Biology subjects

Welch, D.

Publications and source records attributed to Welch, D..

14 recordsLinked to original sources

bioRxiv2026

A collicular somatostatinergic circuit gates sensory access to action

Animals are exposed to far more sensory information than can be converted into action and must prioritise behaviourally salient events. Although salience is commonly studied as modulation of sensory representations, stimulus prioritisation may also arise at premotor stages, through mechanisms that regulate the readiness of action-generating circuits to be recruited by sensory input. The superior colliculus links visual signals to spatially directed orienting and contains Pitx2-expressing spatial-motor modules that coordinate spatially targeted actions, providing a substrate for premotor regulation of sensory access to action. However, the circuit elements that regulate this access remain unknown. Here we identify an intersectionally targeted population of somatostatin-expressing inhibitory neurons in the mouse superior colliculus that is, at the population level, suppressed during orienting movements and visual stimulation. These neurons provide input to Pitx2-expressing spatial-motor modules, and their optogenetic silencing increased retinally evoked firing in Pitx2 neurons, showing that somatostatinergic inhibition constrains the visual recruitment of collicular motor output. Increasing somatostatinergic tone reduced interception of low- and intermediate-contrast visual targets while sparing responses to high-contrast targets, consistent with graded control of sensory access to action. Cholecystokinin-expressing inhibitory neurons and multiple cortical and subcortical regions provide anatomical input to the somatostatinergic population, identifying candidate routes for local and context-dependent regulation. Together, these findings establish somatostatinergic inhibition as a premotor control point that regulates the readiness of spatial-motor circuits for sensory recruitment and identify a circuit architecture through which the behavioural impact of salient sensory events could be regulated downstream of sensory encoding.

neuroscience↗

bioRxiv2026

Genomic epidemiology of the 2017-2023 outbreak of Mycoplasma bovis sequence type ST21 in New Zealand

Mycoplasma bovis was first detected in cattle in New Zealand in 2017, prompting an eradication programme that incorporated extensive surveillance and a test-and-cull policy. Genome sequence data and phylodynamic models were used to inform decision making throughout the eradication programme. Isolates from 697 cattle on 126 farms were collected and sequenced between July 2017 and December 2023. Phylodynamic models were used to estimate the time of most recent common ancestor, the effective reproduction number (Reff) and effective population size, and long-range and local between-farm transmission dynamics. The analysis revealed the dramatic impact of movement restrictions and culling up to early 2020, with a sharp reduction in the Reff to less than 1 in 2018/9 and the extinction of two of three major lineages in 2020. This was followed by three-years of residual infection in farms in the South Island, associated with persistent infection of a large feedlot farm and nearby farms. The comprehensive dataset of genomic and epidemiological data provided a unique opportunity to study the dynamics of a country-wide outbreak of a single-host pathogen from first detection to potential eradication, underlining the utility of integrated genomic surveillance during an outbreak response. Author summaryThe economically important cattle pathogen, Mycoplasma bovis, was first detected in New Zealand in 2017. This led to a large-scale, successful control programme aimed at eradication of the pathogen. The decision to undertake an eradication programme was informed by initial analyses of whole genome sequences from isolates collected as part of the surveillance programme. The analysis showed that the bacteria had entered New Zealand relatively recently and was unlikely to be widespread. Over the subsequent years, genome sequencing and modelling of transmission dynamics informed important policy decisions made by the New Zealand Government and the cattle industry, and helped to monitor progress of the eradication programme. The impact of the detection, movement control and culling programme was profound, with sharp reductions in transmission between 2018 and 2020. This was followed by a long tail of localised infection in the South Island, involving transmission from a large feedlot farm. Provisional eradication was achieved after depopulation of this feedlot. This analysis highlights the role of genomic surveillance and modelling to inform decision making during an infectious disease outbreak.

genomics↗

bioRxiv2025

SMART Sensors for Cell Growth Monitoring in Closed System G-Rex for Scalable, Cost-Conscious Cell and Gene Therapy Manufacturing

Cell and gene-modified cell therapy (CGT), commonly referred to as the fourth pillar of cancer treatment, includes creating advanced cancer killing cells ex vivo and then subsequently putting them into the patients body to selectively attack cancerous cells. Typically, immune cells from a patients body are removed, genetically modified to find and kill cancer, grown to a large army of cancer killing cells, and put back into the patient. This complex process is being simplified through innovation, some of which we describe here. One key innovation is an immune cell manufacturing device configuration called G-Rex (for "gas permeable rapid expansion"), which is now widely used to create armies of cancer killing cells for clinical trials and for commercially approved drug products on a worldwide basis. G-Rex is uniquely simple and popular because it is the only technology that eliminates the need for pumps and flow circuits to deliver oxygen and nutrients. Instead, the material and geometry of G-Rex allow cancer killing cells to get access to oxygen and nutrients on demand. This greatly minimizes complexity and sets the stage for high throughput manufacturing. To further simplify G-Rex relative to all CGT drug product manufacturing alternatives, it would be ideal to eliminate any need of physical intervention to assess cell quantity. With that goal, we conceived a novel approach to determining cell quantity in a non-invasive manner. More specifically, we invented and built a sensor into G-Rex that continuously reports the quantity of cells in G-Rex without any intervention or sampling to an external reader. Herein, we call the sensor a "single-use metabolite absorbing resonant transducer in G-Rex (SMART G-Rex)" and the reader a "SMART Reader." The SMART G-Rex is wirelessly interrogated by the SMART Reader to determine the extent of cell expansion in the G-Rex at any given time. More specifically, as cell quantity increases, the SMART G-Rex absorbs cell secreted metabolites (organic compounds such as eicosanoids) which cause a change in resonant frequency (measured as % of frequency change, or Skroot Growth Index (SGI)). By placing SMART G-Rex in proximity of the SMART Reader, whether in or out of an incubator, changes in resonant frequency are detected and translated into cell quantity with high reliability. For example, using 45 sensors across multiple donor cell samples, we established 99% confidence in SMARTs accuracy at signaling a >60X expansion (3B cells at harvest). The SMART G-Rex provides a non-invasive way of instantly quantifying the number of cells in a CGT drug production process and informing manufacturers when a CGT drug product has reached the desired quantity of cells necessary to proceed with formulation, fill, and finish. By integrating SMART technology, G-Rex is the only technology for CGT manufacturing that can avoid intervention when determining cells quantity or allow real-time knowledge of cell quantity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/676768v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1557118org.highwire.dtl.DTLVardef@740652org.highwire.dtl.DTLVardef@14b0430org.highwire.dtl.DTLVardef@ac0_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Robotic performance is comparable to human operators for cell therapy manufacturing tasks

Although numerous cell and gene therapies have received regulatory approval, their adoption has been hampered by high cost and challenges in scaling out manufacturing. Many autologous cell therapies are individually manufactured for each patient using traditional manual methods in high-cost environments. Therefore, robotics and automation offer a potential solution to meet the growing demand for such therapies. To ensure identical biological outcomes, automation must replicate validated manual workflows, a requirement that poses significant engineering challenges, especially for aseptic manipulation and compatibility with manual-centric instruments and consumables. Here we describe the design and performance of a modular robotic cluster consisting of specialized modules containing widely adopted equipment. The robotic arm uses custom end-effectors to handle standard consumables and instruments such as syringes, vials, bags, cell counters, bioreactors, incubators, and closed centrifuges. We compared the performance of skilled human operators against the robotic cluster across multiple tasks: transferring cells between sterile bags, cell counting, drawing volume from a vial to a syringe, and resuspension and sampling from both a bag and G-Rex 100M-CS bioreactor. The robotic system also executed high-complexity operations with industry-standard instruments: cell selection using a CytoSinct 1000 and wash/buffer exchange with a CTS Rotea Counterflow centrifugation system. Experimental results for each unit operation show that the robotic clusters performance is equivalent to manual operations on the selected key metrics. These data demonstrate that the robotic system can efficiently and robustly perform specific unit operations, which can be combined in any order for end-to-end cell therapy manufacturing processes. One Sentence summaryA modular robotic system can perform key unit operations in cell therapy manufacturing with accuracy comparable to human operators while ensuring throughput and flexibility.

bioengineering↗

bioRxiv2024

Extending the Acute Skin Response Spectrum to Include the Far-UVC

Guidance on maximal limits for ultraviolet (UV) exposure has been developed by national and international organizations to protect against adverse effects on human skin and eyes. These guidelines consider the risk of both acute effects (i.e. erythema and photokeratitis) and delayed effects (e.g., skin and ocular cancers) when determining exposure limits, and specify the dose a person can safely receive during an 8-hour period without harmful effects. The determination of these exposure limits relies on the action spectra of photobiological responses triggered by UV radiation that quantify the effectiveness of each wavelength at eliciting each of these effects. With growing interest in using far-UVC (200-235 nm) radiation to control the spread of airborne pathogens, recent arguments have emerged about revisiting exposure limits for UV wavelengths. However, the standard erythema action spectra, which provides some of the quantitative basis for these limits, has not been extended below 240 nm. This study assists to expand the erythema action spectrum to far-UVC wavelengths using a hairless albino mice model. We estimate that inducing acute effects on mouse skin with 222 nm radiation requires a dose of 1,162 mJ/cm2, well above the current ACGIH skin exposure limit of 480 mJ/cm2.

biophysics↗

bioRxiv2023

Crowdsourcing and phylogenetic modelling reveal parrot tool use is not rare

Studying the prevalence of putatively rare behaviours, such as tool use, is challenging because absence of evidence can arise either from a species inability to produce the behaviour or from insufficient research effort. Here, we tackle this challenge by combining crowdsourcing and phylogenetic modelling to approximate actual rates of a rarely observed behaviour based on limited data, targeting tool use in parrots. Crowdsourcing on a social media platform revealed novel instances of tool use in 17 parrot species, more than doubling the confirmed number of tool-using parrot species from 11 (3%) to 28 (7%). Phylogenetic modelling ranked additional species that are most likely to be unobserved tool users, suggesting that between 11% and 17% of extant parrot species may be tool users. These discoveries have implications for inferences about the evolutionary drivers and origins of tool use in parrots, revealing associations with relative brain size and feeding generalism and indicating several genera where tool use was likely an ancestral trait. Overall, our findings challenge the assumption that current sampling effort captures the full distribution of putatively rare animal behaviours. Combining our sampling and analysis methods offers a fruitful approach for investigating the distribution, drivers, and origins of other rare behaviours. This working paper has not yet been peer-reviewed.

animal behavior and cognition↗

bioRxiv2022

Optimization of cryo-electron microscopy for quantitative analysis of lipid bilayers

Cryogenic electron microscopy (cryo-EM) is among the most powerful tools available for interrogating nanoscale structure of biological structures. We recently showed that cryo-EM can be used to measure the bilayer thickness of lipid vesicles and biological membranes with sub-angstrom precision, resulting in the direct visualization of nanoscopic domains of different thickness in multicomponent lipid mixtures and giant plasma membrane vesicles. Despite the great potential of cryo-EM for revealing the lateral organization of biomembranes, a large parameter space of experimental conditions remains to be optimized. Here, we systematically investigate the influence of instrument parameters and image post-processing steps on the ability to accurately measure bilayer thickness and discriminate regions of different thickness within unilamellar liposomes. We also demonstrate a spatial autocorrelation analysis to extract additional information about lateral heterogeneity. SignificanceRaft domains in unstimulated cells have proven difficult to directly visualize owing to their nanoscopic size and fleeting existence. The few techniques capable of nanoscopic spatial resolution typically rely on interpretation of indirect spectroscopic or scattering signals or require stabilizing the membrane on a solid support. In contrast, cryo-EM yields direct images of nanoscale domains in probe-free, unsupported membranes. Here, we systematically optimize key steps in the experimental and analysis workflow for this new and specialized application. Our findings represent an important step toward developing cryo-EM into a robust method for investigating phase behavior of membranes at length scales relevant to lipid rafts.

biophysics↗

bioRxiv2022

Ocular and Facial Far-UVC Doses from Ceiling-Mounted 222 nm Far-UVC Fixtures

Far-UVC radiation, commonly defined as wavelengths from 200 nm - 235 nm, is a promising tool to help prevent the spread of disease. The unique advantage of far-UVC technology over traditional ultraviolet germicidal irradiation lies in the potential for direct application of far-UVC into occupied spaces since antimicrobial doses of far-UVC are significantly below the recommended daily safe exposure limits. This study used a ceiling-mounted far-UVC fixture emitting at 222 nm to directly irradiate an indoor space and then evaluated the doses received upon a manikin. Radiation sensitive film was affixed to the head, nose, lip, and eyes of the manikin, and the 8-hour equivalent exposure dose was determined. Variables examined included manikin height (sitting or standing position), manikin offset from directly below the fixture, tilt of the manikin, the addition of glasses, the addition of hair, and different anatomical feature sizes. Importantly, at the manikin position with the highest dose to eyes, the average eye dose was only 5.8% of the maximum directly measured dose. These results provide the first experimental analysis of possible exposure doses a human would experience from an indoor far-UVC installation.

bioengineering↗

bioRxiv2022

No evidence of induced skin cancer or other skin abnormalities after long term (66 week) chronic exposure to 222-nm far-UVC radiatio

Far-UVC radiation, typically defined as 200-235 nm, has similar or greater anti-microbial efficacy compared to conventional 254-nm germicidal radiation. In addition, biophysical considerations of the interaction of far-UVC with tissue, as well as multiple short-term safety studies in animal models and humans, suggest that far-UVC exposure may be safe for skin and eye tissue. Nevertheless, the potential for skin cancer after chronic long-term exposure to far-UVC has not been studied. Here, we assessed far-UVC induced carcinogenic skin changes and other pathological dermal abnormalities in 96 SKH-1 hairless mice of both sexes that were exposed to average daily dorsal skin doses of 396 mJ/cm2, 126 mJ/cm2 or 56 mJ/cm2 of 222 nm far-UVC radiation for 66 weeks, 5 days per week, 8 hours per day, as well as similarly-treated unexposed controls. No evidence for increased skin cancer, abnormal skin growths, or incidental skin pathology findings was observed in the far-UVC exposed mice. In addition, there were no significant changes in morbidity or mortality. The findings from this study support the long-term safety of long-term chronic exposure to far-UVC radiation, and therefore its potential suitability as a practical anti-microbial approach to reduce airborne viral and bacterial loads in occupied indoor settings.

cancer biology↗

bioRxiv2021

Wavelength-dependent DNA photodamage in a 3-D human skin model over the far-UVC and germicidal-UVC wavelength ranges from 215 to 255 nm

The effectiveness of UVC to reduce airborne-mediated disease transmission is well-established. However conventional germicidal UVC (~254 nm) cannot be used directly in occupied spaces because of the potential for damage to the skin and eye. A recently studied alternative with the potential to be used directly in occupied spaces is far-UVC (200 to 235 nm, typically 222 nm), as it cannot penetrate to the key living cells in the epidermis. Optimal far-UVC use is hampered by limited knowledge of the precise wavelength dependence of UVC-induced DNA damage, and thus we have used a monochromatic UVC exposure system to assess wavelength-dependent DNA damage in a realistic 3-D human skin model. We exposed a 3-D human skin model to mono-wavelength UVC exposures of 100 mJ/cm2, at UVC wavelengths from 215 to 255 nm (5-nm steps). At each wavelength we measured yields of DNA-damaged keratinocytes, and their distribution within the layers of the epidermis. No increase in DNA damage was observed in the epidermis at wavelengths from 215 to 235 nm, but at higher wavelengths (240-255 nm) significant levels of DNA damage were observed. These results support use of far-UVC light to safely reduce the risk of airborne disease transmission in occupied locations.

biophysics↗

bioRxiv2021

Ignoring errors causes inaccurate timing of single-cell phylogenies

Single-cell sequencing provides a new way to explore the evolutionary history of cells. Compared to traditional bulk sequencing, where a population of heterogeneous cells is pooled to form a single observation, single-cell sequencing isolates and amplifies genetic material from individual cells, thereby preserving the information about the origin of the sequences. However, single-cell data is more error-prone than bulk sequencing data due to the limited genomic material available per cell. Here, we present error and mutation models for evolutionary inference of single-cell data within a mature and extensible Bayesian framework, BEAST2. Our framework enables integration with biologically informative models such as relaxed molecular clocks and population dynamic models. Our simulations show that modeling errors increase the accuracy of relative divergence times and substitution parameters. We reconstruct the phylogenetic history of a colorectal cancer patient and a healthy patient from single-cell DNA sequencing data. We find that the estimated times of terminal splitting events are shifted forward in time compared to models which ignore errors. We observed that not accounting for errors can overestimate the phylogenetic diversity in single-cell DNA sequencing data. We estimate that 30-50% of the apparent diversity can be attributed to error. Our work enables a full Bayesian approach capable of accounting for errors in the data within the integrative Bayesian software framework BEAST2.

evolutionary biology↗

bioRxiv2018

Inferring Species Trees Using Integrative Models of Species Evolution

Evolutionary models account for either population- or species-level processes, but usually not both. We introduce a new model, the FBD-MSC, which makes it possible for the first time to integrate both the genealogical and fossilization phenomena, by means of the multispecies coalescent (MSC) and the fossilized birth-death (FBD) processes. Using this model, we reconstruct the phylogeny representing all extant and many fossil Caninae, recovering both the relative and absolute time of speciation events. We quantify known inaccuracy issues with divergence time estimates using the popular strategy of concatenating molecular alignments, and show that the FBD-MSC solves them. Our new integrative method and empirical results advance the paradigm and practice of probabilistic total evidence analyses in evolutionary biology.

evolutionary biology↗

bioRxiv2017

Far-UVC light: A new tool to control the spread of airborne-mediated microbial diseases

Airborne-mediated microbial diseases such as influenza and tuberculosis represent major public health challenges. A direct approach to prevent airborne transmission is inactivation of airborne pathogens, and the airborne antimicrobial potential of UVC ultraviolet light has long been established; however, its widespread use in public settings is limited because conventional UVC light sources are both carcinogenic and cataractogenic. By contrast, we have previously shown that far-UVC light (207-222 nm) efficiently kills bacteria without harm to exposed mammalian skin. This is because, due to its strong absorbance in biological materials, far-UVC light cannot penetrate even the outer (non living) layers of human skin or eye; however, because bacteria and viruses are of micrometer or smaller dimensions, far-UVC can penetrate and inactivate them. We show for the first time that far-UVC efficiently kills airborne aerosolized viruses, a very low dose of 2 mJ/cm2 of 222-nm light inactivating >95% of aerosolized H1N1 influenza virus. Continuous very low dose-rate far-UVC light in indoor public locations is a promising, safe and inexpensive tool to reduce the spread of airborne-mediated microbial diseases.

bioengineering↗

bioRxiv2017

Directly Estimating Epidemic Curves From Genomic Data

Modern phylodynamic methods interpret an inferred phylogenetic tree as a partial transmission chain providing information about the dynamic process of transmission and removal (where removal may be due to recovery, death or behaviour change). Birth-death and coalescent processes have been introduced to model the stochastic dynamics of epidemic spread under common epidemiological models such as the SIS and SIR models, and are successfully used to infer phylogenetic trees together with transmission (birth) and removal (death) rates. These methods either integrate analytically over past incidence and prevalence to infer rate parameters, and thus cannot explicitly infer past incidence or prevalence, or allow such inference only in the coalescent limit of large population size. Here we introduce a particle filtering framework to explicitly infer prevalence and incidence trajectories along with phylogenies and epidemiological model parameters from genomic sequences and case count data in a manner consistent with the underlying birth-death model. After demonstrating the accuracy of this method on simulated data, we use it to assess the prevalence through time of the early 2014 Ebola outbreak in Sierra Leone.

epidemiology↗