Biology subjects

Warner, M.

Publications and source records attributed to Warner, M..

6 recordsLinked to original sources

bioRxiv2026

Directed Evolution in Codon Space

Directed evolution is commonly used in protein engineering, where mature molecules are routinely improved through iterative local search of amino acid space. Here, we extend this principle to coding DNA. We developed a language-model-guided framework that iteratively refined industry-optimized coding sequences of clinical-stage therapeutics through synonymous exploration of codon space. Across 23 antibody-based therapeutics, SynCodonLM-guided refinement significantly increased recombinant expression in CHO cells for 17 molecules (74% responder rate), without significant compromise of product-quality or biophysical attributes. Moreover, changes in model likelihood predicted expression gains more effectively than heuristic statistical or mRNA-structure descriptors, despite no explicit expression objective. Codon-level likelihood also tracked temporal progression in influenza A H1N1 sequences, indicating the model captures evolutionary signal. These results show that even production-optimized sequences retain accessible fitness in synonymous codon space, establishing directed evolution as a practical strategy to improve biologic expression, a key manufacturing bottleneck, without altering protein sequence.

bioengineering↗

bioRxiv2026

Buried in two places: Lineages from elite Maya tombs also found in distant caves

Classic Maya societies (250-900 CE) carved out urban centers in the rainforest reaching population heights and political complexity previously unknown in the Mesoamerican tropics. Kinship was a central feature of the social fabric, and rulership was legitimized through claims of direct descent from mythical ancestors. Mortuary practices kept the dead close to the living, and ancestor veneration sometimes produced complex deposits of disarticulated remains that are difficult to identify and whose biological relationships to one another cannot be understood without genetic data. We screened 487 human tooth and bone samples and successfully generated genome-wide data for 430 of them. Of these, 341 samples representing 107 distinct individuals were recovered from both elite and non-elite tombs in a Classic period kingdom (250-900) CE in the rugged Maya Mountains of Belize. Remarkably, 24 of these individuals have skeletal elements in both an elite tomb and in a ritual tooth cache in a distant cave located 26.5km away on the other side of the Maya Mountains. These results indicate that elite lineages created ancestors from their deceased relatives in geographically expansive ways and highlights the importance of caves in the belief system of Classic Maya elites.

genetics↗

bioRxiv2026

Impairment of bacteriophage activity in blood: a case study revealing constraints in phage isolation and translation

BackgroundPhage therapy is increasingly considered a promising alternative for treating multidrug-resistant (MDR) infections. However, its clinical application remains limited by challenges in isolating effective phages against resistant clinical strains and by the limited ability of in vitro assays to predict performance in real biological environments. While biological matrices are known to influence phage activity, these effects are not well characterised. MethodsA phage-resistant Pseudomonas aeruginosa isolate from a patient with recurrent MDR urinary tract infection was used as the model organism. Conventional isolation methods failed to recover effective phages, leading to the development of TEASER-i (Transient EDTA- and Ion-Assisted Sequential Enrichment & Recovery). Recovered phages were characterised using adsorption assays, one-step growth kinetics, and time-kill experiments. Their antibacterial activity was evaluated both in vitro and in ex vivo human matrices (whole blood, serum, plasma, and urine). Phage efficacy was quantified using maximum log reduction (Emax), area under the curve (AUC), and phage-to-bacteria ratio (PBR). ResultsA novel TEASER-i method optimised for difficult-to-treat Gram-negative infections, enabled recovery of a functionally effective Osewage-derived P. aeruginosa phage, which outperformed a Ourine-derived P. aeruginosa phage that showed slower replication and lower burst size. Phage activity varied significantly in blood, serum, and plasma. Urine supported the most sustained antibacterial effect. In many cases, early bacterial reduction was followed by regrowth. Sustained activity was associated with maintenance of favourable PBR values, while negative PBR corresponded to treatment failure. At 96 h, only two conditions maintained favourable phage load (log 10 PBR > 0): the S. aureus phage in urine (+1.66) and the sewage-derived P. aeruginosa phage in serum (+1.32). ConclusionsPhage efficacy depends not only on intrinsic lytic capacity but also on the ability to persist and amplify within specific biological environments. Conventional isolation and in vitro screening may therefore overestimate therapeutic potential. Combining optimised isolation strategies with ex vivo evaluation provides a more realistic framework for phage selection and clinical translation.

microbiology↗

bioRxiv2026

Ionic regulation of Gram-positive phage adsorption governs host range and improves phage isolation efficiency

Antimicrobial-resistant Staphylococcus aureus and S. epidermidis remain major causes of invasive infection, yet isolation of therapeutically robust lytic phages targeting Gram-positive pathogens is often constrained by adsorption barriers imposed by thick peptidoglycan cell walls. We demonstrate that these limitations are primarily methodological. By optimising the ionic microenvironment during isolation through divalent cation supplementation (10 mM CaCl2 and MgSO4), controlled enrichment, phage polyclonal mixtures, and limited lysozyme-assisted release, we recovered 28 genomically distinct lytic phages compared with six obtained using conventional protocols. Host-range profiling across 103 clinical isolates showed broad infectivity, with 51.7% of interactions supporting high-efficiency infection and multiple phages exhibiting cross-species activity. Ion-supplemented adaptive passaging restored and expanded lytic capacity against resistant strains within five rounds. These findings show that ionic regulation of adsorption reshapes Gram-positive phage-host dynamics and provide a scalable framework for precision targeting of resistant Staphylococcus infections.

microbiology↗

bioRxiv2019

Full-waveform inversion imaging of the human brain

Magnetic resonance imaging and X-ray computed tomography provide the two principal methods available for imaging the brain at high spatial resolution, but these methods are not easily portable and cannot be applied safely to all patients. Ultrasound imaging is portable and universally safe, but existing modalities cannot image usefully inside the adult human skull. We use in-silico simulations to demonstrate that full-waveform inversion, a computational technique originally developed in geophysics, is able to generate accurate three-dimensional images of the brain with sub-millimetre resolution. This approach overcomes the familiar problems of conventional ultrasound neuroimaging by using: transcranial ultrasound that is not obscured by strong reflections from the skull, low frequencies that are readily transmitted with good signal-to-noise ratio, an accurate wave equation that properly accounts for the physics of wave propagation, and an accurate model of the skull that compensates properly for wavefront distortion. Laboratory ultrasound data, using ex-vivo human skulls, demonstrate that our computational experiments mimic the penetration and signal-to-noise ratios expected in clinical applications. This form of non-invasive neuroimaging has the potential for the rapid diagnosis of stroke and head trauma, and for the provision of routine monitoring of a wide range of neurological conditions.

neuroscience↗

bioRxiv2017

Pharaoh ant colonies dynamically regulate colony demography by culling young queen and male-destined larvae

The success of social insect colonies is dependent upon efficient and dynamic allocation of resources to alternate queen and worker castes. The developmental and molecular mechanisms regulating the caste fate of individual larvae in response to environmental cues have been the focus of intense study. However, the mechanisms regulating colony-level resource allocation into alternate castes (i.e. caste allocation ratios) are less well studied. Here, we systematically manipulate colony demography to elucidate the social regulatory mechanisms of caste allocation in the ant Monomorium pharaonis. We find that differences in caste allocation result from differences in timing and efficiency of culling of very young reproductive-destined larvae, which are always present in colonies. Based on our results, we develop a conceptual model depicting how colonies integrate numerous individual-level caste determination decisions to regulate colony-level caste allocation. We propose that adult workers make decisions about culling larvae based on the ratio of the number of workers to the number of eggs contained in colonies, likely signalled by pheromone present on eggs. This strategy is a bet-hedging strategy which enables the dynamic alteration of colony demography in response to internal and external conditions. The strategy is likely key to the ability of M. pharaonis and similar ants to thrive in disturbed habitats and to become widespread invasive species.\n\nSignificance StatementThe defining feature of social insect societies is the presence of alternate queen (reproductive) and worker (non-reproductive) castes of individuals. The fitness of social insect colonies is dependent upon efficient allocation of resources to alternate castes, particularly in the case of highly polygynous (multi-queen) societies. However, the mechanisms by which such societies regulate caste allocation are largely unknown. In this study, we show that colonies manipulate their production of queens (and also males) versus workers according to the present density of eggs in the colony, which serves as a reliable indicator of queens fertility. Provided egg density is high, colonies kill queen-and male-destined larvae; when egg density falls, colonies begin to rear queens and males. This flexible resource allocation strategy is key to the ability of highly polygynous species to thrive in marginal (often human-associated) habitats.

ecology↗