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Research into the biological role of the Ca 2+ -releasing second messenger NAADP (nicotinic acid adenine dinucleotide phosphate) has been hampered by a lack of chemical probes. To find new chemical probes for exploring NAADP signaling, we turned to virtual screening, which can evaluate millions of molecules rapidly and inexpensively. We used NAADP as the query ligand to screen the chemical library ZINC for compounds with similar three-dimensional shape and electrostatic properties. We tested the top-ranking hits in a sea urchin egg bioassay and found that one hit, Ned-19, blocks NAADP signaling at nanomolar concentrations. In intact cells, Ned-19 blocked NAADP signaling and fluorescently labeled NAADP receptors. Moreover, we show the utility of Ned-19 as a chemical probe by using it to demonstrate that NAADP is a key causal link between glucose sensing and Ca 2+ increases in mouse pancreatic beta cells.

[...]many cases go unrecognised or are diagnosed late.

Lithium is the most effective mood stabilizer for the treatment of bipolar disorder, but it is toxic at only twice the therapeutic dosage and has many undesirable side effects. It is likely that a small molecule could be found with lithium-like efficacy but without toxicity through target-based drug discovery; however, therapeutic target of lithium remains equivocal. Inositol monophosphatase is a possible target but no bioavailable inhibitors exist. Here we report that the antioxidant ebselen inhibits inositol monophosphatase and induces lithium-like effects on mouse behaviour, which are reversed with inositol, consistent with a mechanism involving inhibition of inositol recycling. Ebselen is part of the National Institutes of Health Clinical Collection, a chemical library of bioavailable drugs considered clinically safe but without proven use. Therefore, ebselen represents a lithium mimetic with the potential both to validate inositol monophosphatase inhibition as a treatment for bipolar disorder and to serve as a treatment itself. Lithium is commonly used to treat bipolar disorder, but it exerts side effects at doses close to the therapeutic range. Singh and colleagues screen a collection of clinical compounds and find that ebselen induces lithium-like effects on mouse models of bipolar disorder by inhibiting inositol monophosphatase.

Bipolar disorder is a chronic neuropsychiatric condition associated with mood instability, where patients present significant sleep and circadian rhythm abnormalities. Currently, the pathophysiology of bipolar disorder remains elusive, but treatment with lithium continues as the benchmark pharmacotherapy, functioning as a potent mood stabilizer in most, but not all patients. Lithium is well documented to induce period lengthening and amplitude enhancement of the circadian clock. Based on this, we sought to investigate whether lithium differentially impacts circadian rhythms in bipolar patient cell lines and crucially if lithium’s effect on the clock is fundamental to its mood-stabilizing effects. We analyzed the circadian rhythms of bipolar patient-derived fibroblasts (n = 39) and their responses to lithium and three further chronomodulators. Here we show, relative to controls (n = 23), patients exhibited a wider distribution of circadian period (p < 0.05), and that patients with longer periods were medicated with a wider range of drugs, suggesting lower effectiveness of lithium. In agreement, patient fibroblasts with longer periods displayed muted circadian responses to lithium as well as to other chronomodulators that phenocopy lithium. These results show that lithium differentially impacts the circadian system in a patient-specific manner and its effect is dependent on the patient’s circadian phenotype. We also found that lithium-induced behavioral changes in mice were phenocopied by modulation of the circadian system with drugs that target the clock, and that a dysfunctional clock ablates this response. Thus, chronomodulatory compounds offer a promising route to a novel treatment paradigm. These findings, upon larger-scale validation, could facilitate the implementation of a personalized approach for mood stabilization.

The death of a patient given an overdose of diamorphine by an out of hours doctor has raised questions about out of hours services. Paul Cosford and Justyn Thomas argue that wide ranging changes are required

We present observations of SN 2021csp, the second example of a newly identified type of supernova (SN) hallmarked by strong, narrow, P Cygni carbon features at early times (Type Icn). The SN appears as a fast and luminous blue transient at early times, reaching a peak absolute magnitude of −20 within 3 days due to strong interaction between fast SN ejecta (v ≈ 30,000 km s−1) and a massive, dense, fast-moving C/O wind shed by the WC-like progenitor months before explosion. The narrow-line features disappear from the spectrum 10–20 days after explosion and are replaced by a blue continuum dominated by broad Fe features, reminiscent of Type Ibn and IIn supernovae and indicative of weaker interaction with more extended H/He-poor material. The transient then abruptly fades ∼60 days post-explosion when interaction ceases. Deep limits at later phases suggest minimal heavy-element nucleosynthesis, a low ejecta mass, or both, and imply an origin distinct from that of classical Type Ic SNe. We place SN 2021csp in context with other fast-evolving interacting transients, and discuss various progenitor scenarios: an ultrastripped progenitor star, a pulsational pair-instability eruption, or a jet-driven fallback SN from a Wolf–Rayet (W-R) star. The fallback scenario would naturally explain the similarity between these events and radio-loud fast transients, and suggests a picture in which most stars massive enough to undergo a W-R phase collapse directly to black holes at the end of their lives.

Accretion plays a central role in the physics that governs the evolution and dispersal of protoplanetary disks. The primary goal of this paper is to analyze the stability over time of the mass accretion rate onto TW Hya, the nearest accreting solar-mass young star. We measure veiling across the optical spectrum in 1169 archival high-resolution spectra of TW Hya, obtained from 1998–2022. The veiling is then converted to accretion rate using 26 flux-calibrated spectra that cover the Balmer jump. The accretion rate measured from the excess continuum has an average of 2.51 × 10−9 M ⊙ yr−1 and a Gaussian distribution with an FWHM of 0.22 dex. This accretion rate may be underestimated by a factor of up to 1.5 because of uncertainty in the bolometric correction and another factor of 1.7 because of excluding the fraction of accretion energy that escapes in lines, especially Lyα. The accretion luminosities are well correlated with He line luminosities but poorly correlated with Hα and Hβ luminosity. The accretion rate is always flickering over hours but on longer timescales has been stable over 25 years. This level of variability is consistent with previous measurements for most, but not all, accreting young stars.

While CD19- and BCMA-directed immunotherapies have improved outcomes for B-lymphoid and plasma cell malignancies, frequent relapses with antigen loss/downregulation highlight the need for new targets. Here, using transcriptomic datasets and newly-developed monoclonal antibodies, we show that , long considered a pseudogene in humans, encodes a stable protein in 80% of individuals of African descent carrying the ancestral haplotype. Like CD19, P2RX5 displays B-cell lineage-restricted expression in normal tissues. Unlike CD19, P2RX5 is expressed not only in B-cell neoplasms, but also in T-cell leukemia (T-ALL) and multiple myeloma (MM). We developed P2RX5-directed bispecific T-cell engagers and CAR T cells, which killed T-ALL cells with no evidence of T-cell fratricide. These agents were non-inferior to FDA-approved CD19- and BCMA-directed immunotherapeutics in cell culture and xenograft models of Burkitt lymphoma and MM, while maintaining potency against CD19- and BCMA-negative variants. Hence, P2RX5 is a unique multi-lineage target for frontline or salvage immunotherapy.

G protein-coupled receptors (GPCRs) play key roles in physiology and are central targets for drug discovery and development, yet the design of protein agonists and antagonists has been challenging as GPCRs are integral membrane proteins and conformationally dynamic. Here we describe computational design methods and a high throughput \"receptor diversion\" microscopy-based screen for generating GPCR binding miniproteins with high affinity, potency and selectivity, and the use of these methods to generate MRGPRX1 agonists and CXCR4, GLP1R, GIPR, GCGR and CGRPR antagonists. Cryo-electron microscopy data reveals atomic-level agreement between designed and experimentally determined structures for CGRPR-bound antagonists and MRGPRX1-bound agonists, confirming precise conformational control of receptor function. Our design and screening approach opens new frontiers in GPCR drug discovery and development.