Biology subjects

Johnson, T.

Publications and source records attributed to Johnson, T..

3 recordsLinked to original sources

bioRxiv2018

Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank

Osteoarthritis is the most common musculoskeletal disease and the leading cause of disability globally. Here, we perform the largest genome-wide association study for osteoarthritis to date (77,052 cases and 378,169 controls), analysing 4 phenotypes: knee osteoarthritis, hip osteoarthritis, knee and/or hip osteoarthritis, and any osteoarthritis. We discover 64 signals, 52 of them novel, more than doubling the number of established disease loci. Six signals fine map to a single variant. We identify putative effector genes by integrating eQTL colocalization, fine-mapping, human rare disease, animal model, and osteoarthritis tissue expression data. We find enrichment for genes underlying monogenic forms of bone development diseases, and for the collagen formation and extracellular matrix organisation biological pathways. Ten of the likely effector genes, including TGFB1, FGF18, CTSK and IL11 have therapeutics approved or in clinical trials, with mechanisms of action supportive of evaluation for efficacy in osteoarthritis.

genetics↗

bioRxiv2017

An Mtb-Human Protein-Protein Interaction Map Reveals that Bacterial LpqN Antagonizes CBL, a Host Ubiquitin Ligase that Regulates the Balance Between Anti-Viral and Anti-Bacterial Responses

Although macrophages are armed with potent anti-bacterial functions, Mycobacterium tuberculosis (Mtb) replicates inside these innate immune cells. Determinants of macrophage-intrinsic bacterial control, and the Mtb strategies to overcome them are poorly understood. To further study these processes, we used a systematic affinity tag purification mass spectrometry (AP-MS) approach to identify 187 Mtb-human protein-protein interactions (PPIs) involving 34 secreted Mtb proteins. This interaction map revealed two new factors involved in Mtb pathogenesis - the secreted Mtb protein, LpqN, and its binding partner, the human ubiquitin ligase CBL. We discovered that an lpqN Mtb mutant is attenuated in macrophages, but growth is restored when CBL is removed. Conversely, Cbl-/- macrophages are resistant to viral infection, indicating that CBL regulates cell-intrinsic polarization between anti-bacterial and anti-viral immunity. Collectively, these findings illustrate the utility of this Mtb-human PPI map as a resource for developing a deeper understanding of the intricate interactions between Mtb and its host.

microbiology↗

bioRxiv2017

Reward sensitivity following boredom and cognitive effort: A high-powered neurophysiological investigation

What do people feel like doing after they have exerted cognitive effort or are bored? Here, we empirically test whether people are drawn to rewards (at the neural level) following cognitive effort and when bored. This elucidates the experiences and consequences of engaging in cognitive effort, and compares it to the consequences of experiencing boredom, an affective state with predicted similar motivational consequences. Event-related potentials were recorded after participants (N=243) were randomized into one of three conditions - boredom (observing strings of numbers), cognitive effort (adding 3 to each digit of a four-digit number), or control. In the subsequent task, we focused on the feedback negativity (FN) to assess the brains immediate response to the presence or absence of reward. Phenomenologically, participants in the boredom condition reported more fatigue than those in the cognitive effort condition. Results suggest participants in the boredom condition exhibited larger FN amplitude than participants in the control condition, while the cognitive effort condition was neither different from boredom nor control. The neural and methodological implications for ego depletion research, including issues of replicability, are discussed.

neuroscience↗