Biology subjects

Baldwin, A. S.

Publications and source records attributed to Baldwin, A. S..

9 recordsLinked to original sources

bioRxiv2026

Folate metabolism in tumor-associated macrophages drives immunosuppressive function to promote tumor growth

Tumor-associated macrophages (TAMs) promote tumor growth, inhibit effector lymphocytes, and induce resistance to immune checkpoint inhibitors (ICI). Therapies designed to deplete TAMs have had little success in the clinic, and strategies aimed to repolarize immunosuppressive TAMs to pro-inflammatory states have struggled with systemic toxicity. We have identified that the combination of low folate in the tumor microenvironment and TAM dependency on the high affinity folate receptor beta (FR{beta}) for folate uptake results in a unique metabolic dependency of TAMs necessary for their immunosuppressive function. FR{beta} (encoded by Folr2) is uniquely expressed on myeloid cells and upregulated on TAMs. FR{beta}+ TAMs exhibit an immunosuppressive phenotype in melanoma and are associated with worse clinical outcomes and resistance to ICI in melanoma patients. We generated a novel Folr2-/- mouse model to study why TAMs express a unique folate receptor and showed that tumor growth was slowed in the absence of Folr2 in a T-cell dependent manner. We observed a dramatic repolarization of Folr2-/- TAMs in vivo to pro-inflammatory states, resulting in increased cytotoxic T cell and NK cell infiltration into tumors. Importantly, we show that folate is low in the tumor microenvironment by performing metabolomics on melanoma tumors and adjacent normal tissue from warm autopsy patient specimens, and that we could increase tumor growth in Folr2-/- mice by increasing serum folate to supraphysiologic concentrations with a high folate diet. Integrated metabolomics and transcriptomic analysis demonstrated that Folr2-/- macrophages have impaired folate uptake and 1C metabolism-based reduction of oxidized glutathione in low folate conditions, resulting in increased mitochondrial reactive oxygen species (ROS) in Folr2-/- cells. Excess ROS results in leakage of mitochondrial DNA into the cytoplasm, activating cGAS-STING signaling and promoting pro-inflammatory macrophage polarization through TBK1 and NF-kB. Together, our data demonstrate that TAM expression of FR{beta} promotes their immunosuppressive functions by maintaining folate uptake in the low folate tumor microenvironment, suggesting that FR{beta} is a novel metabolic checkpoint on TAMs.

immunology↗

bioRxiv2025

The amblyopic acuity deficit: impact on the identification of letters distorted by spatial scrambling algorithms

The letter acuity impairment in the amblyopic eye often exceeds predictions made from the cut-off spatial frequency for grating detection. Spatial scrambling in the amblyopic eyes projections to the visual cortex has been proposed to bear some responsibility for this additional deficit. Using a novel stimulus algorithm that creates spatially scrambled bandpass letters, we generated stimuli simulating either: i) "cortical scrambling" at the output of oriented model "simple cells", or ii) "subcortical scrambling" of isotropic subunits that combine to form these simple cells. We also investigated a more conventional "noise masking" with bandpass noise. We performed two bandpass letter identification experiments, equating the stimuli shown to each eye by normalising either: i) their contrast, presenting them at four times their contrast detection threshold; or ii) their spatial scale, presenting them at twice the participants acuity threshold for each eye. At the group level, we found that the amblyopic eye is less efficient at performing letter identification in bandpass noise. We did not find an overall significant difference with either scrambling type when comparing efficiency between the amblyopic and fellow eye, but we did find such a difference when partitioning our participants by their stereopsis ability. In further analyses of the pattern of mistakes, we found the amblyopic eye shows a distinctive behaviour which correlates with the acuity deficit for both types of scrambling. These results demonstrate that our scrambled stimuli interrogate a component of amblyopic vision that is functionally distinct from that addressed by contrast noise masking.

neuroscience↗

bioRxiv2025

Summation of contrast across the visual field: a common "fourth root" rule holds from the fovea to the periphery

AO_SCPLOWBSTRACTC_SCPLOWIncreasing the area of grating-like stimuli reduces their contrast detection thresholds. Characterising the visual systems summation rule this way provides insights into early visual architecture. Previous work in the fovea has found linear summation over short distances, consistent with integration within the receptive fields of early cortical neurons. Beyond this range, the benefit of stimulus area is reduced. Here, we investigated whether the same integration rule holds for stimulus elongations centred at different positions across the visual field. We did this for "tiger tail" strips of grating (growing orthogonally to the major axis of the early receptive fields) in the fovea, parafovea (3 deg), and periphery (10.5 deg). The interpretation of results from previous studies has been complicated by variation in local contrast sensitivity across the visual field. We addressed this here by using detailed maps of the inhomogeneity for each participant (their "witch hat") to generate "compensated" stimuli where the local stimulus contrast was amplified by the reciprocal of their local sensitivity. Our results followed a common fourth-root summation rule for tiger-tails in the fovea, parafovea, and periphery. We explained this by a "noisy energy" model that combined: i) a "witch hat" sensitivity surface, ii) linear filtering by receptive fields, iii) square-law contrast transduction, and iv) an internal template to direct the observers attention to the spatial extent of the stimulus. Fitting this model with a single global sensitivity parameter accounted for foveal and parafoveal results (56 thresholds), with one further parameter needed to model the periphery (84 thresholds).

neuroscience↗

bioRxiv2024

Human visual performance for identifying letters affected by physiologically-inspired scrambling

AO_SCPLOWBSTRACTC_SCPLOWIn the geniculostriate pathway of the human visual system, neuronal projections carry signals from a particular retinal locus in parallel from one anatomical area to the next. Imprecision in the fidelity of these projections would place constraints on the ability of the system to perform tasks requiring positional information. We investigated the impact that "spatial scrambling" between stages would have on visual performance. We consider two stages in a simple canonical model of the early visual cortex where scrambling might occur: either the input to the first orientation-tuned mechanisms (analogous to V1 simple cells), or the output from those mechanisms. These are referred as "subcortical" (SCS) and "cortical scrambling" (CS). We developed a wavelet decomposition and resynthesis algorithm to mimic these effects, and measured human performance in letter identification affected by the two types of scrambling. Our results showed SCS and CS have distinguishable effects on both perceived noisiness of letters and letter identification threshold. Comparing human performance against a suite of pre-trained and custom convolutional neural networks (CNNs) that were trained on the scrambled stimuli, relative efficiency (calculated from the ratio of human:CNN thresholds) is higher for CS than SCS. However, in modelling human inefficiency by reducing the proportion of wavelets available to the CNNs, humans are less efficient in CS than SCS. These differences in efficiencies show humans are better at processing orientation redundant stimuli (CS) than orientation noisy stimuli (SCS). We hypothesize this reflects differences in integration properties at the input and output stages of simple cells in the cortex. Author SummaryThe brain makes sense of the input from our eyes through a system where features are extracted and combined in successive stages. Our study concerns the spatial fidelity of the connections between visual areas. Previous behavioural and physiological evidence has suggested a scrambling of neuronal projections is present in biological visual systems. In our study, we investigate the ability of the human visual system to perform letter identification with stimuli affected by different types of on-screen distortions. These distortions simulate internal scrambling occurring at two early stages in the visual hierarchy. We used convolutional neural network (CNN) models as a benchmark, against which we compared human performance to find human efficiency in handling the distortions. We found that the type of scrambling in which humans were determined to have greater "efficiency" (relative to the CNNs) depended on the analysis used. The threshold magnitude of scrambling at which the letters could no longer be identified was greater for letters scrambled after the oriented features were extracted. Conversely, when efficiency was calculated by starving the CNNs of samples until their performance declined to the human level we instead found that the effective "number of samples" used by our humans was much higher for stimuli simulating scrambling before the oriented feature stage. These differences reflect how information is pooled and combined for these two stages.

neuroscience↗

bioRxiv2023

Stereo-anomaly is found more frequently in tasks that require discrimination between depths

AO_SCPLOWBSTRACTC_SCPLOWWithin the population of humans with otherwise normal vision, there exists some proportion whose ability to perceive depth from binocular disparity is poor or absent. The prevalence of this "stereoanomaly" has been investigated in previous studies, some finding the proportion to be as small as 2%, others finding it to be as great as 30%. In this study, we set out to investigate the possible reason for the wide range of results found in these studies. We used a digital stereoacuity measurement tool that could measure performance in tasks requiring either the detection of disparity or the discrimination of the sign of disparity. The stimulus design was otherwise similar between the two tasks. In a cohort of 228 participants, we found that 98% were able to consistently perform the detection task. In contrast, only 69% consistently performed the discrimination task. The 31% of participants who had difficulty with the discrimination task could further be divided into 17% who were consistently unable to perform the task (seeming to behave at chance), and 14% who showed some ability to perform the task. We propose that the greater prevalence of stereo-anomaly is revealed when tasks require the judgement of the direction of disparity.

neuroscience↗

bioRxiv2020

Exercise does not enhance short-term deprivation-induced ocular dominance plasticity: evidence from dichoptic surround suppression

AO_SCPLOWBSTRACTC_SCPLOWThe input from the two eyes is combined in the brain. In this combination, the relative strength of the input from each eye is determined by the ocular dominance. Recent work has shown that this dominance can be temporarily shifted. Covering one eye with an eye patch for a few hours makes its contribution stronger. It has been proposed that this shift can be enhanced by exercise. Here, we test this hypothesis using a dichoptic surround suppression task, and with exercise performed according to American College of Sport Medicine guidelines. We measured detection thresholds for patches of sinusoidal grating shown to one eye. When an annular mask grating was shown simultaneously to the other eye, thresholds were elevated. The difference in the elevation found in each eye is our measure of relative eye dominance. We made these measurements before and after 120 minutes of monocular deprivation (with an eye patch). In the control condition, subjects rested during this time. For the exercise condition, 30 minutes of exercise were performed at the beginning of the patching period. This was followed by 90 minutes of rest. We find that patching results in a shift in ocular dominance that can be measured using dichoptic surround suppression. However, we find no effect of exercise on the magnitude of this shift. We further performed a meta-analysis on the four studies that have examined the effects of exercise on the dominance shift. Looking across these studies, we find no evidence for such an effect.

neuroscience↗

bioRxiv2020

Ocular Dominance Plasticity: Measurement Reliability and Variability

AO_SCPLOWBSTRACTC_SCPLOWIn the last decade, studies have shown that short-term monocular deprivation strengthens the deprived eyes contribution to binocular vision. However, the magnitude of the change in eye dominance after monocular deprivation (i.e., the patching effect) has been found to be different between for different methods and within the same method. There are three possible explanations for the discrepancy. First, the mechanisms underlying the patching effect that are probed by different measurement tasks might exist at different neural sites. Second, test-retest variability in the measurement might have led to inconsistencies, even within the same method. Third, the patching effect itself in the same subject might fluctuate across separate days or experimental sessions. To explore these possibilities, we assessed the test-retest reliability of the three most commonly used tasks (binocular rivalry, binocular combination, and dichoptic masking) and the repeatability of the shift in eye dominance after short-term monocular deprivation for each of the task. Two variations for binocular phase combination were used, at one and many contrasts of the stimuli. Also, two variations of the dichoptic masking task was tested, in which the orientation of the mask grating was either horizontal or vertical. This makes five different measurement methods in all. We hope to resolve some of the inconsistencies reported in the literature concerning this form of visual plasticity. In this study, we also aim to recommend a measurement method that will allow us to better understand its physiological basis and the underpinning of visual disorders.

neuroscience↗

bioRxiv2019

Integration of contours defined by second-order contrast-modulation of texture

AO_SCPCAPBSTRACTC_SCPCAPBoundaries in the visual world can be defined by changes in luminance and texture in the input image. A \"contour integration\" process joins together local changes into percepts of lines or edges. A previous study tested the integration of contours defined by second-order contrast-modulation. Their contours were placed in a background of random wavelets. Subjects performed near chance. We re-visited second-order contour integration with a different task. Subjects distinguished contours with \"good continuation\" from distractors. We measured thresholds in different amounts of external orientation or position noise. This gave two noise-masking functions. We also measured thresholds for contours with a baseline curvature to assess performance with more curvy targets. Our subjects were able to discriminate the good continuation of second-order contours. Thresholds were higher than for first-order contours. In our modelling, we found this was due to multiple factors. There was a doubling of equivalent internal noise between first- and second-order contour integration. There was also a reduction in efficiency. The efficiency difference was only significant in our orientation noise condition. For both first- and second-order stimuli, subjects were also able to perform our task with more curved contours. We conclude that humans can integrate second-order contours, even when they are curved. There is however reduced performance compared to first-order contours. We find both an impaired input to the integrating mechanism, and reduced efficiency seem responsible. Second-order contour integration may be more affected by the noise background used in the previous study. Difficulty segregating that background may explain their result.

neuroscience↗

bioRxiv2018

Visual plasticity and exercise revisited: no evidence for a \"cycling lane\"

Experiments using enriched environments have shown that physical exercise modulates visual plasticity in rodents. A recent study (Lunghi & Sale, 2015, doi: 10.1016/j.cub.2015.10.026) investigated whether exercise also affects visual plasticity in adult humans. The plastic effect they measured was the shift in ocular dominance caused by 2 hours of monocular deprivation (e.g. by an eye patch). They used a binocular rivalry task to measure this shift. They found that the magnitude of the shift was increased by exercise during the deprivation period. This effect of exercise was later disputed by a study that used a different behavioural task (Zhou et al., 2017, doi: 10.1155/2017/4780876). Our goal was to determine whether the difference in task was responsible for that studys failure to find an exercise effect. We set out to replicate Lunghi & Sale (2015). We measured ocular dominance with a rivalry task before and after 2 hours of deprivation. We measured data from two conditions in 30 subjects. On two separate days they either performed exercise or rested during the deprivation period. Contrary to the previous study, we find no significant effect of exercise. We hypothesise that exercise may affect rivalry dynamics in a way that interacts with the measurement of the deprivation effect.

neuroscience↗