Biology subjects

Lopes, P.

Publications and source records attributed to Lopes, P..

4 recordsLinked to original sources

bioRxiv2026

Type 2B VWD substitutions trigger enhanced macrophage-mediated clearance that is attenuated by the BT200 aptamer

Type 2B von Willebrand disease (VWD) is characterized by missense variants in exon 28 of the von Willebrand factor (VWF) gene that encodes the VWF-A1 domain. These missense mutations result in single amino acid residue substitutions that cause activation of VWF-A1 and promote spontaneous interaction with platelet GPIba;. Importantly, enhanced VWF clearance has been shown to play a key pathogenic role in >90% patients with Type 2B VWD. Although this VWF clearance occurs via mechanisms that are independent of VWF-platelet complex formation, the biological mechanisms responsible for the increased clearance of type 2B VWD variants remain poorly understood. In this study, we investigated a series of different type 2B amino acid substitutions within the VWF-A1 domain (R1306W, R1308C, W1313C and R1379L). We demonstrate that these variants all exhibit significantly increased macrophage binding. In part, the enhanced macrophage interactions are mediated via increased binding of type 2B VWD variants to LRP1 extracellular cluster II and IV. Our findings further demonstrate that the K1405-K1408 lysine cluster in the VWF-A1 domain plays a key role in enabling enhanced LRP1 interactions for type 2B VWD variants. In addition, we show that type 2B VWF variants demonstrate significantly enhanced interaction with the macrophage MGL receptor. Finally, and importantly from a clinical perspective, we demonstrate that the increase in macrophage binding for type 2B variants is significantly attenuated in the presence of BT200. Collectively, our findings have direct translational relevance with respect to the clinical heterogeneity and treatment of type 2B VWD.

biochemistry↗

bioRxiv2026

Chloroplast movements in siphonous macroalgae in response to high light and grazing

Fast cytoplasmic streaming enables extensive chloroplast movements in the giant cells of unicellular, siphonous macroalgae. Here, we studied chloroplast movements in two such algae: the Dasycladalean Acetabularia acetabulum and the Bryopsidales Bryopsis sp.. We hypothesised that chloroplast movements function as a protective avoidance mechanism under excess light, particularly in Bryopsis sp., which lacks capacity for fast induction of photoprotective non-photochemical quenching (NPQ) and state transitions. In addition, we also investigated whether chloroplast movements are involved in responses to wounding and herbivory. The movements were studied by light microscopy, photography and pulse modulated chlorophyll a fluorescence quenching analysis. Chemical inhibitors of actin polymerization and microtubules assembly were used to confirm that the observed effects were active responses controlled by the cytoskeleton. A. acetabulum responded to high light by reversible chloroplast aggregation, probed by macro-imaging; and chemical inhibition of chloroplast movements led to an enhancement of Photosystem II photoinhibition, as probed by the fluorescence parameter FV/FM. No chloroplast movements were observed in Bryopsis sp. in response to high light. In A. acetabulum, wounding caused either by cutting or due to feeding by the sap-sucking sea slug Elysia timida triggered aggregation of chloroplasts within minutes of incurring the damage. Interestingly, the aggregation also occurred in intact cells away from the cutting site. Furthermore, the addition of media collected from the vicinity of cut algae was sufficient to induce chloroplast aggregation in intact algae, suggesting that water-borne cues or signals triggered the aggregation response in A. acetabulum. Bryopsis sp., however, responded to cutting by only local chloroplast aggregation. The relevance of chloroplast movements in protection against both abiotic and biotic stressors in A. acetabulum, and the potential reasons behind the different defence strategies of the algae, are discussed.

cell biology↗

bioRxiv2024

Overlapping Cortical Substrate of Biomechanical Control and Subjective Agency

Every movement requires the nervous system to solve a complex biomechanical control problem, but this process is mostly veiled from ones conscious awareness. Simultaneously, we also have conscious experience of controlling our movements--our sense of agency (SoA). Whether SoA corresponds to those neural representations that implement actual neuromuscular control is an open question with ethical, medical, and legal implications. If SoA is the conscious experience of control, this predicts that SoA can be decoded from the same brain structures that implement the so-called "inverse dynamics" computations for planning movement. We correlated human (male and female) fMRI measurements during hand movements with the internal representations of a deep neural network (DNN) performing the same hand control task in a biomechanical simulation- revealing detailed cortical encodings of sensorimotor states, idiosyncratic to each subject. We then manipulated SoA by usurping control of participants muscles via electrical stimulation, and found that the same voxels which were best explained by modeled inverse dynamics representations-- which, strikingly, were located in canonically visual areas--also predicted SoA. Importantly, model-brain correspondences and robust SoA decoding could both be achieved within single subjects, enabling relationships between motor representations and awareness to be studied at the level of the individual. Significance StatementThe inherent complexity of biomechanical control problems is belied by the seeming simplicity of directing movements in our subjective experience. This aspect of our experience suggests we have limited conscious access to the neural and mental representations involved in controlling the body - but of which of the many possible representations are we, in fact, aware? Understanding which motor control representations percolate into awareness has taken on increasing importance as emerging neural interface technologies push the boundaries of human autonomy. In our study, we leverage machine learning models that have learned to control simulated bodies to localize biomechanical control representations in the brain. Then, we show that these brain regions predict perceived agency over the musculature during functional electrical stimulation.

neuroscience↗

bioRxiv2023

Illusion of agency over involuntary muscle movements reveals temporal dynamics of neural activity underlying self-agency judgments

Our muscles are the primary means through which we affect the external world, and the sense of agency (SoA) over the action through those muscles is fundamental to our self-awareness. However, SoA research to date has focused almost exclusively on agency over action outcomes rather than over the musculature itself, as it was believed that SoA over the musculature could not be manipulated directly. Drawing on methods from human-computer interaction and adaptive experimentation, we use human-in-the-loop Bayesian optimization to tune the timing of electrical muscle stimulation so as to robustly elicit a sense of agency over electrically-actuated muscle movements in male and female human subjects. We use time-resolved decoding of subjects EEG to estimate the time course of neural activity which predicts reported agency on a trial-by-trial basis. Like paradigms which assess SoA over action consequences, we found that the late (post-conscious) neural activity predicts SoA. Unlike typical paradigms, however, we also find patterns of early (sensorimotor) activity with distinct temporal dynamics predicts agency over muscle movements, suggesting that the "neural correlates of agency" may depend on the level of abstraction (i.e., direct sensorimotor feedback vs. downstream consequences) most relevant to a given agency judgement. Moreover, fractal analysis of the EEG suggests that SoA-contingent dynamics of neural activity may modulate the sensitivity of the motor system to external input. Significance StatementThe sense of agency - the feeling of "I did that" - when directing ones own musculature is a core feature of human experience. We show that we can robustly manipulate the sense of agency over electrically actuated muscle movements, and we investigate the time course of neural activity that predicts the sense of agency over these actuated movements. We find evidence of two distinct neural processes - a transient sequence of patterns that begins in the early sensorineural response to muscle stimulation and a later, sustained signature of agency. These results shed light on the neural mechanisms by which we experience our movements as volitional.

neuroscience↗