Biology subjects

Griffith, J.

Publications and source records attributed to Griffith, J..

6 recordsLinked to original sources

bioRxiv2026

MULTI-COHORT TRANSCRIPTOMIC ANALYSIS REVEALS SHARED INFLAMMATORY SIGNALING AND UROTHELIAL DYSFUNCTION ACROSS IC/BPS PHENOTYPES

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a heterogeneous disorder characterized by bladder pain, inflammation, and urothelial dysfunction, yet the molecular features shared across clinically defined disease phenotypes remain incompletely understood. Toll-like receptor 4 (TLR4) and acyloxyacyl hydrolase (AOAH), a regulator of TLR4 ligand activity, have been implicated in IC/BPS in clinical and preclinical mechanistic studies. Here, we performed a multi-cohort reanalysis of four independent human IC/BPS transcriptomic datasets spanning bladder tissue and urine sediment from non-ulcer/non-Hunner, ulcerative/Hunner, normal-capacity, low-capacity, non-lesion, and lesion phenotypes. We evaluated immune cell-associated expression, urothelial differentiation and barrier integrity, TLR4 and pro-inflammatory signaling, and AOAH expression. IC/BPS exhibited phenotype-specific immune remodeling, yet shared features were also identified. Bladder-tissue IC/BPS was consistently associated with reduced expression of urothelial differentiation and barrier markers, together with increased TLR4 recognition and pro-inflammatory signaling. AOAH expression was elevated across all three bladder-tissue cohorts and was associated with monocyte/macrophage and pro-inflammatory transcriptional states. TLR4 signaling similarly paralleled myeloid and inflammatory features, whereas inflammatory programs generally showed inverse relationships with urothelial barrier markers. Notably, independently defined severe phenotypes of ulcerative IC and low-capacity IC showed concordant molecular remodeling characterized by increased leukocyte and monocyte/macrophage signatures, enhanced TLR4 signaling, elevated AOAH expression, and reduced urothelial barrier-associated expression. Together, these findings identify reproducible molecular signatures that extend across IC/BPS phenotypes and support a model in which urothelial dysfunction and TLR4-AOAH-associated myeloid inflammatory states coexist across disease phenotypes. These results provide a molecular framework for stratifying IC/BPS beyond clinical labels and identify shared and subtype-specific molecular signatures that may inform therapeutic response evaluation and clinical management.

immunology↗

bioRxiv2026

Transposon mutagenesis uncovers the genetic landscape of streptomycin susceptibility and implicates SbmA in aminoglycoside uptake in Escherichia coli

Aminoglycosides are critical antibiotics with partially elucidated mechanisms of uptake and action in Gram-negative bacteria. Importantly, although energy-dependent uptake across the inner membrane has been well-established, the specific molecular mechanisms involved have not been definitively identified. To deepen understanding of genetic factors influencing susceptibility and resistance to streptomycin, we applied transposon insertion sequencing in Escherichia coli K-12. This approach identified both known and novel genes whose disruption increased susceptibility, including those involved in respiration, protein export, cell division, and uncharacterised functions. Notably, voltage-sensitive membrane dye-based assays revealed that many susceptible mutants did not display inner membrane hyperpolarisation as often assumed. Conversely, disruption of certain genes, such as the inner membrane antimicrobial peptide transporter sbmA, conferred low-level resistance, with sbmA overexpression increasing streptomycin sensitivity, suggesting its role in aminoglycoside uptake. These findings refine the model of aminoglycoside interaction with various pathways and highlight potential targets for adjuvant therapies to combat antimicrobial resistance.

microbiology↗

bioRxiv2026

In Vivo Selection of anti-glioblastoma DNA aptamer-drug conjugates in an orthotopic patient-derived xenograft model

Glioblastoma (GBM) is an aggressive, high-grade glioma with a near-universally fatal prognosis. Therapeutic failure is often attributed to the highly selective blood brain barrier (BBB), the diffuse infiltrative nature of the tumor, and the marked intratumoral heterogeneity of GBM. Although antibody drug conjugates ADCs have shown promise for high grade gliomas such as GBM, efficacy is limited by ADC size. Aptamers--short, synthetic, single-stranded DNA or RNA molecules--can be [~]6-fold lower in molecular weight than IgG antibodies and have the potential to cross the intact BBB. Unlike other nucleic acid-based therapies, aptamer function arises from three-dimensional shape rather than genetic coding. Here we aim to replace the targeting component of the ADC paradigm with a DNA aptamer, thus creating an aptamer-drug conjugate (ApDC). We employed in vivo SELEX using an orthotopic patient-derived xenograft (PDX) GBM mouse model and a vast ([~]100 trillion 80-mer sequences) ApDC library. We report the results from this first in vivo ApDC selection of its kind. We characterize target tissue binding ex vivo, cell association, biodistribution, and pharmacokinetics from this selection. This study exemplifies an unbiased approach to a problem that rational design has yet to overcome, offering a new direction for GBM therapeutic development.

cancer biology↗

bioRxiv2025

Urbanization weakens the latitudinal diversity gradient in birds

The latitudinal diversity gradient of increasing species richness toward the tropics is Earths most ubiquitous and ancient macroecological pattern, but may not be immune to modern anthropogenic change. Urbanization represents a particularly severe and globally-distributed ecological change; while urbanization generally reduces local diversity, whether it affects large- scale diversity patterns is unclear. Analyzing global databases including >10,000 bird species on five continents, we show that the avian latitudinal diversity gradient is 3x weaker in urban than natural areas. Urbanization reduces diversity across latitudes, but tropical cities lose disproportionately more species, partly because tropical bird assemblages contain more specialists and specialists are particularly excluded by urbanization. Our results show that urbanization is disrupting macroecological patterns, and suggest that specialization mediates both latitudinal diversity gradients and urbanization impacts.

ecology↗

bioRxiv2022

Host and Water Microbiota are Differentially Linked to Potential Human Pathogen Accumulation in Oysters

Oysters play an important role in coastal ecology and are a globally popular seafood source. However, their filter feeding lifestyle enables coastal pathogens, toxins, and pollutants to accumulate in their tissues, potentially endangering human health. For example, bacterial pathogens from both marine and terrestrial sources concentrate in oysters and can cause human illness when oysters are consumed raw. While pathogen concentrations in coastal waters are often linked to environmental conditions and runoff events, these do not always correlate with pathogen concentrations in oysters. Additional factors related to oyster hosts and the microbial ecology of pathogenic bacteria likely play a role in accumulation but are poorly understood. In this study, we investigated whether microbial communities in water and oysters were linked to accumulation of fecal indicators, Vibrio parahaemolyticus, and Vibrio vulnificus. Site-specific environmental conditions significantly influenced the composition and diversity of water microbial communities, which were linked to the highest concentrations of both Vibrio spp. and fecal indicator bacteria. Oyster microbial communities, however, were less impacted by environmental variability and exhibited less variability in microbial community diversity and accumulation of target bacteria. Instead, changes in specific microbial taxa in oyster and water samples, particularly in oyster digestive glands, were linked to elevated potential pathogens in oysters, especially V. parahaemolyticus. This included an increase in cyanobacteria in both water and oyster digestive gland microbial communities, which could represent an environmental vector for Vibrio spp. transport and decreased relative abundance of Mycoplasma and other key members of the oyster digestive gland microbiota. These findings suggest that host and microbial factors, in addition to environmental variables, may influence pathogen accumulation in oysters.

microbiology↗

bioRxiv2021

The interplay of RNA:DNA hybrid structure and G-quadruplexes determines the outcome of R-loop-replisome collisions

R-loops are a major source of genome instability associated with transcription-induced replication stress. However, how R-loops inherently impact replication fork progression is not understood. Here, we characterize R-loop-replisome collisions using a fully reconstituted eukaryotic DNA replication system. We find that RNA:DNA hybrids and G-quadruplexes at both co-directional and head-on R-loops can impact fork progression by inducing fork stalling, uncoupling of leading strand synthesis from replisome progression, and nascent strand gaps. RNase H1 and Pif1 suppress replication defects by resolving RNA:DNA hybrids and G-quadruplexes, respectively. We also identify an intrinsic capacity of replisomes to maintain fork progression at certain R-loops by unwinding RNA:DNA hybrids, repriming leading strand synthesis downstream of G-quadruplexes, or utilizing R-loop transcripts to prime leading strand restart during co-directional R-loop-replisome collisions. Collectively, the data demonstrates that the outcome of R-loop-replisome collisions is modulated by R-loop structure, providing a mechanistic basis for the distinction of deleterious from non-deleterious R-loops.

biochemistry↗