Biology subjects

Dallmann, R.

Publications and source records attributed to Dallmann, R..

9 recordsLinked to original sources

bioRxiv2026

Targeting intracellular mycobacteria using novel antibiotic-loaded nanoparticles

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a significant global health challenge. Currently treatment of drug-sensitive TB, involves a six-month regimen consisting of a combination of four anti-TB drugs, with drug-resistant TB requiring over two years of treatment and additional drugs. As toxicity of anti-TB drugs often leads to poor compliance, disease relapse and the emergence of drug-resistant strains, new strategies to reduce drug toxicity and shorten treatment duration are critical. We report nanocarrier-based drug delivery systems targeting macrophages, which primarily support replication and survival of Mtb. We have developed mannose-functionalized nanoparticles that bind to mannose receptors on macrophages and feature a pH-sensitive core which releases an encapsulated drug in the acidic lysosomal environment of macrophages. Rifampicin (RIF), a main anti-TB drug currently in use clinically, was encapsulated within the nanoparticles. We demonstrate that antibiotic-containing nanocarriers efficiently accumulated in macrophages without causing toxicity. Encapsulated RIF showed enhanced efficacy against both BCG and Mtb in primary macrophages. Biodistribution studies in mice revealed that the nanoparticles have extended circulation time and do not induce toxicity. In addition, the encapsulated RIF showed better targeting of mycobacteria when compared to free RIF in a murine model of mycobacterial infection. Such an enhanced bacterial killing using mannose-functionalised nanocarriers loaded with the key anti-TB drug rifampicin offers excellent potential for TB therapy.

microbiology↗

bioRxiv2026

A robust negative association between estimated tumour circadian clock function and survival in early stage breast cancer

Recent studies have established that the circadian clock influences onset, progression and therapeutic outcomes in a number of chronic conditions including cardio-metabolic diseases and cancer. For the latter, they also suggest that chronotherapy offers the potential to refine current treatments and improve the development of future anti-cancer medicines. Therefore, there is a need for tools to measure the functional state of the tumoural circadian clock in patients. We have previously developed a model-led machine-learning algorithm called TimeTeller which has the potential to provide such a tool. Here we demonstrate its potential for clinical relevance by a study of 1286 breast cancer patients in which we characterise the nature of the circadian clock disruption in their tumours and demonstrate a strong nonlinear association between 10-year survival and TimeTellers tumoural clock disfunction score {Theta}. We find that good tumour clock function is antagonistic to survival.

cancer biology↗

bioRxiv2025

Machine learning assisted classification of cell and brain penetrating peptides

Crossing the blood-brain barrier (BBB) remains a major obstacle for central nervous system therapeutics. Short peptides have emerged as promising vectors, including cell-penetrating peptides (CPPs) and brain-penetrating peptides (BPPs). However, the structural and physicochemical features that distinguish CPPs from BPPs remain poorly understood, limiting rational design. Here, we compiled a curated dataset of 490 peptides, encompassing CPPs, BPPs, and non-BPP controls, and systematically analysed their amino acid composition, sequence distribution, and physicochemical descriptors. BPPs were found to exhibit a more balanced distribution of cationic, polar, and hydrophobic residues compared to CPPs, which were enriched in contiguous arginine and lysine blocks. Physicochemical analysis revealed that BPPs had lower charge density, greater stability, and reduced aromaticity relative to CPPs. Dimensionality reduction confirmed BPPs occupy an intermediate chemical space between CPPs and non-BPPs. Machine learning classification, particularly with Extra Trees models, achieved strong performance in discriminating peptide classes, with charge, instability index, and aromaticity identified as the most predictive features. These findings suggest that BBB penetration is not a simple extension of cell penetration but requires finely tuned physicochemical properties. This study provides mechanistic insights into BPP design and highlights machine learning as a valuable tool for engineering next-generation BBB-penetrating peptides and peptide-mimetic materials.

cell biology↗

bioRxiv2025

The cellular mammalian clock regulates Staphylococcus aureus invasion in epithelial cells

An endogenous biological clock, the circadian clock, coordinates life with the 24-hour day/night environmental cycle. In mammals, a central pacemaker in the suprachiasmatic nucleus of the hypothalamus coordinates timing between peripheral clocks and with the environment and, for example, modulates immune responses to infections. However, its role in controlling bacterial infections at a cellular level is not understood. Here, we investigate the role of the host cellular clock during infection by a highly drug-resistant human pathogen, Staphylococcus aureus. Our findings revealed that S. aureus invasion into epithelial cells was dependent on the host circadian phase. Interestingly, cells deficient in BMAL1, a transcriptional activator and an essential clock protein, demonstrated increased bacterial uptake compared to parental A549 cells. The BMAL1-knockdown (KD) cells showed significant induction of GP340, a receptor of the S. aureus adhesin, SraP. An S. aureus sraP mutant did not exhibit rhythmic uptake into A549 cells or an increased uptake into BMAL1-KD compared to parental A549 cells. Of note, other bacterial adhesin mutants showed rhythmic and higher uptake in BMAL1-KD cells. Hence, we report that S. aureus epithelial cell invasion is clock-modulated and mediated through the S. aureus SraP-GP340 pathway, suggesting potential for host clock-directed therapy against this pathogen.

microbiology↗

bioRxiv2025

Cationic antimicrobial copolymers reveal immunomodulatory properties in LPS stimulated macrophages in vitro

Antimicrobial polymers, which have emerged as a promising alternative to antibiotics in the fight against antimicrobial resistance, are based on the design of cationic host defence peptides (CHDPs). Being a part of the mammalian innate immune system, CHDPs possess both antimicrobial and immunoregulatory effects to manage bacterial infections. However, the immunomodulatory effects of antimicrobial polymers remain largely unexplored. Within this work, a library of 15 copolymers were synthesised by reversible addition-fragmentation chain transfer (RAFT) polymerisation and their abilities to modulate pro-inflammatory pathways in LPS-activated murine and human macrophages were investigated. We found that two diblock copolymers with cationic units copolymerised with either apolar or hydrophilic comonomers appeared to have anti-inflammatory activity through suppression of the activation of the NF-{kappa}B signalling pathway, scavenging of reactive oxygen species and reduced production of the pro-inflammatory cytokine IL-6. Furthermore, the cationic-apolar copolymer exhibits significant antimicrobial activity against P. aeruginosa. Thus, this promising copolymer holds potential as a dual-action therapeutic, effectively combating bacterial infections while curbing prolonged inflammation and thereby preventing sepsis at the site of infection.

microbiology↗

bioRxiv2023

Adenosine Kinase regulates Sleep Timing and the Homeostatic Sleep Response through Distinct Molecular Pathways

Sleep behaviour is broadly regulated by two drives, the circadian (Process C), which is orchestrated by the suprachiasmatic nuclei (SCN), and controls sleep timing, and the homeostatic (Process S), which controls sleep amount and the response to sleep deprivation (Borbely et al., 2016). However, the molecular pathways that mediate their independent effects, and their interactions remain unclear. Adenosine is an important integrator of both processes (Bjorness & Greene, 2009; Jagannath et al., 2021, 2022), such that adenosine levels track and modulate wakefulness, whilst adenosine signalling inhibits the circadian response to light. Therefore, we studied the sleep/circadian behaviour, and cortical and SCN transcriptomic profiles of a mouse model overexpressing Adenosine Kinase (Adk-Tg) (Fedele et al., 2005), (Palchykova et al., 2010). We found that overall, the Adk-Tg mouse slept less and showed lower amplitude circadian rhythms with an altered sleep/wake distribution across the 24h day, which correlated with changes in transcription of synaptic signalling genes that would shift the excitatory/inhibitory balance. In addition, the Adk-Tg mouse showed a reduced level of ERK phosphorylation, and attenuation of DNA repair related pathways. After sleep deprivation, however, the Adk-Tg mouse significantly increased relative to wildtype, immediate early gene expression levels including of Arc, but paradoxically reduced ERK phosphorylation. Thus, baseline sleep levels and timing are regulated by ERK signalling, whereas the response to sleep loss is mediated by the alteration of the transcriptomic landscape independently of ERK.

molecular biology↗

bioRxiv2023

TimeTeller: a tool to probe the circadian clock as a multigene dynamical system

AO_SCPLOWBSTRACTC_SCPLOWRecent studies have established that the circadian clock influences onset, progression and therapeutic outcomes in a number of diseases including cancer and heart diseases. Therefore, there is a need for tools to measure the functional state of the molecular circadian clock and its downstream targets in patients. Moreover, the clock is a multi-dimensional stochastic oscillator and there are few tools for analysing it as a system. In this paper we consider the methodology behind Time-Teller, a machine learning tool that analyses the clock as a system and aims to estimate circadian clock function from a single transcriptome by modelling the multi-dimensional state of the clock. We demonstrate its potential for clock systems assessment by applying it to mouse, baboon and human microarray and RNA-seq data and show how to visualise and quantify the global structure of the clock, quantitatively stratify individual transcriptomic samples by clock dysfunction and globally compare clocks across individuals, conditions and tissues thus highlighting its potential relevance for advancing circadian medicine.

systems biology↗

bioRxiv2022

Sleep and circadian rhythm disruption alters the lung transcriptome to predispose to viral infection

Sleep and circadian rhythm disruption (SCRD), as encountered during shift work, increases the risk of respiratory viral infection including SARS-CoV-2. However, the mechanism(s) underpinning higher rates of respiratory viral infection following SCRD remain poorly characterised. To address this, we investigated the effects of acute sleep deprivation on the mouse lung transcriptome. Here we show that sleep deprivation profoundly alters the transcriptional landscape of the lung, causing the suppression of both innate and adaptive immune systems, disrupting the circadian clock, and activating genes implicated in SARS-CoV-2 replication, thereby generating a lung environment that promotes viral infection and associated disease pathogenesis. Our study provides a mechanistic explanation of how SCRD increases the risk of respiratory viral infections including SARS-CoV-2 and highlights therapeutic avenues for the prevention and treatment of COVID-19.

neuroscience↗

bioRxiv2021

Cell-type specific circadian bioluminescence rhythms recorded from Dbp reporter mice reveal circadian oscillator misalignment

Circadian rhythms are endogenously generated physiological and molecular rhythms with a cycle length of about 24 h. Bioluminescent reporters have been exceptionally useful for studying circadian rhythms in numerous species. Here, we report development of a reporter mouse generated by modification of a widely expressed and highly rhythmic gene encoding D-site albumin promoter binding protein (Dbp). In this line of mice, firefly luciferase is expressed from the Dbp locus in a Cre-recombinase-dependent manner, allowing assessment of bioluminescence rhythms in specific cellular populations. A mouse line in which luciferase expression was Cre-independent was also generated. The Dbp reporter alleles do not alter Dbp gene expression rhythms in liver or circadian locomotor activity rhythms. In vivo and ex vivo studies show the utility of the reporter alleles for monitoring rhythmicity. Our studies reveal cell-type specific characteristics of rhythms among neuronal populations within the suprachiasmatic nuclei ex vivo. In vivo studies show Dbp-driven bioluminescence rhythms in the liver of Albumin-Cre;DbpKI/+ "liver reporter" mice. After a shift of the lighting schedule, locomotor activity achieved the proper phase relationship with the new lighting cycle more rapidly than hepatic bioluminescence did. As previously shown, restricting food access to the daytime altered the phase of hepatic rhythmicity. Our model allowed assessment of the rate of recovery from misalignment once animals were provided with food ad libitum. These studies confirm the previously demonstrated circadian misalignment following environmental perturbations and reveal the utility of this model for minimally invasive, longitudinal monitoring of rhythmicity from specific mouse tissues.

physiology↗