Biology subjects

Gosling, J.

Publications and source records attributed to Gosling, J..

3 recordsLinked to original sources

bioRxiv2026

A prioritization strategy for protecting Conservation Imperatives Sites

To prevent species extinctions, targeted action must focus on areas of threatened biodiversity facing intense human pressures. This objective is even more important in the run-up to 2030, the target date to conserve 30% of lands and waters globally. Conservation Imperatives (unprotected terrestrial sites that harbour rare, range-restricted, and threatened species) are critical to preventing imminent species losses. To prioritize among the 16,825 Conservation Imperatives Sites spanning 1.64 million km2, we ranked each site using a prioritization framework based on four criteria: number of threatened species per site; irreplaceability of the site; the proportion of an ecoregions remaining habitat contained in the site; and conversion pressure. Our approach prioritizes 1,667 sites representing 501,426 km2, or 0.37% of Earths terrestrial surface, most in need of urgent protection, with 87.34% of these sites occurring in 20 countries and in 250 ecoregions. This prioritization directly addresses the concern that protected areas must be targeted to protect endangered species, habitats and populations: 33.46% of the prioritized Conservation Imperatives Sites scored higher in irreplaceability than 90% of existing protected areas. Additionally, 51.53% are within 2.5 km2 of an existing protected area, making extending protection or restoring connectivity more feasible. Targeting conservation actions, especially in this small set of countries and ecoregions identified here, would contribute "high quality" areas for biodiversity as part of reaching the 30% coverage target by 2030.

ecology↗

bioRxiv2026

Discovery and characterization of small molecule inhibitors of CBL-B that act as intramolecular glue to enhance T-cell anti-tumor activity

CBL-B is a RING-type E3 ubiquitin ligase that acts as a critical negative regulator of T-cell activation. It promotes T-cell anergy and suppresses immune responses through ubiquitin-mediated control of signaling proteins at the immunological synapse. T cells deficient in CBL-B activity lose their dependence on CD28 co-stimulation, exhibit heightened activation and increased cytokine production, and fail to re-establish anergy. In addition, mice deficient in CBL-B activity reject tumors. Together, this cellular mechanism and in vivo phenotype suggest inhibition of CBL-B may be a viable immuno-oncology therapeutic strategy. Here, we report the rational design and execution of a high-throughput screen (HTS) to identify small molecule inhibitors of CBL-B. This campaign led to the discovery of a scaffold that inhibits CBL-B E3 ligase activity with micromolar potency. Structural characterization revealed an intramolecular glue mechanism, in which the compound stabilizes the closed state of CBL-B, preventing phosphorylation of a tyrosine residue that is critical for activation and E2 binding. Iterative structure-activity optimization yielded compounds with nanomolar activity that enhanced T-cell activation and cytokine secretion in primary human T cells and suppressed tumor growth in a syngeneic colorectal mouse model. Together, these studies validate the biological rationale for pharmacological CBL-B inhibition and enabled the de novo discovery of intramolecular CBL-B glue inhibitors. This work culminated in the identification of NX-1607, a first-in-class oral CBL-B inhibitor now in clinical development for cancer immunotherapy.

immunology↗

bioRxiv2023

Wireless Electrical-Molecular Quantum Signalling for Cancer Cell Induced Death

Quantum biological tunnelling for electron transfer (QBET) is involved in controlling cellular behaviour. Control of electrical-molecular communication could revolutionise the development of disruptive technologies for understanding and modulating electrically induced molecular signalling. Current communication technology is not appropriate for interfacing with cells at a spatial/temporal level equivalent to the native biological signalling. This limits our ability to tune cell function by controlling single molecular events. Here, we merge wireless nano-electrochemical tools with cancer cells. Gold-bipolar nanoelectrodes functionalised with redox active species were developed as electric field stimulated bio-actuators, that we term bio-nanoantennae. We show that a remote electrical input regulates electron transport between the redox molecules on the bio-nanoantennae in a selective manner. The wireless modulation of electron transport results in QBET triggering apoptosis in patient-derived cancer cells, representing electrical-induced induced controlled molecular signalling. Transcriptomics data highlight the electric field-induced nanoantenna targets the cancer cells in a unique manner. The insight concerning action and functional nanomaterials opens a plethora of applications in healthcare. This approach may lead to new quantum-based medical diagnostics and treatments, as well as a fundamental understanding of biological physics.

biophysics↗