Biology subjects

Grainger, D.

Publications and source records attributed to Grainger, D..

3 recordsLinked to original sources

bioRxiv2026

A Broad-Spectrum Chemokine Inhibitor Prevents Preterm Labor in Mice by Supressing Inflammation Induced by Intra-Amniotic Injection of Interleukin-1 alpha

Preterm birth (PTB) is a leading cause of perinatal and infant mortality worldwide. PTB can be induced by systemic maternal or intra-uterine infection or by sterile intra-amniotic inflammation driven by alarmins such as interleukin-1 (IL-1). We reported earlier that a Broad-Spectrum Chemokine Inhibitor (BSCI) prevented PTB in murine and non-human primate models of infection-mediated preterm labor. Here, we investigated whether BSCI can prevent PTB in pregnant C57BL/6 mice following ultrasound-guided intra-amniotic injection of IL-1 (400 ng per sac) on gestational day (GD)16.5. Half the mice received BSCI (10 mg/kg, intravenous daily) beginning GD15.5 and through to term. The impact of IL-1 alone or IL-1 plus BSCI was assessed on (i) injection-to-delivery interval, fetal survival, placental and neonatal weight; (ii) cytokine and chemokine levels in maternal plasma and amniotic fluid and inflammatory gene expression in maternal and fetal tissues (Real-Time RT-qPCR); (iii) global transcriptomic profiling of myometrial tissues at 2 and 24 hrs (RNA sequencing) together with examination of myometrial chromatin accessibility (Assay for transposase accessible chromatin sequencing) at 24 hrs; (iv) uterine leukocyte infiltration (immunofluorescence). Pretreatment with BSCI i) prevented IL-1-induced PTB; (ii) significantly attenuated cytokine and chemokine signals in maternal plasma, myometrium, decidua, and placenta, and amniotic fluid; (iii) suppressed myometrial contraction-associated genes, including Nfkb1, Ptgs2, Akr1c18, and Gja1; (iv) prevented global IL-1-induced changes in myometrial gene expression and chromatin accessibility (v) reduced uterine macrophage (F4/80+) counts and prevented the increase in pro-inflammatory M1-like macrophages observed with IL-1-treatment. BSCI-treated dams that delivered at term had live pups with normal placental and fetal weight. Taken together, BSCI reduced the incidence of IL-1-mediated PTB and maintained uterine quiescence by suppressing uterine inflammation and genome-wide changes in labor gene expression and chromatin accessibility. BSCI represents a promising therapeutic approach for PTB prevention in high-risk pregnant women.

physiology↗

bioRxiv2024

The remarkable similarity in the serum proteome between type 2 diabetics and controls

Type 2 diabetes mellitus (T2DM) is a rapidly increasing threat to global health, which brings with it a demand for better treatments. This study aimed to identify differences in the proteome of patients with T2DM to identify new targets for therapeutic intervention. We used a highly reproducible bottom-up proteomics protocol to investigate differences in protein, peptide and post-translational modifications between subjects with T2DM and matched controls in an untargeted manner. The serum proteome was remarkably similar at the protein level with no differences between the subject groups across 175 proteins and five orders of magnitude. Strong associations were found, however, between fasting serum glucose levels and glycations of abundant serum proteins, including sites on apolipoprotein A1, apolipoprotein A2 and 2- macroglobulin. We also investigated proteome differences associated with BMI, and found all three components of the ternary complex (IGF-binding protein complex acid-labile subunit (ALS), IGF-binding protein 3 (IGFBP-3) and IGF-2) were strongly negatively associated with BMI. The results show the power of a proteomics protocol optimised for precision rather than depth of coverage, which here has identified strong correlations between physiological measurements and very low abundance post-translational modifications. In T2DM any differences in the serum proteome are very small, and likely a consequence rather than a cause of hyperglycaemia. Article highlightsO_LIOur goal was to use high-precision label-free bottom-up LC-MS/MS proteomics to investigate differences in the proteome of patients with T2DM and controls, and potentially identify novel targets for future research. C_LIO_LIThe serum proteome is remarkably similar in patients with T2DM and controls, with the only major difference being glycations of abundant serum proteins C_LIO_LIAll three components of the ternary complex (comprised of ALS, IGFBP-3 and IGF-2) were strongly negatively associated with BMI. C_LIO_LIThe results highlight the power of a proteomics study designed with three key features at its core: a proteomics protocol optimised for precision rather than depth of coverage; an open bioinformatics approach investigating proteins, peptides and PTMs without prior assumptions about which features are important; and analysis of individual subject samples so that results take into account person-to-person variability C_LI

pathology↗

bioRxiv2021

Genome-wide mapping of Vibrio cholerae VpsT binding identifies a mechanism for c-di-GMP homeostasis

Many bacteria use cyclic dimeric guanosine monophosphate (c-di-GMP) to control changes in lifestyle. The molecule, synthesised by proteins having diguanylate cyclase activity, is often a signal to transition from motile to sedentary behaviour. In Vibrio cholerae, c-di-GMP can exert its effects via the transcription factors VpsT and VpsR. Together, these proteins activate genes needed for V. cholerae to form biofilms. In this work, we have mapped the genome-wide distribution of VpsT in a search for further regulatory roles. We show that VpsT binds 23 loci and recognises a degenerate DNA palindrome having the consensus 5-W-5R-4[CG]-3Y-2W-1W+1R+2[GC]+3Y+4W+5-3. Most genes targeted by VpsT encode functions related to motility, biofilm formation, or c-di-GMP metabolism. Most notably, VpsT activates expression of the vpvABC operon that encodes a diguanylate cyclase. This creates a positive feedback loop needed to maintain intracellular levels of c-di-GMP. Mutation of the key VpsT binding site, upstream of vpvABC, severs the loop and c-di-GMP levels fall accordingly. Hence, as well as relaying the c-di-GMP signal, VpsT impacts c-di-GMP homeostasis.

microbiology↗