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Davies, J. L.

Publications and source records attributed to Davies, J. L..

5 recordsLinked to original sources

Minimal social context decouples affective response modalities

Emotions often occur within social interactions where affective cues are partly accessible or inferable by others. This raises questions regarding how and to which degree social context modulates subjective, physiological and behavioural affective responses, as well as their coherence, questions which remain points of tension in emotion research. To investigate this, we measured subjective affective ratings, autonomic sympathetic and parasympathetic activity, and facial behaviour while participants completed an emotion-induction task. In the social-context condition (but not control), participants believed that their video feed was accessible to a potential future interaction partner. Results show that even such "minimal social context" selectively and differentially modulated affective response modalities, characterised by both intensification of autonomic responses and dampening of overt facial and subjective affect. Multivariate dimensionality analysis further identified a cross-modal affective dimension. Notably, social context reduced participants coupling with this shared affective response structure, indicating weaker cross-modal coherence. These findings suggest that emotional responding relies on a flexible, rather than rigid, configuration of affective features, likely recruited to meet the socioemotional demands of a given context. This has important implications for understanding the structure and function of emotion, as well as typical and atypical socioemotional responding.

neuroscience↗

Parental-fetal interplay of immune genes leads to intrauterine growth restriction

Intrauterine growth restriction (IUGR) of fetuses affects 5-10% of pregnancies and is associated with perinatal morbidity, mortality and long-term health issues. Understanding genetic predisposition to IUGR is challenging, owing to extensive gene polymorphisms, linkage disequilibrium, and maternal and paternal influence. Here, we demonstrate that the inhibitory receptor, KIR2DL1, expressed on maternal uterine natural killer (uNK) cells, in interaction with the paternally-inherited HLA-C*05, an HLA-C group 2 allotype, expressed on fetal trophoblast cells, causes IUGR in a humanised mouse model. Micro-CT imaging of the uteroplacental vasculature revealed reduced uterine spiral artery diameter and increased segment length, increasing fetal blood flow resistance. Single cell RNA-Seq from the maternal-fetal interface highlighted expression programs activated by KIR2DL1-induced IUGR in several placental cell types, including degradation of extracellular matrix components, angiogenesis, and uNK cell communication, suggesting a complex response underlying IUGR. As current IUGR treatments are insufficient, our findings provide important insight for drug development.

immunology↗

An integrated platform to systematically identify causal variants and genes for polygenic human traits.

Genome-wide association studies (GWAS) have identified over 150,000 links between common genetic variants and human traits or complex diseases. Over 80% of these associations map to polymorphisms in non-coding DNA. Therefore, the challenge is to identify disease-causing variants, the genes they affect, and the cells in which these effects occur. We have developed a platform using ATAC-seq, DNaseI footprints, NG Capture-C and machine learning to address this challenge. Applying this approach to red blood cell traits identifies a significant proportion of known causative variants and their effector genes, which we show can be validated by direct in vivo modelling.

genetics↗

Using transcranial magnetic stimulation to map the cortical representation of lower-limb muscles

The aim of this study was to evaluate the extent to which transcranial magnetic stimulation (TMS) can identify discrete cortical representation of lower-limb muscles in healthy individuals. Data were obtained from 16 young healthy adults (12 women, four men; mean [SD] age 23.0 [2.6] years). Motor evoked potentials were recorded from the resting vastus medialis, rectus femoris, vastus lateralis, medial and lateral hamstring, and medial and lateral gastrocnemius muscles on the right side of the body using bipolar surface electrodes. TMS was delivered through a 110-mm double-cone coil at 63 sites over the left hemisphere. Location and size of the cortical representation and the number of discrete peaks were quantified for each muscle. Within the quadriceps muscle group there was a main effect of muscle on anterior-posterior centre of gravity (p = 0.010), but the magnitude of the difference was very small. Within the quadriceps there was a main effect of muscle on medial-lateral hotspot (p = 0.027) and map volume (p = 0.047), but no post-hoc tests were significant. The topography of each lower-limb muscle was complex, displaying multiple peaks that were present across the stimulation grid, and variable across individuals. The results of this study indicate that TMS delivered with a 110-mm double-cone coil could not reliably identify discrete cortical representations of resting lower-limb muscles when responses were measured using bipolar surface electromyography. The characteristics of the cortical representation of lower-limb muscles reported here provide a basis against which to evaluate cortical reorganisation in clinical populations.

neuroscience↗

Small molecule inhibitors of a human recombination-associated ATPase, RAD54

Homologous recombination (HR) is a principal support pathway for DNA replication and for recovery from DNA breaks and interstrand crosslinks, making it a rational target for inhibition in cancer therapy. The ATPase RAD54 functions in molecular events that promote DNA sequence-preservation during HR-mediated damage repair, including homology search, DNA strand exchange, and transition to DNA repair synthesis within a displacement loop intermediate. We developed a high-throughput biochemical screen to identify small-molecule inhibitors of human RAD54, using a phosphate detection assay to monitor RAD54 ATPase activity in the presence of double-stranded DNA (dsDNA). After filtering potential DNA intercalators and frequent hitters, we identified two chemotypes that reproducibly inhibited RAD54 ATPase in vitro. We evaluated these chemotypes for inhibition of RAD54-dsDNA binding and cancer cell survival. A halogenated carbazole/dihydroacridine scaffold inhibited a panel of SWI2/SNF2-related ATPases but not VCP/p97, an unrelated ATPase. Small molecules that interfere with key steps in HR-- such as inhibitors of RAD54--may expose DNA repair-dependent vulnerabilities in cancer cells.

biochemistry↗