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Supervised learning in DNA neural networks
Evolution of short trichomes and long hairs on Nigella petals through co-option of bHLH and non-MIXTA MYB genes
Author Correction: Targeting ferroptosis protects against experimental (multi)organ dysfunction and death
Author Correction: Lung cancer deficient in the tumor suppressor GATA4 is sensitive to TGFBR1 inhibition
The bactericidal FabI inhibitor Debio 1453 clears antibiotic-resistant Neisseria gonorrhoeae infection in vivo
Abstract Gonorrhoea is a prevalent sexually transmitted infection caused by the bacterial pathogen Neisseria gonorrhoeae. N. gonorrhoeae has demonstrated a remarkable capacity to evolve antibiotic resistance, with emerging strains that show resistance to all standard treatment options. The development of new antibiotics for gonorrhoea, especially those with novel targets and no pre-existing resistance, is critical. One such untapped antibacterial target in N. gonorrhoeae is FabI, an enoyl-acyl carrier protein reductase enzyme that is essential for fatty acid biosynthesis in this pathogen. In the current report, structure-based drug design using novel N. gonorrhoeae FabI inhibitor co-crystals guides medicinal chemistry toward increasing potency in the sub-nanomolar range and drives the discovery of Debio 1453. Debio 1453 is optimized for activity against N. gonorrhoeae and is highly active in vitro against diverse N. gonorrhoeae isolates including those resistant to the last remaining treatment options. Additionally, the compound presents a low propensity for selection of mutants with reduced susceptibility. Debio 1453 is efficacious in vivo against N. gonorrhoeae isolates with clinically relevant multi-drug resistance phenotypes in a murine vaginal gonorrhoea infection model underscoring Debio 1453 as a promising candidate for the treatment of gonorrhoea.
Risks of AI scientists: prioritizing safeguarding over autonomy
Abstract AI scientists powered by large language models have demonstrated substantial promise in autonomously conducting experiments and facilitating scientific discoveries across various disciplines. While their capabilities are promising, these agents also introduce novel vulnerabilities that require careful consideration for safety. However, there has been limited comprehensive exploration of these vulnerabilities. This perspective examines vulnerabilities in AI scientists, shedding light on potential risks associated with their misuse, and emphasizing the need for safety measures. We begin by providing an overview of the potential risks inherent to AI scientists, taking into account user intent, the specific scientific domain, and their potential impact on the external environment. Then, we explore the underlying causes of these vulnerabilities and provide a scoping review of the limited existing works. Based on our analysis, we propose a triadic framework involving human regulation, agent alignment, and an understanding of environmental feedback (agent regulation) to mitigate these identified risks. Furthermore, we highlight the limitations and challenges associated with safeguarding AI scientists and advocate for the development of improved models, robust benchmarks, and comprehensive regulations.
Stabilizing a mammalian RNA thermometer confers neuroprotection in subarachnoid hemorrhage
Abstract Mammals tightly regulate their core body temperature, yet how cells sense and respond to small temperature changes remains incompletely understood. Here, we discover RNA G-quadruplexes (rG4s) as key thermosensors enriched near splice sites of cold-repressed exons. These thermosensing RNA structures, when stabilized, mask splice sites, reducing exon inclusion. Specifically, rG4s near splice sites of a cold-repressed poison exon in the neuroprotective RBM3 are stabilized at low temperatures, leading to exon exclusion. This enables evasion of nonsense-mediated decay, increasing RBM3 expression at cold. Importantly, stabilizing rG4 through increasing intracellular potassium with an FDA-approved potassium channel blocker, mimics the hypothermic effect on alternative splicing, thereby increasing RBM3 expression, leading to RBM3-dependent neuroprotection in a mouse model of subarachnoid hemorrhage. Our findings unveil a mechanism how mammalian RNAs directly sense temperature and potassium perturbations, integrating them into gene expression programs. This opens new avenues for treating diseases arising from splicing defects and disorders benefiting from therapeutic hypothermia, especially hemorrhagic stroke.
Structural basis for DNA break sensing by human MRE11-RAD50-NBS1 and its regulation by telomeric factor TRF2
Abstract The MRE11-RAD50-NBS1 (MRN) complex is a central, multifunctional factor in the detection, signaling and nucleolytic processing of DNA double-strand breaks (DSBs). To clarify how human MRN binds generic and telomeric DNA ends and can separate DNA end sensing from nuclease activities, we determined cryo-electron microscopy (cryo-EM) structures of human MRN bound to DNA and to DNA and the telomere protection factor TRF2. MRN senses DSBs through a tight clamp-like sensing state with closed coiled-coil domains, but auto-inhibited MRE11 nuclease. NBS1 wraps around the MRE11 dimer, with NBS1’s ATM recruitment motif sequestered by binding to the regulatory RAD50 S site, necessitating a switch in the NBS1 C helix for ATM activation. At telomeric DNA, TRF2 blocks the second S site via the iDDR motif to prevent nuclease and ATM activation. Our results provide a structural framework for DNA sensing via a gating mechanism and separation of sensing, signaling and processing activities of mammalian MRN.
Author Correction: Endocannabinoids disinhibit the ventral tegmental nucleus of Gudden to dorsal premammillary nucleus pathway to enhance escape behavior following learned threat experience
Bioinspired transfer methylation enabled by a photoactive reagent
Optimized in vivo base editing restores auditory function in a DFNA15 mouse model
5-ALA photodynamic metabolite-powered zero-waste ferroptosis amplifier for enhanced hypertrophic scar therapy
Photonic-electronic arbitrary-waveform generation using quadrature multiplexing and active optical-phase stabilization
Abstract Generation of electrical waveforms with bandwidths of 100 GHz or more is key to many applications in science and industry, comprising high-speed communications, radar, or test and measurement equipment. However, while conventional digital-to-analog converters based on electronic circuits still represent the technological mainstay for broadband waveform generation, further bandwidth scaling comes with a series of challenges related to circuit design and implementation, packaging, and system integration. In this paper, we show that photonic-electronic signal-processing techniques may overcome these limitations. We demonstrate a photonic-electronic waveform generator that exploits quadrature multiplexing in the optical domain in combination with phase-stabilized coherent down-conversion to the electrical domain. In a proof-of-concept experiment, we generate electrical multi-level data signals at symbol rates up to 200 GBd at quality levels that can already compete with best-in-class electronic systems. We believe that our concept opens an attractive path to waveforms generation at bandwidths beyond the limitations of current microelectronics, leveraging advanced photonic integration technologies that are currently being developed.