Biology subjects

Milner, D.

Publications and source records attributed to Milner, D..

7 recordsLinked to original sources

bioRxiv2026

Severe malarial anaemia is associated with parasite enrichment and host alterations in the bone marrow

BackgroundMalaria poses a significant global health challenge, with over 200 million infections and around 500,000 deaths annually, predominantly affecting children under 5 in sub-Saharan Africa. Severe malarial anaemia (SMA), a major contributor to morbidity and mortality in this demographic, results from various factors including red blood cell destruction and immune-mediated clearance. The role of these mechanisms in SMA differs based on age and infection history. Recent studies indicate increased accumulation of P. falciparum in the bone marrow and spleen, highlighting the need for understanding localized host-parasite interactions. MethodsThis study examines the bone marrow response to malarial infection in young children with SMA or mild malarial malaria in Mozambique, contrasting it with responses observed in peripheral blood in the two cohorts. Results and conclusionsThe study demonstrated that SMA is associated with increased red blood cell production, iron metabolism and tissue injury, as well as higher total parasite biomass including peripheral and bone marrow parasitaemia. We also demonstrate that direct analysis of bone marrow aspirates provides far more resolution in stratifying host signatures and drivers of malarial anaemia across a spectrum of severity than systemic measures from blood samples.

microbiology↗

bioRxiv2025

ESPWA: a deep learning-enabled tool for precision-based use of endocrine therapy in resource-limited settings

Immunohistochemistry for estrogen receptor (ER) expression is often unavailable in low-and-middle-income countries (LMICs), leading to empiric use of endocrine therapy (ET) and unnecessary toxicity in ER-negative patients. To address this unmet need, we developed ESPWA, a deep-learning model trained on 3448 H&E slides and tissue-matched ER status from breast cancer patients treated at Zanmi Lasante (ZL), Haiti. A model trained on The Cancer Genome Atlas (TCGA) exhibited substantial domain shift when applied to the ZL cohort, with AUROCs dropping from 0.846 on TCGA cross-validation to 0.671 on the ZL cohort. In contrast, ESPWA demonstrated improved performance on ZL cross-validation (AUROC=0.790; p=0.005). In an independent test set of 134 Haitian patients with parallel slides prepared and scanned in Mirebalais Hospital (Haiti) and Brigham and Womens Hospital, ESPWA was robust to variations in slide preparation, quality, and scanners, achieving AUROCs of 0.794 on BWH-prepared WSIs and 0.805 on Mirebalais-prepared WSIs. Prospective studies using ESPWA are underway in sub-Saharan Africa to evaluate its utility in informing precision-based use of ET.

cancer biology↗

bioRxiv2022

Nutrient and salt depletion synergistically boosts glucose metabolism in individual Escherichia coli cells

The interaction between a cell and its environment shapes fundamental intracellular processes such as cellular metabolism. In most cases growth rate is treated as a proximal metric for understanding the cellular metabolic status. However, changes in growth rate might not reflect metabolic variations in individuals responding to environmental fluctuations. Here we use single-cell microfluidics-microscopy combined with transcriptomics, proteomics and mathematical modelling to quantify the accumulation of glucose within Escherichia coli cells. In contrast to the current consensus, we reveal that environmental conditions which are comparatively unfavourable for growth, where both nutrients and salinity are depleted, increase glucose accumulation rates in individual bacteria and population subsets. We find that these changes in metabolic function are underpinned by variations at the translational and posttranslational level but not at the transcriptional level and are not dictated by changes in cell size. The metabolic response-characteristics identified greatly advance our fundamental understanding of the interactions between bacteria and their environment and have important ramifications when investigating cellular processes where salinity plays an important role.

microbiology↗

bioRxiv2021

Membrane permeability differentiation at the lipid divide

One of the deepest branches in the tree of life separates the Archaea from the Bacteria. These prokaryotic groups have distinct cellular systems including fundamentally different phospholipid membrane bilayers. This dichotomy has been termed the lipid divide and possibly bestows different biophysical and biochemical characteristics on each cell type. Classic experiments suggest that bacterial membranes (formed from lipids extracted from Escherichia coli for example) show permeability to key metabolites comparable to archaeal membranes (formed from lipids extracted from Halobacterium salinarum), yet systematic analyses based on direct measurements of membrane permeability are absent. Here we develop a new approach for assessing the membrane permeability of ~10 m unilamellar vesicles, consisting of an aqueous medium enclosed by a single lipid bilayer. Comparing the permeability of eighteen metabolites demonstrates that diether glycerol-1-phosphate lipids with methyl branches, often the most abundant membrane lipids of known archaea, are permeable to a wide range of compounds useful for core metabolic networks, including amino acids, sugars, and nucleobases. Permeability is significantly lower in diester glycerol-3-phosphate lipids without methyl branches, the common building block of bacterial membranes. To identify the membrane characteristics that determine permeability we use this experimental platform to test a variety of lipid forms bearing a diversity of intermediate characteristics. We found that increased membrane permeability is dependent on both the methyl branches present on the archaeal phospholipid tails and the ether bond between the tails and the head group. These permeability differences must have had profound effects on the cell physiology and proteome evolution of early prokaryotic forms. To explore this further, we compare the abundance and distribution of transmembrane transporter-encoding protein families present on genomes sampled from across the prokaryotic tree of life. Archaea have a reduced repertoire of transporter gene families, consistent with increased membrane permeation. These results demonstrate that the lipid divide demarcates a clear difference in permeability function with implications for understanding some of the earliest transitions in cell evolution.

evolutionary biology↗

bioRxiv2021

A functional bacterial-derived restriction modification system in the mitochondrion of a heterotrophic protist

The overarching trend in mitochondrial evolution is functional streamlining coupled with gene loss; therefore, gene acquisition by mitochondria is considered to be exceedingly rare. Selfish elements in the form of self-splicing introns occur in many organellar genomes, but the wider diversity of selfish elements, and how they persist in organellar genomes, has not been explored. In the mitochondrial genome of a marine heterotrophic katablepharid protist, we identify a functional type II restriction modification system originating from a horizontal gene transfer event involving bacteria related to flavobacteria. This restriction modification system consists of an HpaII-like endonuclease and a cognate cytosine methyltransferase. We demonstrate that these proteins are functional by heterologous expression in both bacterial and eukaryotic cells. These results suggest that toxin-antitoxin selfish elements, such as restriction modification systems, could be co-opted by eukaryotic genomes to drive uniparental organellar inheritance.

evolutionary biology↗

bioRxiv2020

Biomarkers to distinguish bacterial from viral pediatric clinical pneumonia in a malaria endemic setting

BACKGROUNDDifferentiating the etiology of acute febrile respiratory illness in children is a challenge in low-income, malaria-endemic settings because the main pathogens responsible (viruses, bacteria, and malaria parasites) overlap in clinical presentation and frequently occur together as mixed infections. The critical task is to rapidly identify bacterial pneumonia to enable appropriate antibiotic treatment, ideally at point of care. Current diagnostic tests are insufficient and there is a need for the discovery and development of new tools. Here we report the identification of a unique biomarker signature that can be identified in blood samples. METHODSBlood samples from 195 pediatric Mozambican patients with clinical pneumonia were analyzed with an aptamer-based high dynamic range assay to quantify [~]1200 proteins. For discovery of new biomarkers, we identified a training set of patient samples in which the underlying etiology of the pneumonia was established as bacterial, viral or malaria. Proteins whose abundances varied significantly between patients with verified etiologies (FDR<0.01) formed the basis for predictive diagnostic models that were created using machine learning techniques (Random Forest, Elastic Net). These models were validated on a dedicated test set of samples. RESULTS219 proteins had significantly different abundances between bacterial and viral infections, and 151 differed between bacterial infections and a mixed pool of viral and malaria infections. Predictive diagnostic models achieved >90% sensitivity and >80% specificity, regardless of whether one or two pathogen classes were present. Bacterial pneumonia was strongly associated with markers of neutrophil activity, in particular neutrophil degranulation. Degranulation markers included HP, LCN2, LTF, MPO, MMP8, PGLYRP1, RETN, SERPINA1, S100A9, and SLPI. CONCLUSIONBlood protein signatures highly associated with neutrophil biology reliably differentiated bacterial pneumonia from other causes. With appropriate technology, these markers could provide the basis for a rapid diagnostic for field-based triage for antibiotic treatment of pediatric pneumonia.

genomics↗

bioRxiv2020

Mineralized collagen scaffolds fabricated with amniotic membrane matrix increase osteogenesis under inflammatory conditions

Defects in craniofacial bones occur congenitally, after high-energy impacts, and during the course of treatment for stroke and cancer. These injuries are difficult to heal due to the overwhelming size of the injury area and the inflammatory environment surrounding the injury. Significant inflammatory response after injury may greatly inhibit regenerative healing. We have developed mineralized collagen scaffolds that can induce osteogenic differentiation and matrix biosynthesis in the absence of osteogenic media or supplemental proteins. The amniotic membrane is derived from placentas and has been recently investigated as an extracellular matrix to prevent chronic inflammation. Herein, we hypothesized that a mineralized collagen-amnion composite scaffold could increase osteogenic activity in the presence of inflammatory cytokines. We report mechanical properties of a mineralized collagen-amnion scaffold and investigated osteogenic differentiation and mineral deposition of porcine adipose derived stem cells within these scaffolds as a function of inflammatory challenge. Incorporation of amniotic membrane matrix promotes osteogenesis similarly to un-modified mineralized collagen scaffolds, and increases in mineralized collagen-amnion scaffolds under inflammatory challenge. Together, these findings suggest that a mineralized collagen-amnion scaffold may provide a beneficial environment to aid craniomaxillofacial bone repair, especially in the course of defects presenting significant inflammatory complications.

bioengineering↗