Fast, high-fidelity, and quantum nondemolition (QND) qubit readout is an essential element of quantum information processing. For superconducting qubits, state-of-the-art readout is based on a dispersive cross-Kerr coupling between a qubit and its readout resonator. The resulting readout can be high fidelity and QND, but readout times are currently limited to the order of 50 nanoseconds due to the dispersive cross-Kerr of magnitude 10 megahertz. Here, we present a readout scheme that uses the quarton coupler to facilitate a large (greater than 200 megahertz) cross-Kerr between a transmon qubit and its readout resonator. Full master equation simulations of the coupled system show a 5-nanosecond readout time with greater than 99% readout fidelity and greater than 99.9% QND fidelity. The quartonic readout circuit is experimentally feasible and preserves the coherence properties of the qubit. Our work reveals a path for order of magnitude improvements of superconducting qubit readout by engineering nonlinear light-matter couplings in parameter regimes unreachable by existing designs.

We discuss prototype formation in the Hopfield network. Typically, Hebbian learning with highly correlated states leads to degraded memory performance. We show that this type of learning can lead to prototype formation, where unlearned states emerge as representatives of large correlated subsets of states, alleviating capacity woes. This process has similarities to prototype learning in human cognition. We provide a substantial literature review of prototype learning in associative memories, covering contributions from psychology, statistical physics, and computer science. We analyze prototype formation from a theoretical perspective and derive a stability condition for these states based on the number of examples of the prototype presented for learning, the noise in those examples, and the number of nonexample states presented. The stability condition is used to construct a probability of stability for a prototype state as the factors of stability change. We also note similarities to traditional network analysis, allowing us to find a prototype capacity. We corroborate these expectations of prototype formation with experiments using a simple Hopfield network with standard Hebbian learning. We extend our experiments to a Hopfield network trained on data with multiple prototypes and find the network is capable of stabilizing multiple prototypes concurrently. We measure the basins of attraction of the multiple prototype states, finding attractor strength grows with the number of examples and the agreement of examples. We link the stability and dominance of prototype states to the energy profile of these states, particularly when comparing the profile shape to target states or other spurious states.

Here, we report a magnetogenetic system, based on a single anti-ferritin nanobody-TRPV1 receptor fusion protein, which regulated neuronal activity when exposed to magnetic fields. Adeno-associated virus (AAV)-mediated delivery of a floxed nanobody-TRPV1 into the striatum of adenosine-2a receptor-Cre drivers resulted in motor freezing when placed in a magnetic resonance imaging machine or adjacent to a transcranial magnetic stimulation device. Functional imaging and fiber photometry confirmed activation in response to magnetic fields. Expression of the same construct in the striatum of wild-type mice along with a second injection of an AAVretro expressing Cre into the globus pallidus led to similar circuit specificity and motor responses. Last, a mutation was generated to gate chloride and inhibit neuronal activity. Expression of this variant in the subthalamic nucleus in PitX2-Cre parkinsonian mice resulted in reduced c-fos expression and motor rotational behavior. These data demonstrate that magnetogenetic constructs can bidirectionally regulate activity of specific neuronal circuits noninvasively in vivo using clinically available devices.

While cell fate determination and maintenance are important in establishing and preserving tissue identity and function during development, aberrant cell fate transition leads to cancer cell heterogeneity and resistance to treatment. Here, we report an unexpected role for the transcription factor p63 (Trp63/TP63) in the fate choice of the squamous versus neuroendocrine lineage in esophageal development and malignancy. Deletion of p63 results in extensive neuroendocrine differentiation in the developing mouse esophagus and esophageal progenitors derived from human embryonic stem cells. In human esophageal neuroendocrine carcinoma (eNEC) cells, p63 is transcriptionally silenced by EZH2-mediated H3K27 trimethylation (H3K27me3). Up-regulation of the major p63 isoform ΔNp63α, through either ectopic expression or EZH2 inhibition, promotes squamous transdifferentiation of eNEC cells. Together, these findings uncover p63 as a rheostat in coordinating the transition between squamous and neuroendocrine cell fates during esophageal development and tumor progression.

Human acetyl-coenzyme A (CoA) carboxylases (ACCs) catalyze the carboxylation of acetyl-CoA, which is the rate-limiting step in fatty acid synthesis. The molecular mechanism underlying the dynamic organization of ACCs is largely unknown. Here, we determined the cryo-electron microscopy (EM) structure of human ACC1 in its inactive state, which forms a unique filament structure and is in complex with acetyl-CoA. We also determined the cryo-EM structure of human ACC1 activated by dephosphorylation and citrate treatment, at a resolution of 2.55 Å. Notably, the covalently linked biotin binds to a site that is distant from the acetyl-CoA binding site when acetyl-CoA is absent, suggesting a potential coordination between biotin binding and acetyl-CoA binding. These findings provide insights into the structural dynamics and regulatory mechanisms of human ACCs.

The water channel aquaporin-4 (AQP4) is crucial for water balance in the mammalian brain. AQP4 has two main canonical isoforms, M23, which forms supramolecular structures called Orthogonal Arrays of Particles (OAP) and M1, which does not, along with two extended isoforms (M23ex and M1ex). This study examines these isoforms’ roles, particularly AQP4ex, which influences water channel activity and localization at the blood-brain barrier. Using mice lacking both AQP4ex isoforms (AQP4ex-KO) and lacking both AQP4M23 isoforms (OAP-null) mice, we explored brain water dynamics under osmotic stress induced by an acute water intoxication (AWI) model. AQP4ex-KO mice had lower basal brain water content than WT and OAP-null mice. During AWI, brain water content increased rapidly in WT and AQP4ex-KO mice, but was delayed in OAP-null mice. AQP4ex-KO mice had the highest water content increase at 20 min. Immunoblot analysis showed stable total AQP4 in WT mice initially, with increases at 30 min. AQP4ex and its phosphorylated form (p-AQP4ex) levels rose quickly, but the p-AQP4ex/AQP4ex ratio dropped at 20 min. AQP4ex-KO mice showed a compensatory rise in canonical AQP4 at 20 min post-AWI. These findings highlight the important role of AQP4ex in water content dynamics in both normal and pathological states. To evaluate brain waste clearance, amyloid-β (Aβ) removal was assessed using a fluorescent Aβ intra-parenchyma injection model. AQP4ex-KO mice demonstrated markedly impaired Aβ clearance, with extended diffusion distances and reduced fluorescence in cervical lymph nodes, indicating inefficient drainage from the brain parenchyma. Mechanistically, the polarization of AQP4 at astrocytic endfeet is essential for efficient clearance flow, aiding interstitial fluid movement into the CSF and lymphatic system. In AQP4ex-KO mice, disrupted polarization forces reliance on slower, passive diffusion for solute clearance, significantly reducing Aβ removal efficiency and altering extracellular space dynamics. Our results underscore the importance of AQP4ex in both brain water homeostasis and solute clearance, particularly Aβ. These findings highlight AQP4ex as a potential therapeutic target for enhancing waste clearance mechanisms in the brain, which could have significant implications for treating brain edema and neurodegenerative diseases like Alzheimer’s.

With its 12 optical filters, the Javalambre-Photometric Local Universe Survey (J-PLUS) provides an unprecedented multicolor view of the local Universe. The third data release (DR3) covers 3,192 deg$^2$ and contains 47.4 million objects. However, the classification algorithms currently implemented in the J-PLUS pipeline are deterministic and based solely on the morphology of the sources. Our goal is to classify the sources identified in the J-PLUS DR3 images as stars, quasi-stellar objects (QSOs), or galaxies. For this task, we present a machine learning pipeline that utilizes Bayesian neural networks to provide the full probability distribution function (PDF) of the classification. has been trained on photometric, astrometric, and morphological data from J-PLUS DR3 DR3, and using over 1.2 million objects with spectroscopic classification from DR18 DR9, the Early Data Release, and DR3. Results were validated on a test set of about $1.4 10^5$ objects and cross-checked against theoretical model predictions. outperforms all previous classifiers in terms of accuracy, precision, and completeness across the entire magnitude range. It delivers over $95<!PCT!>$ accuracy for objects brighter than $r = 21.5$ mag and $ 90<!PCT!>$ accuracy for those up to $r = 22$ mag, where J-PLUS completeness is $ 25<!PCT!>$. is also the first object classifier to provide the full PDF of the classification, enabling precise object selection for high purity or completeness, and for identifying objects with complex features, such as active galactic nuclei with resolved host galaxies. effectively classified J-PLUS sources into around 20 million galaxies, one million QSOs, and 26 million stars, with full PDFs for each, which allow for later refinement of the sample. The upcoming J-PAS survey, with its 56 color bands, will further enhance 's ability to detail the nature of each source.

Dominant X-linked diseases are uncommon due to female X chromosome inactivation (XCI). While random XCI usually protects females against X-linked mutations, Rett syndrome (RTT) is a female neurodevelopmental disorder caused by heterozygous MECP2 mutation. After 6-18 months of typical neurodevelopment, RTT girls undergo a poorly understood regression. We performed longitudinal snRNA-seq on cerebral cortex in a construct-relevant Mecp2e1 mutant mouse model of RTT, revealing transcriptional effects of cell type, mosaicism, and sex on progressive disease phenotypes. Across cell types, we observed sex differences in the number of differentially expressed genes (DEGs) with 6x more DEGs in mutant females than males. Unlike males, female DEGs emerged prior to symptoms, were enriched for homeostatic gene pathways in distinct cell types over time and correlated with disease phenotypes and human RTT cortical cell transcriptomes. Non-cell-autonomous effects were prominent and dynamic across disease progression of Mecp2e1 mutant females, indicating that wild-type-expressing cells normalize transcriptional homeostasis. These results advance our understanding of RTT progression and treatment.

BackgroundTo examine whether weekday-to-weekend sleep duration (WWD) difference and specific WWD patterns are associated with mental and somatic health and academic performance in a student population.MethodsThis study utilized cross-sectional data from the SHoT-2018 survey which includes responses from 50,054 full-time university/college students in Norway. Participants completed online questionnaires and reported sleep duration separately for weekdays and weekends. Medium sleep duration was defined as 7 to 9 h, short sleep duration as < 7 h and long sleep duration as > 9 h. Regression analyses were used to examine whether the degree and patterns of WWD was associated with health-related outcomes and academic performance.ResultsThe mean age of the sample was 23.2 years and comprised of 68.8% women. Most students (81.7%) slept longer on weekends compared to weekdays and 30.0% of the students reported a mean sleep duration shorter than 7 h. WWD difference was positively associated with higher odds of overweight/obesity, dissatisfaction with life, psychological distress, somatic burden and failed study exam. Concerning WWD patterns, the odds of students reporting unfavorably on the outcomes were particularly high for those who slept short on both weekdays and weekends, while those who slept short on weekdays seemed to benefit from sleeping longer (“catching up”) on weekends.ConclusionsOverall, WWD was associated with adverse health outcomes for students. Short sleep duration both on weekday and weekend was associated with the most detrimental outcomes in terms of health and academic performance, while sleeping in on weekends may alleviate some of the detriments.