BackgroundBrepocitinib is a first-in-class, oral, selective TYK2–JAK1 inhibitor that blocks cytokine signaling, which has been implicated in dermatomyositis.MethodsIn this phase 3, double-blind, randomized, placebo-controlled trial, adults with dermatomyositis were assigned in a 1:1:1 ratio to receive once-daily oral brepocitinib at a dose of 30 mg, brepocitinib at a dose of 15 mg, or placebo for 52 weeks. Standard therapies were continued, and glucocorticoids were tapered. The primary end point was the Total Improvement Score, a validated composite myositis index (with scores ranging from 0 to 100 and higher scores indicating greater improvement) at week 52. Key secondary end points, including skin disease activity, glucocorticoid tapering, and physical function, were tested in a multiplicity-controlled sequence.ResultsA total of 241 patients underwent randomization: 81 to receive brepocitinib 30 mg, 81 to receive brepocitinib 15 mg, and 79 to receive placebo. At week 52, the mean Total Improvement Score was 46.5, 37.5, and 31.2, respectively (difference with brepocitinib 30 mg vs. placebo, 15.3; 95% confidence interval [CI], 6.7 to 24.0; P<0.001; difference with brepocitinib 15 mg vs. placebo, 6.3; 95% CI, −2.4 to 14.9). Brepocitinib 30 mg was superior to placebo across all nine key secondary end points, including skin disease activity, systemic glucocorticoid tapering, and functional disability, with improvements observed as early as week 4. Serious infections were more frequent in the brepocitinib 30-mg group than in the placebo group (10% vs. 1%). No deaths occurred during the trial.ConclusionsIn adults with dermatomyositis that was resistant to previous therapy, the use of brepocitinib at a dose of 30 mg (but not at a dose of 15 mg) resulted in significant benefits with respect to a composite myositis index, skin disease severity, glucocorticoid tapering, and functional disability. (Funded by Priovant Therapeutics; ClinicalTrials.gov number, NCT05437263.)

Cytokines dimerize two receptor chains to activate Janus kinases and STAT transcription factors that regulate immune cells but have therapeutic liabilities. We engineered “Trikines” to compel cis formation of three-chain cytokine receptor complexes at the cell surface that induce bespoke STAT transcriptional signaling programs optimized for therapeutic efficacy. Designed Trikines co-activated pSTAT5 and pSTAT3 signatures distinct from any natural cytokines, by assembling trimeric combinations of Interleukin-2 (IL-2), Interleukin-10 (IL-10), and Interleukin-21 (IL-21) receptors. An IL-2-based-Trikine restrained terminal differentiation of T cells, promoted stemness, and enhanced durability of tumor control without toxicity. Unexpectedly, an IL-10-based Trikine induced immune infiltration into poorly immunogenic tumors, showing striking efficacy in small cell lung cancer and pancreatic cancer models. Trikines obviate the need for cell engineering to customize STAT signatures for immunotherapy.

Objective.The complexity of neural data changes as the brain processes information during events. Universal lossless compression algorithms, which are broadly applicable and grounded in information theory, identify and exploit redundancies in data in order to compress it to essentially-optimal sizes regardless of underlying statistics. These algorithms may be used to efficiently estimate a signal's Shannon entropy rate, a biologically relevant measure of the complexity of a signal. It is therefore natural to explore their effectiveness in the analysis of spiking neural data.Approach.This work uses the inverse compression ratio (ICR) to analyze recordings (Utah arrays) taken from motor cortex of animals performing reaching tasks three days before and three days after administering electrolytic lesions (SubjectU: 4 lesions,H: 3). We calculate ICR with temporally-independent lossless compression (gzip) and temporally-dependent lossy compression (H.264, MPEG-2). Compression-based ICR was compared to single-neuron measures used to understand spiking data (average firing rates and Fano factor), as well as common dimensionality reduction techniques (principal component analysis and factor analysis).Main Results.ICR is able to significantly (Mann-Whitney U test,p<0.01) detect lesions with higher accuracy than single-neuron metrics, but not dimensionality reduction (ICR methods: 85.7%, single-neuron methods: 78.6%, dimensionality reduction: 100%). Additionally, statistical results on the same data show that ICR metrics remain more stable than single-neuron methods after lesion. The bitrate parameter of lossy compression algorithms is swept to better understand the effect of information rates and 'optimal' compression on lesion detection performance. Simulated data shows that ICR is computationally advantageous.Significance.These results suggest that compression algorithms may be a useful tool to detect and better understand perturbations to the underlying structure of neural data. Information-theoretic analyses may complement techniques like dimensionality reduction and firing rate tuning as a convenient and useful tool to characterize neural data.

Existing positively tuned ASAP-family voltage indicators such as ASAP4e exhibit superior photostability compared to the negatively tuned ASAP3 and ASAP5, but signal-to-noise ratios for spike detection remained similar to ASAP3. To improve spike detection by positively tuned ASAP indicators, we performed multiple rounds of structure-guided saturation mutagenesis of an ASAP4e predecessor while screening directly for faster responses. One variant, ASAP6c, demonstrated ∼100% increases in fluorescence in response to single action potentials in both one-photon and two-photon imaging in vivo, achieving a 3-fold improvement in signal-to-noise ratios over ASAP4e.

Utilizing aggregated, US electronic medical record data at the state level, we found that increased mpox incidence was associated with increased bacterial sexually transmitted infection (STI) rates in men for the same month and higher STI rates after the second mpox vaccination. Those seeking vaccination or testing for mpox should be screened for other STIs.

Rising global demand for food quantity and quality requires precision strategies on fine-tuning trait-related gene expression targeting crop improvement. Dynamic covalent modifications on mRNA add a reversible layer of post-transcriptional regulation on gene expression, yet their trait-level logic in crops remains fragmented. Recent studies connect epitranscriptomic enzymes and readers to yield components, quality traits and stress resilience. Here, we summarize regulatory mechanisms of covalent modifications emerging from 13 functionally validated crop cases across cereals, fiber and horticultural species, focusing on how m6A, m5C, m1A, ac4C, and Ψ reprogramme mRNA molecular functions, such as stability, translation, and RNA compartmentalization. We further discuss the sufficiency and insufficiency of applying current Arabidopsis-based mechanisms to crop improvements, where whole-genome duplication and paralog specialization diversify writer-eraser-reader repertoires and enable species-specific control circuits. Finally, we highlight future directions to transform descriptive maps into predictive breeding tools, emphasizing the need for quantitative, base-resolution profiling with stoichiometric accuracy and the development of programmable, site-specific perturbation systems that can test causal relationships in defined tissues and developmental stages. These advances position epitranscriptomic reprogramming as a complementary route to precision engineering of crop yield and quality.