Brain-computer interfaces (BCIs) have the potential to restore communication for people who have lost the ability to speak owing to a neurological disease or injury. BCIs have been used to translate the neural correlates of attempted speech into text1-3. However, text communication fails to capture the nuances of human speech, such as prosody and immediately hearing one's own voice. Here we demonstrate a brain-to-voice neuroprosthesis that instantaneously synthesizes voice with closed-loop audio feedback by decoding neural activity from 256 microelectrodes implanted into the ventral precentral gyrus of a man with amyotrophic lateral sclerosis and severe dysarthria. We overcame the challenge of lacking ground-truth speech for training the neural decoder and were able to accurately synthesize his voice. Along with phonemic content, we were also able to decode paralinguistic features from intracortical activity, enabling the participant to modulate his BCI-synthesized voice in real time to change intonation and sing short melodies. These results demonstrate the feasibility of enabling people with paralysis to speak intelligibly and expressively through a BCI.

Vision enables many animals to perform spatial reasoning from remote locations1. By viewing distant landmarks, animals recall spatial memories and plan future trajectories. Although these spatial functions depend on hippocampal place cells2,3, the relationship between place cells and active visual behaviour is unknown. Here we studied a highly visual animal, the chickadee, in a behaviour that required alternating between remote visual search and spatial navigation. We leveraged the head-directed nature of avian vision to track gaze in freely moving animals. We discovered a profound link between place coding and gaze. Place cells activated not only when the chickadee was in a specific location, but also when it simply gazed at that location from a distance. Gaze coding was precisely timed by fast ballistic head movements called 'head saccades'4,5. On each saccadic cycle, the hippocampus switched between encoding a prediction of what the bird was about to see and a reaction to what it actually saw. The temporal structure of these responses was coordinated by subclasses of interneurons that fired at different phases of the saccade. We suggest that place and gaze coding are components of a unified process by which the hippocampus represents the location that is relevant to the animal in each moment. This process allows the hippocampus to implement both local and remote spatial functions.

Although cell-fate specification is generally attributed to transcriptional regulation, emerging data also indicate a role for molecules linked with intermediary metabolism. For example, α-ketoglutarate (αKG), which fuels energy production and biosynthetic pathways in the tricarboxylic acid (TCA) cycle, is also a co-factor for chromatin-modifying enzymes1-3. Nevertheless, whether TCA-cycle metabolites regulate cell fate during tissue homeostasis and regeneration remains unclear. Here we show that TCA-cycle enzymes are expressed in the intestine in a heterogeneous manner, with components of the αKG dehydrogenase complex4-6 upregulated in the absorptive lineage and downregulated in the secretory lineage. Using genetically modified mouse models and organoids, we reveal that 2-oxoglutarate dehydrogenase (OGDH), the enzymatic subunit of the αKG dehydrogenase complex, has a dual, lineage-specific role. In the absorptive lineage, OGDH is upregulated by HNF4 transcription factors to maintain the bioenergetic and biosynthetic needs of enterocytes. In the secretory lineage, OGDH is downregulated through a process that, when modelled, increases the levels of αKG and stimulates the differentiation of secretory cells. Consistent with this, in mouse models of colitis with impaired differentiation and maturation of secretory cells, inhibition of OGDH or supplementation with αKG reversed these impairments and promoted tissue healing. Hence, OGDH dependency is lineage-specific, and its regulation helps to direct cell fate, offering insights for targeted therapies in regenerative medicine.

Developing bioelectronics capable of stably tracking brain-wide, single-cell, millisecond-resolved neural activity in the developing brain is critical for advancing neuroscience and understanding neurodevelopmental disorders. During development, the three-dimensional structure of the vertebrate brain arises from a two-dimensional neural plate1,2. These large morphological changes have previously posed a challenge for implantable bioelectronics to reliably track neural activity throughout brain development3-9. Here we introduce a tissue-level-soft, submicrometre-thick mesh microelectrode array that integrates into the embryonic neural plate by leveraging the tissue's natural two-dimensional-to-three-dimensional reconfiguration. As organogenesis progresses, the mesh deforms, stretches and distributes throughout the brain, seamlessly integrating with neural tissue. Immunostaining, gene expression analysis and behavioural testing confirm no adverse effects on brain development or function. This embedded electrode array enables long-term, stable mapping of how single-neuron activity and population dynamics emerge and evolve during brain development. In axolotl models, it not only records neural electrical activity during regeneration but also modulates the process through electrical stimulation.

The James Webb Space Telescope (JWST) has revealed unexpectedly rapid galaxy assembly in the early Universe, in tension with galaxy-formation models1-3. At the low abundances of heavy elements (metals) and dust typical in early galaxies, the formation of molecular hydrogen and its connection to star formation remain poorly understood. Some models predict that stars form in predominantly atomic gas at low metallicity4,5, in contrast to molecular gas at higher metallicities6. Despite repeated searches7, cold molecular gas has not yet been observed in any galaxy below 7% solar metallicity8. Here we report the detection of rotational emission from molecular hydrogen near the only O-type star in the 3% solar metallicity galaxy Leo P (refs. 9,10) with JWST's Mid-Infrared Instrument/Medium Resolution Spectroscopy (MIRI-MRS) observing mode. These observations place a lower limit on Leo P's molecular gas content, and modelling of the photodissociation region illuminated by the O star suggests a compact (≤2.6 pc radius), approximately 104 M⊙ cloud. We also report a stringent upper limit on carbon monoxide (CO) emission from a deep search with the Atacama Large Millimeter/submillimeter Array (ALMA). Our results highlight the power of MIRI-MRS to characterize even small ultraviolet-illuminated molecular clouds in the low-metallicity regime, in which the traditional observational tracer CO is uninformative. This discovery pushes the limiting metallicity at which molecular gas is present in detectable quantities more than a factor of two lower, providing crucial empirical guidance for models of the interstellar medium in early galaxies.

Sex inequalities in cancer are well documented, but the current limited understanding is hindering advances in precision medicine and therapies1. Consideration of ethnicity, age and sex is essential for the management of cancer patients because they underlie important differences in both incidence and response to treatment2,3. Age-related hormone production, which is a consistent divergence between the sexes, is underestimated in cancers that are not recognized as being hormone dependent4-6. Here, we show that premenopausal women have increased vulnerability to cancers, and we identify the cell-cell adhesion molecule E-cadherin as a crucial component in the oestrogen response in various cancers, including melanoma. In a mouse model of melanoma, we discovered an oestrogen-sensitizing pathway connecting E-cadherin, β-catenin, oestrogen receptor-α and GRPR that promotes melanoma aggressiveness in women. Inhibiting this pathway by targeting GRPR or oestrogen receptor-α reduces metastasis in mice, indicating its therapeutic potential. Our study introduces a concept linking hormone sensitivity and tumour phenotype in which hormones affect cell phenotype and aggressiveness. We have identified an integrated pro-tumour pathway in women and propose that targeting a G-protein-coupled receptor with drugs not commonly used for cancer treatment could be more effective in treating E-cadherin-dependent cancers in women. This study emphasizes the importance of sex-specific factors in cancer management and offers hope of improving outcomes in various cancers.

Ultracold fermionic atoms in optical lattices offer pristine realizations of Hubbard models1, which are fundamental to modern condensed-matter physics2,3. Despite notable advancements4-6, the accessible temperatures in these optical lattice material analogues are still too high to address many open problems7-10. Here we demonstrate a several-fold reduction in temperature6,11-13, bringing large-scale quantum simulations of the Hubbard model into an entirely new regime. This is accomplished by transforming a low-entropy product state into strongly correlated states of interest via dynamic control of the model parameters14,15, which is extremely challenging to simulate classically10. At half-filling, the long-range antiferromagnetic order is close to saturation, leading to a temperature of T/t=0.05-0.05+0.06 based on comparisons with numerically exact simulations. Doped away from half-filling, it is exceedingly challenging to realize systematically accurate and predictive numerical simulations9. Importantly, we are able to use quantum simulation to identify a new pathway for achieving similarly low temperatures with doping. This is confirmed by comparing short-range spin correlations to state-of-the-art, but approximate, constrained-path auxiliary-field quantum Monte Carlo simulations16-18. Compared with the cuprates2,19,20, the reported temperatures correspond to a reduction from far above to below room temperature, at which physics such as the pseudogap and stripe phases may be expected3,19,21-24. Our work opens the door to quantum simulations that solve open questions in material science, develop synergies with numerical methods and theoretical studies, and lead to discoveries of new physics8,10.

Type I interferons are essential for antiviral immunity1 but must be tightly regulated2. The conserved transcriptional repressor SP140 inhibits interferon-β (Ifnb1) expression through an unknown mechanism3,4. Here we report that SP140 does not directly repress Ifnb1 transcription. Instead, SP140 negatively regulates Ifnb1 mRNA stability by directly repressing the expression of a previously uncharacterized regulator that we call RESIST (regulated stimulator of interferon via stabilization of transcript; previously annotated as annexin 2 receptor). RESIST promotes Ifnb1 mRNA stability by counteracting Ifnb1 mRNA destabilization mediated by the tristetraprolin (TTP) family of RNA-binding proteins and the CCR4-NOT deadenylase complex. SP140 localizes within punctate structures called nuclear bodies that have important roles in silencing DNA-virus gene expression in the nucleus3. Consistent with this observation, we find that SP140 inhibits replication of the gammaherpesvirus MHV68. The antiviral activity of SP140 is independent of its ability to regulate Ifnb1. Our results establish dual antiviral and interferon regulatory functions for SP140. We propose that SP140 and RESIST participate in antiviral effector-triggered immunity5,6.