratories routinely use formalin-fixed paraffin-embedded (FFPE) tissue or cell block cytology samples in oncology panel sequencing to identify mutations that can predict patient response to targeted therapy. To understand the technical error due to FFPE processing, a robustly characterized normal cell line was used to create FFPE samples with four different pre-tissue processing formalin fixation times. A total of 96 FFPE sections were then distributed to different laboratories for targeted sequencing analysis by four oncopanels, and variants resulting from technical error were identified. Tissue sections that failed more frequently showed low cellularity, lower than recommended library preparation DNA input, or target sequencing depth. Importantly, sections from block surfaces were more likely to show FFPE-specific errors, akin to "edge effects" seen in histology, and the depth of formalin damage was related to fixation time. To assure reliable results, we recommend avoiding the block surface portion and restricting mutation detection to genomic regions of high confidence.

cancer biology↗

bioRxiv2021

Advancing quality-control for NGS measurement of actionable mutations in circulating tumor DNA

The primary objective of the FDA-led Sequencing and Quality Control Phase 2 (SEQC2) project is to develop standard analysis protocols and quality control metrics for use in DNA testing to enhance scientific research and precision medicine. This study reports a targeted next generation sequencing (NGS) method that enables more accurate detection of actionable mutations in circulating tumor DNA (ctDNA) clinical specimens. This advancement was enabled by designing a synthetic internal standard spike-in for each actionable mutation target, suitable for use in NGS following hybrid-capture enrichment and unique molecular index (UMI) or non-UMI library preparation. When mixed with contrived ctDNA reference samples, internal standards enabled calculation of technical error rate, limit of blank, and limit of detection for each variant at each nucleotide position, in each sample. True positive mutations with variant allele fraction too low for detection by current practice were detected with this method, thereby increasing sensitivity.

genomics↗