Biology subjects

Gleason, C.

Publications and source records attributed to Gleason, C..

10 recordsLinked to original sources

bioRxiv2026

N1 neuraminidase monoclonal antibodies 2H08 and 3H03 have decreased binding and inhibition properties against H1N1 influenza viruses circulating after 2018

Influenza viruses are global public health problem. Vaccines are available but have to be updated annually due to antigenic drift of the main vaccine component, the surface glycoprotein hemagglutinin (HA). The second surface glycoprotein of the virus, neuraminidase (NA), has recently moved into the spotlight of vaccine development. However, its antigenic evolution is understudied. We found that two broadly protective N1 NA antibodies, which had previously been shown to bind and inhibit most N1 NA, lost activity to recent N1s from seasonal H1N1 viruses. Here, we show that this drop in activity can mostly be attributed to a change in electrostatic surface potential from neutral to positively charged. This effect was not observed when historic human plasma samples were tested, suggesting that the drop of activity is specific to the two tested mAbs but does not broadly impact the polyclonal human response. Finally, we confirmed that the tested mAbs were fully active against recently emerged pan-zootic clade 2.3.4.4b H5N1 NA.

microbiology↗

bioRxiv2026

Cross-source proteogenomic profiling of human microglia reveals a conserved core membrane protein and HERV signature

Microglia are essential immune cells of the brain parenchyma which are responsible for maintaining homeostasis and responding to brain injury. When activated, they induce immune signaling and become phagocytic. In the context of neurodegenerative diseases, they exhibit both pro- and anti-inflammatory properties. Human endogenous retroviruses (HERVs) are the remnants of ancient retroviral germline infections that integrated into the human genome, and their expression has been directly linked to microglial-mediated neurodegenerative diseases. Despite this, HERV expression is not consistently included in analyses characterizing microglia. Investigating the function of microglia across different diseases is critical for elucidating mechanisms of disease progression and for the development of effective therapeutic interventions. Approaches to studying microglia include isolation from post-mortem brain tissues, differentiation from peripheral blood monocytes or differentiation of induced pluripotent stem cells (iPSC). Ex vivo brain derived microglia (BdMG) are considered most physiologically relevant, but constraints including the unpredictable timing of availability, labor-intensive protocols, and low yields reduce their practicality. Existing alternatives are iPSC-derived microglia (iMG) and monocyte-derived microglia (MDMi) models that circumvent sample accessibility and scalability issues. Here, we explored the transcriptome and proteome of these three microglia sources and identified a common microglia surface marker expression profile, establishing that MDMi and iMG exhibit similar phenotypes relative to BdMG. We also identified a common HERV expression profile across BdMG, iMG and MDMi, indicating deeper similarities across different sources. Altogether, our findings indicate that given the phenotypic similarities of the 2 models, MDMi represent a practical and reliable model for investigating microglial function with iMG models serving for more molecular based approaches, such as CRISPRa/i.

neuroscience↗

bioRxiv2026

Toxic Effects of Solanum sisymbriifolium Extracts on Meloidogyne hapla and Meloidogyne chitwoodi

Plant-parasitic nematodes (PPNs) are among the most destructive agricultural pests worldwide, causing significant economic losses across diverse cropping systems. Soil fumigation, the most common management strategy, is costly, detrimental to soil health, and increasingly restricted due to environmental and regulatory concerns. As a result, there is a critical need for alternative, sustainable approaches for PPN control. Solanum sisymbriifolium is resistant to several Meloidogyne species and represents a promising source of natural nematicidal compounds. In this study, we evaluated the effects of S. sisymbriifolium extracts on Meloidogyne chitwoodi and M. hapla, two economically important nematodes. Compounds were extracted using solvents of increasing polarity and then reconstituted in water. The water-solubilized extracts were then used in bioassays to assess their effects on nematode egg hatching, egg viability, and second-stage juvenile (J2) survival. Egg hatching and J2 viability of both Meloidogyne species were consistently affected by compounds in the 1-butanol fraction. Further characterization of these compounds may enable the development of novel, environmentally sustainable alternatives to conventional nematode management strategies.

Plant Biology↗

bioRxiv2026

Three immunoregulatory signatures define non-productive HIV infection in CD4+ T memory stem cells

The persistent HIV reservoir constitutes the main obstacle to curing HIV/AIDS disease. Our understanding of how non-productive HIV infections are established in primary human CD4+ T cells during the first round of infection remains, however, incomplete. In this study, we leveraged the HIV reporter virus pMorpheus-V5 to delineate cellular expression patterns that are upregulated in non-productively infected primary CD4+ T memory stem cells (TSCM). We found that CD4+ TSCM harboring non-productive proviruses displayed a distinct transcriptomic signature comprising 118 upregulated genes. This non-productive expression profile was distinct from that of productively infected cells as well as from negative-exposed and mock-infected cells. Among the cellular genes most upregulated in CD4+ T cells harboring non-productive proviruses were CCR4-binding migratory chemokines (CCL22, CCL17), tryptophan catabolic enzymes (IDO1, KYNU), and genes encoding cytoskeletal rearrangement proteins (BASP1, TNFAIP2). Intracellular flow cytometry-based analyses confirmed that non-productively infected CD4+ TSCM cells were enriched for CCL22 and IDO1 co-expression compared to the other CD4+ memory subsets, underscoring a clear CD4+ T cell subset specificity for the upregulation of these two immune gene sets associated with non-productive infections. These findings suggest that primary human CD4+ TSCM harboring non-productive proviruses display a distinct immunoregulatory phenotype which may facilitate immune evasion and contribute to the persistence of the HIV reservoir.

microbiology↗

bioRxiv2026

The buried S2 apex of SARS-CoV-2 spike elicits an immunodominant germline-restricted public antibody response

The continued mutational pressure on the SARS-CoV-2 S1 subunit underscores the need to target the conserved S2 region for pan-coronavirus vaccine development. A detailed molecular understanding of S2-directed immune responses is therefore essential. In this study, we identified the S2 apex as the most immunodominant epitope within the S2 subunit, eliciting robust antibody responses despite occlusion by S1, using electron-microscopy-based polyclonal epitope mapping (EMPEM) of plasma from infected and vaccinated individuals. Structure-guided sequence analysis with antibody databases revealed that antibodies targeting a poorly characterized S2 Apex-B site form a convergent public clonotype, which is predominantly derived from the IGHV3-30 germline with a 14-residue CDRH3 containing a G/S-G-S/N-Y motif. This clonotype is extensively expanded, accounting for up to 40% of total spike-reactive antibody sequence counts in individual vaccinated donors. This study elucidates the molecular basis the high-frequency elicitation of this non-neutralizing clonotype emphasizing that its immunodominance acts as a primary hurdle for universal coronavirus vaccines and underscore the need for precision antigen design to redirect immunity toward more potent neutralizing targets.

immunology↗

bioRxiv2025

Genome reannotation and effector candidate identification in Meloidogyne chitwoodi through gland-specific transcriptome analysis

The root-knot nematode (RKN) Meloidogyne chitwoodi is a threat for potato production in the western United States, negatively impacting potato yield and product value. Meloidogyne chitwoodi produce proteins, called effectors, in their esophageal glands that are secreted during parasitism and play integral roles in plant-nematode interactions. Because the esophageal glands are the main effector secretory organ, we performed juvenile gland isolation and gland transcriptome analysis. The data allowed us to improve the M. chitwoodi genome annotation. Additionally, the gland-specific transcriptome data gave us an enrichment of gland-localized genes, which was validated by in situ hybridization. The gland transcriptome analysis led to the identification of 111 effector candidates. One of the effectors, Mc15g003960, which was highly expressed in the pre-parasitic J2 gland tissue, was further characterized. Expression of Mc15g003960 in Arabidopsis resulted in increased galling by M. chitwoodi. However, the ectopic expression of Mc15g003960 in planta did not suppress defense-related callose deposition, suggesting that this effector might be involved in processes other than interfering with plant basal defense responses. Our data shows that using the gland transcriptome, good quality genome annotation and stringent criteria, we can increase the efficiency of effector identification, which can be used to develop more sustainable management tools. Authors summaryThe root-knot nematode Meloidogyne chitwoodi is a major problem for potato farmers in the western U.S., reducing crop yield and quality. These nematodes produce special proteins, called effectors, in their esophageal glands, which help them infect plants. Since these glands are the main source of effectors, we isolated them from juvenile nematodes and analyzed their gene expression. This helped us improve the nematodes genome map and identify genes specific to the glands. From this study, we found 111 potential effector genes. One of them, Mc15g003960, was highly active before the nematode started feeding. When we introduced this gene into Arabidopsis plants, the nematodes caused more damage, but it didnt seem to weaken the plants basic defense system. This suggests Mc15g003960 is not suppressing plant defenses and has a different role in helping the nematode with successful infection. Overall, our approach helped us identify key effectors more efficiently, which could lead to better ways to manage nematode infestations in the future.

molecular biology↗

bioRxiv2024

Appraising the natural root-knot nematode resistance inSolanum sisymbriifolium, a wild relative of potato

Root-knot nematodes (RKNs) are a major pest of Solanum and other economically important crops worldwide. Two species of RKNs (Meloidogyne chitwoodi and Meloidogyne hapla) are persistent threats to potato growers of the United States. These RKNs infect potato roots and tubers, causing tuber blemishes that decrease potato market value and significantly impact the profitability of the infected potato crop. Due to environmental, health, and economic concerns, the longstanding control methods of using soil fumigants and post-plant nematicides are not favored by producers and consumers. Therefore, deploying RKN resistant cultivars is an alternative method to control RKN damage. However, there is no genetic resistance to RKN in commercially-available, cultivated potatoes. Therefore, the critical first step to breed a RKN resistant plant is to identify a genetic source of RKN resistance. A wild Solanum species, Solanum sisymbriifolium, also known as litchi tomato, can effectively control several agronomically important species of plant parasitic nematodes. Solanum sisymbriifolium is completely resistant to RKNs; only a few nematodes enter the plant roots and those that do, cannot establish a feeding site. To understand its ability to prevent RKNs from forming feeding sites, we performed transcriptomic analysis of S. sisymbriifolium roots inoculated with the Northern root knot nematode, M. hapla. Combined with the annotation of the recently published S. sisymbriifolium genome assembly, we discovered 13 differentially expressed resistance-related genes upon nematode inoculation. By transforming potatoes with candidate resistance genes from S. sisymbriifolium, we aim to understand the strong genetic resistance in S. sisymbriifolium and whether those genes are necessary and sufficient to drive resistance to RKN in potatoes. This information will help us understand gene functions and help us generate RKN resistance in relevant Solanum crops.

plant biology↗

bioRxiv2023

Mucosal antibody responses to SARS-CoV-2 booster vaccination and breakthrough infection

Coronavirus disease 2019 (COVID-19) vaccines have saved millions of lives. However, variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged causing large numbers of breakthrough infections. These developments necessitated the rollout of COVID-19 vaccine booster doses. It has been reported that mucosal antibody levels in the upper respiratory tract, especially for secretory IgA (sIgA), correlate with protection from infection with SARS-CoV-2. However, it is still unclear how high levels of mucosal antibodies can be induced. In this study, we measured serum IgG, saliva IgG and saliva sIgA responses in individuals who received COVID-19 mRNA booster vaccinations or who experienced breakthrough infections. We found that mRNA booster doses could induce robust serum and saliva IgG responses, especially in individuals who had not experienced infections before, but saliva sIgA responses were weak. In contrast, breakthrough infections in individuals who had received the primary mRNA vaccination series induced robust serum and saliva IgG as well as saliva sIgA responses. Individuals who had received a booster dose and then had a breakthrough infection showed low IgG induction in serum and saliva but still responded with robust saliva sIgA induction. These data suggest that upper respiratory tract exposure to antigen is an efficient way of inducing mucosal sIgA while exposure via intramuscular injection is not. ImportanceAntibodies on mucosal surfaces of the upper respiratory tract have been shown to be important for protection from infection with SARS-CoV-2. Here we investigate the induction of serum IgG, saliva IgG and saliva sIgA after COVID-19 mRNA booster vaccination or breakthrough infections.

immunology↗

bioRxiv2022

Structural features of mTORC2 that control substrate-specific activities.

mTORC2 is a multi-subunit kinase complex that is central to multiple essential signaling pathways. Two core subunits, Rictor and mSin1 distinguish it from its relative, mTORC1 and support context-dependent phosphorylation of its substrates. mTORC2 structures have been determined previously, however, important questions remain, particularly regarding structural determinants of substrate specificity and context dependent activities. We used cryo-EM to obtain high resolution structures of the human mTORC2 apo-complex, as well as structures in the presence of substrates, Akt and SGK1. Specific predictions suggested by substrate-induced structural changes were tested in functional assays. First, side chain interactions between Rictor and mTOR that prevent recruitment of mTORC1 substrates and confer resistance to the mTORC1 inhibitor rapamycin were visualized for the first time in the apo-state, demonstrating the steric occlusion that prevents mTORC2 interaction with mTORC1 substrates and rapamycin. Also in the apo-state, mSin1 was seen to form extensive contacts with Rictor, including a pair of short -helices nestled between two Rictor helical repeat clusters, followed by an extended strand, which makes multiple weak contacts with Rictor helical cluster 1. In co-complex structures, SGK1, but not Akt, markedly altered the conformation of the mSin1 N-terminal extended strand, disrupting multiple weak interactions while inducing a large rotation of mSin1/Arg-83, which comes to interact with a negative patch within Rictor. Mutation of Arg-83 to Ala selectively disrupted mTORC2 dependent phosphorylation of SGK1 but not of Akt, supporting context-dependent substrate selection. These findings provide new structural and functional insights into mTORC2 specificity and context-dependent activities.

biochemistry↗

bioRxiv2021

Determining pathogenicity of variants of uncertain significance and identification of a founder variant in the epilepsy-associated gene, SZT2

Biallelic pathogenic variants in SZT2 result in a neurodevelopmental disorder with shared features, including early-onset epilepsy, developmental delay, macrocephaly, and corpus callosum abnormalities. SZT2 is as a critical scaffolding protein in the amino acid sensing arm of the mTOR signaling pathway. Due to its large size (3432 amino acids), lack of crystal structure, and absence of functional domains, it is difficult to determine the pathogenicity of SZT2 missense and in-frame deletions. We report a cohort of twelve individuals with biallelic SZT2 variants and phenotypes consistent with SZT2-related neurodevelopmental disorder. The majority of this cohort contained one or more SZT2 variants of uncertain significance (VUS). We developed a novel individualized platform to functionally characterize SZT2 VUSs. We identified a recurrent in-frame deletion (SZT2 p.Val1984del) which was determined to be a loss-of-function variant and therefore likely pathogenic. Haplotype analysis determined this single in-frame deletion is a founder variant in those of Ashkenazi Jewish ancestry. Overall, we present a FACS-based rapid assay to distinguish pathogenic variants from VUSs in SZT2, using an approach that is widely applicable to other mTORopathies including the most common causes of the focal genetic epilepsies, DEPDC5, TSC1/2, MTOR and NPRL2/3.

genetics↗