Biology subjects

Parkinson, C.

Publications and source records attributed to Parkinson, C..

13 recordsLinked to original sources

bioRxiv2026

Reduced Functional Coordination within the Default Mode Network in Schizophrenia During Naturalistic Neuroimaging

BackgroundSocial dysfunction is a major source of disability in schizophrenia, yet the neural mechanisms that contribute to impaired social understanding remain poorly understood. Converging evidence points to the role of the default mode network (DMN) in integrating social information over time to construct interpretations of social behaviors. Here, we tested the hypothesis that individuals with schizophrenia show reduced stimulus-driven coordination between brain regions within the DMN during free viewing of naturalistic social stimuli. MethodsA sample of 124 adults (schizophrenia: n=63; healthy controls: n=61) viewed naturalistic video clips during fMRI. Inter-subject functional connectivity (ISFC) was computed within the two groups. Group differences were identified via permutation testing. We also explored group differences in other brain networks to examine whether effects were specific to the DMN. ResultsIndividuals with schizophrenia showed weaker stimulus-driven coupling within the DMN compared to healthy controls, specifically between areas such as the parahippocampal gyrus, precuneus, and medial prefrontal cortex. Group differences in ISFC were specific to the DMN. Furthermore, no between-group differences emerged for within-participant functional connectivity in the DMN, suggesting that the observed effects reflect reduced stimulus-driven coordination among DMN regions when processing social stimuli rather than a more general decline in DMN connectivity. ConclusionsSchizophrenia is characterized by impaired coordination within the DMN as it dynamically integrates social information over time, which could contribute to difficulties in constructing coherent interpretations of real-world social situations. These findings suggest that disrupted stimulus-driven network coordination might underlie social cognitive impairments in schizophrenia, highlighting the value of naturalistic paradigms for revealing network-level dysfunction under conditions that closely approximate real-world experience.

neuroscience↗

bioRxiv2026

A dose-dependent switch in translation capacity controls the transcription factor response to H2O2 stress

Hydrogen Peroxide (H2O2) stress activates transcription factors (TFs) in a dose-dependent manner, with distinct TFs activated in response to low versus high H2O2. Here, we show that high H2O2 imposes a translational constraint that prevents accumulation of TFs requiring de novo protein synthesis. Under low H2O2 conditions, TFs including p53, NRF2, and ATF4, accumulate and drive stress-responsive gene expression. In contrast, high H2O2 induces coordinated inhibition of translation initiation and elongation through activation of the integrated stress response (ISR), suppression of mTORC1 signaling, and activation of eEF2K, thereby blocking accumulation of these TFs. Inhibition of translation and repression of p53, NRF2, and ATF4 coincides with nuclear shuttling of pre-existing TFs, including FOXO1, NFAT1, and NF-{kappa}B. We propose that shuttling TFs provide a backup mechanism to respond to severe oxidative stress while translation is inhibited. Together, these findings identify translational control as a central switch governing transcription factor response to H2O2 stress.

molecular biology↗

bioRxiv2025

Getting to Know You: Neural Representations of Other People Grow More Perceiver-Specific Over Time

Mental representations of others are central to social behavior, yet little is known about how these representations evolve over significant periods of time as people get to know one another. In this longitudinal functional magnetic resonance imaging study, we tracked how neural representations of familiar peers changed over the course of a school year among two cohorts of first-year high school students (N = 150) embedded in newly formed social networks. We assessed the extent to which individuals neural representations of their classmates converged with group-level norms--capturing the balance between information that is idiosyncratic to each perceiver and that which is shared across perceivers--and how this changed over time. We identified brain regions where neural representations of familiar peers were well aligned across perceivers, including several areas implicated in person perception, social cognition, and visual processing. Across both cohorts of participants, neural representations in the hippocampus and lateral prefrontal cortex began as highly aligned across participants, then grew more idiosyncratic to each perceiver over time. Similar effects were observed in the ventral medial prefrontal cortex, but only in one cohort of participants. Regions often linked to social cognition (temporoparietal junction, superior temporal sulcus) evinced strong encoding for group normative information at both timepoints. Taken together, these findings suggest that neural representations of familiar others may initially be predominantly driven by information that is consistent across perceivers (e.g., physical appearance, face-based evaluations, and trait impressions), then become more unique over time as each perceiver gains their own experiences with and impressions of these individuals. Significance StatementUnderstanding how humans form mental representations of others is fundamental to the study of social behavior. Yet we know little about how these representations evolve as people get to know each other over time. Using brain imaging in a real-world social network of first-year high school students, we tracked how participants neural representations of their classmates changed over the course of a year. While some brain regions encoded stable, shared representations of peers, others showed increasingly individualized patterns. These findings shed light on how real-world social experiences shape representations of familiar others and delineate how the brain balances both personal experience and shared social information. This work informs theories of social cognition by showing how mental representations evolve over time.

neuroscience↗

bioRxiv2024

Social Decision Preferences for Close Others are Embedded in Neural and Linguistic Representations

Humans frequently make decisions that impact close others. Prior research has shown that people have stable preferences regarding such decisions and maintain rich, nuanced mental representations of their close social partners. Yet, if and how such mental representations shape social decisions preferences remains to be seen. Using a combination of functional magnetic resonance imaging (fMRI) and natural language processing (NLP), this study investigated how neural and linguistic representations of close others relate to social decision-making. After nominating a parent and friend, male and female participants (N = 63) rated their characteristics and made hypothetical social decisions while undergoing fMRI. Neural representations of parents and friends, relative to the self, were linked to social decision preferences. Specifically, greater neural similarity between self and parent in the temporoparietal junction (TPJ) and nucleus accumbens (NAcc) was associated with a preference for parents, while greater self-friend similarity in the medial prefrontal cortex (mPFC) was associated with friend-preference. Additionally, linguistic analysis of written descriptions of close others from a separate sample of males and females (N = 1,641) revealed that social decision preferences could be reliably predicted from semantic features of the text. High correspondence between neural and linguistic data in the imaging sample further strengthened the association with social decision preferences. These findings help elucidate the neural and linguistic underpinnings of social decision-making, emphasizing the critical role of mental representations in guiding choices involving familiar others. Significance StatementThis study provides novel insights into how mental representations of close others relate to social decision-making. By combining brain imaging and natural language processing, we show that both neural and linguistic representations of familiar individuals (parents and friends), can predict social preferences. We found that neural representations of these close others are linked to the choices people make about these individuals. Additionally, the way people describe their close others in writing are reliably associated with their decision preferences. Our approach, integrating neuroscience and language analysis, significantly advances our understanding of the cognitive mechanisms behind social decision-making, posing implications for fields ranging from psychology to artificial intelligence. These findings highlight the complexity of human relationships and their impact on everyday decisions.

neuroscience↗

bioRxiv2023

Gut microbiome remains stable following COVID-19 vaccination in healthy and immuno-compromised individuals

The bidirectional interaction between the immune system and the gut microbiota is a key contributor to various host physiological functions. Immune-associated diseases such as cancer and autoimmunity, as well as the efficacy of immunomodulatory therapies, have been linked to microbiome variation. While COVID-19 infection has been shown to cause microbial dysbiosis, it remains understudied whether the inflammatory response associated with vaccination also impacts the microbiota. Here, we investigate the temporal impact of COVID-19 vaccination on the gut microbiome in healthy and immuno-compromised individuals; the latter included patients with primary immunodeficiency and cancer patients on immunomodulating therapies. We find that the gut microbiome remained remarkably stable post-vaccination irrespective of diverse immune status, vaccine response, and microbial composition spanned by the cohort. The stability is evident at all evaluated levels including diversity, phylum, species, and functional capacity. Our results indicate the resilience of the gut microbiome to host immune changes triggered by COVID-19 vaccination and suggest minimal, if any, impact on microbiome-mediated processes. These findings encourage vaccine acceptance, particularly when contrasted with the significant microbiome shifts observed during COVID-19 infection.

microbiology↗

bioRxiv2021

Mechanistic Insights Revealed by YbtPQ in the Occluded State

Recently, several ATP-binding cassette (ABC) importers have been found to adopt the typical fold of type IV ABC exporters. Presumably, these importers would function under the transport scheme of "alternating access" like those exporters: cycling through conformations of inward-open, occluded, and outward-open. Understanding how the exporter-like importers move substrates in the opposite direction requires structural studies in all the major conformations. To shed light on that, here we report the structure of yersiniabactin importer YbtPQ from uropathogenic Escherichia coli in the occluded conformation trapped by ADP-vanadate (ADP.Vi) at 3.1[A] resolution determined by cryo electron microscopy. The structure shows unusual local rearrangements in multiple helices and loops in its transmembrane domains (TMDs). In addition, the dimerization of nucleotide-binding domains (NBDs) promoted by the vanadate trapping is highlighted by the "screwdriver" action happening at one of the two hinge points. These structural observations are rare and thus provide valuable information to understand the structural plasticity of the exporter-like ABC importers.

biochemistry↗

bioRxiv2020

How does the brain navigate knowledge of social relations? Overlapping but distinct mechanisms for attentional shifts in space and social knowledge

How does the human brain support reasoning about social relations (e.g., social status, friendships)? Converging theories suggest that navigating knowledge of social relations may co-opt neural circuitry with evolutionarily older functions (e.g., shifting attention in space). Here, we analyzed multivoxel response patterns of fMRI data to examine the neural mechanisms for shifting attention in knowledge of a social hierarchy. The "directions" in which participants mentally navigated social knowledge were encoded in multivoxel patterns in superior parietal cortex, which also encoded directions of attentional shifts in space. Exploratory analyses implicated additional regions of posterior parietal and occipital cortex in encoding analogous mental operations in space and social knowledge. However, cross-domain analyses suggested that attentional shifts in space and social knowledge may be encoded in functionally independent response patterns. These results elucidate the neural basis for navigating abstract knowledge of social relations, and its connection to more basic mental operations.

neuroscience↗

bioRxiv2020

Tumour gene expression signature in primary melanoma predicts long-term outcomes: A prospective multicentre study

PurposePredicting outcomes after resection of primary melanoma remains crude, primarily based on tumour thickness. We explored gene expression signatures for their ability to better predict outcomes. MethodsDifferential expression analysis of 194 primary melanomas resected from patients who either developed distant metastasis (n=89) or did not (n=105) was performed. We identified 121 metastasis-associated genes that were included in our prognostic signature, "Cam_121". Several machine learning classification models were trained using nested leave- one-out cross validation (LOOCV) to test the signatures capacity to predict metastases, as well as regression models to predict survival. The prognostic accuracy was externally validated in two independent datasets. ResultsCam_121 performed significantly better in predicting distant metastases than any of the models trained with the clinical covariates alone (pAccuracy=4.92x10-3), as well as those trained with two published prognostic signatures. Cam_121 expression score was strongly associated with progression-free survival (HR=1.7, p=3.44x10-6), overall survival (HR=1.73, p=7.71x10-6) and melanoma-specific survival (HR=1.59, p=0.02). Cam_121 expression score also negatively correlated with measures of immune cell infiltration ({rho}=-0.73, p<2.2x10-16), with a higher score representing reduced tumour lymphocytic infiltration and a higher absolute 5-year risk of death in stage II melanoma. ConclusionsThe Cam_121 primary melanoma gene expression signature outperformed currently available alternatives in predicting the risk of distant recurrence. The signature confirmed (using unbiased approaches) the central prognostic importance of immune cell infiltration in long-term patient outcomes and could be used to identify stage II melanoma patients at highest risk of metastases and poor survival who might benefit most from adjuvant therapies. Translational relevancePredicting outcomes after resection of primary melanoma is currently based on traditional histopathological staging, however survival outcomes within these disease stages varies markedly. Since adjuvant systemic therapies are now being used routinely, accurate prognostic information is needed to better risk stratify patients and avoid unnecessary use of high cost, potentially harmful drugs, as well as to inform future adjuvant strategies. The Cam_121 gene expression signature appears to have this capability and warrants evaluation in prospective clinical trials.

bioinformatics↗

bioRxiv2020

Hotspot KRAS mutations in brain metastases at the first metastatic recurrence of cutaneous melanoma

IMPORTANCEBrain metastases occur in 60% of patients with advanced melanoma and are a major cause of melanoma-related mortality and morbidity. Although our understanding of the molecular alterations associated with melanoma progression is improving, there are currently no validated biomarkers which might help identify those patients at highest risk of developing brain metastases. OBJECTIVETo examine the somatic mutational and copy-number landscape of brain metastases that develop as the isolated first visceral site of recurrence - "early brain-metastasis" compared to extracranial melanoma metastases. DESIGN, SETTING AND PARTICIPANTSWhole-exome sequencing of 50 tumors from patients undergoing surgical resection of one or more brain metastasis occurring as the first site of visceral relapse were identified from prospectively maintained databases in Sydney, Wellington, New York and Cambridge. Whole exome sequencing analyses allowed mutational profiles to be compared to cutaneous melanomas in The Cancer Genome Atlas (SKCM-TCGA; n=358) and the Memorial Sloan Kettering (SKCM-MSK-IMPACT; n=186) datasets. An external dataset comprising a further 18 patients with surgically resected early brain metastasis from two additional academic centers served as an independent validation cohort. MAIN OUTCOMES AND MEASURESTo assess the frequency of driver mutations in early brain metastasis and their influence on survival. RESULTSIn concordance with the landmark melanoma sequencing studies, we identified mutations in BRAF (21/50, 42%), NRAS (14/50, 28%) and NF1 (11/50, 22%) as the most frequently mutated melanoma driver genes. When compared to the mutational landscape of cutaneous melanomas in TCGA (SKCM-TCGA), KRAS was the most significantly enriched driver gene, with 5/50 (10%) of brain metastases harboring non-synonymous mutations, of which 4/5 (80%) were in the hotspot positions of codons 12 and 61. This was significantly higher than the corresponding frequency of KRAS-mutations within the entire SKCM-TCGA (2% (7/358), p=0.009, Fishers Exact Test) as well as the SKCM-MSK-IMPACT cohort (1.6% (3/186), p=0.016). Variants in KRAS were mutually exclusive from BRAFV600, NRAS and HRAS mutations and were associated with a significantly reduced overall survival from resection of brain metastasis (relative to KRAS-wild type brain metastases) in multivariate Cox proportional hazard models (HR 1.80, 95% CI 1.46-24.89, p=0.013). Mutations in KRAS were also clonal and concordant with extracranial disease, which suggests these mutations are present within the primary tumor CONCLUSIONS AND RELEVANCEOur analysis, the largest to date, suggests that early metastases to the brain (presenting as the first site of visceral relapse) are characterized by significant enrichment of hotspot KRAS mutations, potentially implicating constitutive RAS-driven cellular programs in neurotropic metastatic behavior in these cases. Based on these data, we suggest that screening for KRAS mutations might help identify those patients with primary melanoma at higher risk of brain metastases or poor survival, and could help inform future surveillance strategies. Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the frequency of driver mutations in early melanoma brain metastases? FindingsIn this study of 50 patients with melanoma metastasizing first to the brain, KRAS mutations were the most significantly enriched driver gene (n=5, 10% of patients) when compared to landmark cutaneous melanoma studies. The high KRAS mutation frequency was also observed in an external validation cohort of 18 patients with early brain metastases. Mutations in KRAS were mutually exclusive from mutations in the key RAS signaling genes and conferred a worse overall survival from resection of brain metastasis. MeaningHotspot KRAS mutations could help identify those patients with primary melanoma at higher risk of brain metastases that may benefit from more intensive, protracted surveillance as well as earlier use of adjuvant therapy.

genomics↗

bioRxiv2019

Multi-site clonality analyses uncovers pervasive subclonal heterogeneity and branching evolution across melanoma metastases

Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naive patient and by leveraging the analytical power of multi-sample analyses, we reveal that metastatic cells may depart the primary tumour very early in the disease course and follow a branched pattern of evolution. Truncal UV-induced mutations that often swamp downstream analyses of heterogeneity, were found to be replaced by APOBEC-associated mutations in the branches of the evolutionary tree. Multi-sample analyses from a further 7 patients confirmed that branched evolution was pervasive, representing an important mode of melanoma dissemination. Our analyses illustrate that combining cancer cell fraction estimates across multiple metastases provides higher resolution phylogenetic reconstructions relative to single sample analyses and highlights the limitations of accurately inferring inter-tumoural heterogeneity from a single biopsy.

genomics↗

bioRxiv2019

High-sensitivity monitoring of ctDNA by patient-specific sequencing panels and integration of variant reads

Circulating tumor-derived DNA (ctDNA) can be used to monitor cancer dynamics noninvasively. Patients with small tumors have few copies of ctDNA in plasma, resulting in limited sensitivity to detect low-volume or residual disease. We show that sampling limitations can be overcome and sensitivity for ctDNA detection can be improved by massively parallel sequencing when hundreds to thousands of mutations are identified by tumor genotyping. We describe the INtegration of VAriant Reads (INVAR) analysis pipeline, which combines patient-specific mutation lists with both custom error-suppression methods and signal enrichment based on biological features of ctDNA. In this framework, the sensitivity can be estimated independently for each sample based on the number of informative reads, which is the product of the number of mutations analyzed and the average depth of unique sequencing reads. We applied INVAR to deep sequencing data generated by custom hybrid-capture panels, and showed that when ~106 informative reads were obtained INVAR allowed detection of tumor-derived DNA fractions to parts per million (ppm). In serial samples from patients with advanced melanoma on treatment, we detected ctDNA when imaging confirmed tumor volume of ~1cm3. In patients with resected early-stage melanoma, ctDNA was detected in 40% of patients who later relapsed, with higher rates of detection when more informative reads were obtained. We further demonstrated that INVAR can be generalized and allows improved detection of ctDNA from whole-exome and low-depth whole-genome sequencing data.

cancer biology↗

bioRxiv2017

Spontaneous Neural Encoding of Social Network Position

Humans form complex social networks that include numerous non-reproductive bonds with non-kin. Navigating these networks presents a considerable cognitive challenge thought to have comprised a driving force in human brain evolution. Yet, little is known about how and to what extent the human brain encodes the structure of the social networks in which it is embedded. By combining social network analysis and multi-voxel pattern analysis of functional magnetic resonance imaging (fMRI) data, we show that social network information about direct relationships, bonds between third parties, and aspects of the broader network topology is accurately perceived and automatically activated upon seeing a familiar other.

neuroscience↗

bioRxiv2016

Neural Homophily: Similar Neural Responses Predict Friendship

We resemble our friends on a wide range of dimensions (e.g., age, gender), but do similarities between friends reflect deeper similarities in how we perceive, interpret, and respond to the world? To find out, we characterized the social network of a cohort of 279 students, a subset of whom participated in a functional magnetic resonance imaging (fMRI) study involving free-viewing of video stimuli. We compared fMRI response time series between corresponding brain regions across pairs of individuals and found that neural response similarity decreased with increasing distance in the social network. These effects persisted after controlling for demographic similarity. Further, it was possible to accurately classify the distance between individuals in their social network based on the similarity of their fMRI response time series across brain regions. These results suggest that we are exceptionally similar to our friends in how we perceive and react to the world around us.

neuroscience↗