Single-neuron projectomes of mouse paraventricular hypothalamic nucleus oxytocin neurons reveal mutually exclusive projection patterns.

Oxytocin (OXT) plays important roles in autonomic control and behavioral modulation. However, it is unknown how the projection patterns of OXT neurons align with underlying physiological functions. Here, we present the reconstructed single-neuron, whole-brain projectomes of 264 OXT neurons of the mouse paraventricular hypothalamic nucleus (PVH) at submicron resolution. These neurons hierarchically clustered into two groups, with distinct morphological and transcriptional characteristics and mutually exclusive projection patterns. Cluster 1 (177 neurons) axons terminated exclusively in the median eminence (ME) and have few collaterals terminating within hypothalamic regions. By contrast, cluster 2 (87 neurons) sent wide-spread axons to multiple brain regions, but excluding ME. Dendritic arbors of OXT neurons also extended outside of the PVH, suggesting capability to sense signals and modulate target regions. These single-neuron resolution observations reveal distinct OXT subpopulations, provide comprehensive analysis of their morphology, and lay the structural foundation for better understanding the functional heterogeneity of OXT neurons.

Homogeneity Test of the First-Order Agreement Coefficient in a Stratified Design.

Gwet's first-order agreement coefficient (AC1) is widely used to assess the agreement between raters. This paper proposes several asymptotic statistics for a homogeneity test of stratified AC1 in large sample sizes. These statistics may have unsatisfactory performance, especially for small samples and a high value of AC1. Furthermore, we propose three exact methods for small pieces. A likelihood ratio statistic is recommended in large sample sizes based on the numerical results. The exact E approaches under likelihood ratio and score statistics are more robust in the case of small sample scenarios. Moreover, the exact E method is effective to a high value of AC1. We apply two real examples to illustrate the proposed methods.

Comparative gene retention analysis in barley, wild emmer, and bread wheat pangenome lines reveals factors affecting gene retention following gene duplication.

BACKGROUND: Gene duplication is a prevalent phenomenon and a major driving force underlying genome evolution. The process leading to the fixation of gene duplicates following duplication is critical to understand how genome evolves but remains fragmentally understood. Most previous studies on gene retention are based on gene duplicate analyses in single reference genome. No population-based comparative gene retention analysis has been performed to date. RESULTS: Taking advantage of recently published genomic data in Triticeae, we dissected a divergent homogentisate phytyltransferase (HPT2) lineage caught in the middle stage of gene fixation following duplication. The presence/absence of HPT2 in barley (diploid), wild emmer (tetraploid), and bread wheat (hexaploid) pangenome lines appears to be associated with gene dosage constraint and environmental adaption. Based on these observations, we adopted a phylogeny-based orthology inference approach and performed comparative gene retention analyses across barley, wild emmer, and bread wheat. This led to the identification of 326 HPT2-pattern-like genes at whole genome scale, representing a pool of gene duplicates in the middle stage of gene fixation. Majority of these HPT2-pattern-like genes were identified as small-scale duplicates, such as dispersed, tandem, and proximal duplications. Natural selection analyses showed that HPT2-pattern-like genes have experienced relaxed selection pressure, which is generally accompanied with partial positive selection and transcriptional divergence. Functional enrichment analyses showed that HPT2-pattern-like genes are over-represented with molecular-binding and defense response functions, supporting the potential role of environmental adaption during gene retention. We also observed that gene duplicates from larger gene family are more likely to be lost, implying a gene dosage constraint effect. Further comparative gene retention analysis in barley and bread wheat pangenome lines revealed combined effects of species-specific selection and gene dosage constraint. CONCLUSIONS: Comparative gene retention analyses at the population level support gene dosage constraint, environmental adaption, and species-specific selection as three factors that may affect gene retention following gene duplication. Our findings shed light on the evolutionary process leading to the retention of newly formed gene duplicates and will greatly improve our understanding on genome evolution via duplication.

Hierarchical deployment of Tbx3 dictates the identity of hypothalamic KNDy neurons to control puberty onset.

The neuroendocrine system consists of a heterogeneous collection of neuropeptidergic neurons in the brain, among which hypothalamic KNDy neurons represent an indispensable cell subtype controlling puberty onset. Although neural progenitors and neuronal precursors along the cell lineage hierarchy adopt a cascade diversification strategy to generate hypothalamic neuronal heterogeneity, the cellular logic operating within the lineage to specify a subtype of neuroendocrine neurons remains unclear. As human genetic studies have recently established a link between TBX3 mutations and delayed puberty onset, we systematically studied Tbx3-derived neuronal lineage and Tbx3-dependent neuronal specification and found that Tbx3 hierarchically established and maintained the identity of KNDy neurons for triggering puberty. Apart from the well-established lineage-dependent fate determination, we uncovered rules of interlineage interaction and intralineage retention operating through neuronal differentiation in the absence of Tbx3. Moreover, we revealed that human TBX3 mutations disturbed the phase separation of encoded proteins and impaired transcriptional regulation of key neuropeptides, providing a pathological mechanism underlying TBX3-associated puberty disorders.

Superconducting Cavity Electromechanics: The Realization of an Acoustic Frequency Comb at Microwave Frequencies.

We present a nonlinear multimode superconducting electroacoustic system, where the interplay between superconducting kinetic inductance and piezoelectric strong coupling establishes an effective Kerr nonlinearity among multiple acoustic modes at 10 GHz that could hardly be achieved via intrinsic mechanical nonlinearity. By exciting this multimode Kerr system with a single microwave tone, we further demonstrate a coherent electroacoustic frequency comb and provide theoretical understanding of multimode nonlinear interaction in the superstrong coupling limit. This nonlinear superconducting electroacoustic system sheds light on the active control of multimode resonator systems and offers an enabling platform for the dynamic study of microcombs at microwave frequencies.

Experimental and Numerical Investigation on Fatigue Properties of Carbon Fiber Cross-Ply Laminates in Hygrothermal Environments.

The fatigue properties of composite materials are degraded seriously in hygrothermal environments, so taking into account their influence is very important when evaluating the fatigue life of composite structures. Tensile fatigue experiments of carbon fiber reinforced resin composite cross-ply laminates were conducted in room temperature/dry (RTD), cool temperature/dry (CTD) and elevated temperature/wet (ETW) conditions. The S-N curves and fatigue failure modes of the cross-ply laminates were obtained in three conditions. On this basis, a finite element model was established to discuss the influence of temperature and moisture content on the fatigue properties, as well as a method for determining environmental factors of fatigue life of cross-ply laminates was established. The results show that the saturation moisture absorption and temperature have a significant influence on the tensile fatigue properties of cross-ply laminates. The high-cycle fatigue property is weakened significantly by the saturation moisture absorption and high temperature, but the low-cycle fatigue properties were strengthened in cool temperature conditions. The delamination failure mode in ETW is the most severe, presenting with an obvious necking phenomenon. The influence of temperature has a greater effect than that of moisture content, but moisture absorption would play its affect obviously when temperature exceeds 40 °C.

Evolutionarily conservative and non-conservative regulatory networks during primate interneuron development revealed by single-cell RNA and ATAC sequencing.

The differences in size and function between primate and rodent brains, and the association of disturbed excitatory/inhibitory balance with many neurodevelopmental disorders highlight the importance to study primate ganglionic eminences (GEs) development. Here we used single-cell RNA and ATAC sequencing to characterize the emergence of cell diversity in monkey and human GEs where most striatal and cortical interneurons are generated. We identified regional and temporal diversity among progenitor cells which give rise to a variety of interneurons. These cells are specified within the primate GEs by well conserved gene regulatory networks, similar to those identified in mice. However, we detected, in human, several novel regulatory pathways or factors involved in the specification and migration of interneurons. Importantly, comparison of progenitors between our human and published mouse GE datasets led to the discovery and confirmation of outer radial glial cells in GEs in human cortex. Our findings reveal both evolutionarily conservative and nonconservative regulatory networks in primate GEs, which may contribute to their larger brain sizes and more complex neural networks compared with mouse.

Single-cell transcriptomic profiling of the hypothalamic median eminence during aging.

Aging is a slow and progressive natural process that compromises the normal functions of cells, tissues, organs, and systems. The aging of the hypothalamic median eminence (ME), a structural gate linking neural and endocrine systems, may impair hormone release, energy homeostasis, and central sensing of circulating molecules, leading to systemic and reproductive aging. However, the molecular and cellular features of ME aging remain largely unknown. Here, we describe the transcriptional landscape of young and middle-aged mouse ME at single-cell resolution, revealing the common and cell type-specific transcriptional changes with age. The transcriptional changes in cell-intrinsic programs, cell-cell crosstalk, and cell-extrinsic factors highlight five molecular features of ME aging and also implicate several potentially druggable targets at cellular, signaling, and molecular levels. Importantly, our results suggest that vascular and leptomeningeal cells may lead the asynchronized aging process among diverse cell types and drive local inflammation and cellular senescence via a unique secretome. Together, our study uncovers how intrinsic and extrinsic features of each cell type in the hypothalamic ME are changed by the aging process, which will facilitate our understanding of brain aging and provide clues for efficient anti-aging intervention at the middle-aged stage.

ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links Eph receptor gene to autism spectrum disorder.

ASD-associated genes are enriched for synaptic proteins and epigenetic regulators. How those chromatin modulators establish ASD traits have remained unknown. We find haploinsufficiency of Ash1l causally induces anxiety and autistic-like behavior, including repetitive behavior, and alters social behavior. Specific depletion of Ash1l in forebrain induces similar ASD-associated behavioral defects. While the learning ability remains intact, the discrimination ability of Ash1l mutant mice is reduced. Mechanistically, deletion of Ash1l in neurons induces excessive synapses due to the synapse pruning deficits, especially during the post-learning period. Dysregulation of synaptic genes is detected in Ash1l mutant brain. Specifically, Eph receptor A7 is downregulated in Ash1l+/- mice through accumulating EZH2-mediated H3K27me3 in its gene body. Importantly, increasing activation of EphA7 in Ash1l+/- mice by supplying its ligand, ephrin-A5, strongly promotes synapse pruning and rescues discrimination deficits. Our results suggest that Ash1l haploinsufficiency is a highly penetrant risk factor for ASD, resulting from synapse pruning deficits.

Cloning, Expression, and Tobacco Overexpression Analyses of a PISTILLATA/GLOBOSA-like (OfGLO1) Gene from Osmanthus fragrans.

GLOBOSA (GLO), a B-class MADS-box gene, is involved in floral organ determination but has rarely been studied in Osmanthus fragrans, which is a very popular ornamental tree species in China. Here, the full-length cDNA of a homologous GLO1 gene (named OfGLO1) was cloned from a flower bud of O. fragrans using the RACE technique. The OfGLO1 has a 645 bp open reading frame, encoding 214 amino acids. Similar to other PI/GLO proteins, OfGLO1 has two conserved domains, MADS MEF2-like and K-box, and a 16-amino-acid PI motif in the C terminal region. Our phylogeny analysis classified OfGLO1 as a PI-type member of the B-class MADS-box gene family. The qRT-PCR assay showed that the expression of OfGLO1 in O. fragrans was continuously upregulated from the tight bud stage to the full flowering stage but barely expressed in the pistils, sepals, and non-floral organs, such as root, leaf, and stem. The genetic effect of OfGLO1 was assayed by ectopic expression in tobacco plants. Compared with the wild-type, OfGLO1 transformants showed reduced plant size, earlier flowering, shorter stamens, and lower seed setting rates. Furthermore, some stamens were changed into petal-like structures. These findings indicate that OfGLO1 plays an important role in the regulation of flower development. This study improved our understanding of class B gene function in woody plants.

Bidirectional interconversion of microwave and light with thin-film lithium niobate.

Superconducting cavity electro-optics presents a promising route to coherently convert microwave and optical photons and distribute quantum entanglement between superconducting circuits over long-distance. Strong Pockels nonlinearity and high-performance optical cavity are the prerequisites for high conversion efficiency. Thin-film lithium niobate (TFLN) offers these desired characteristics. Despite significant recent progresses, only unidirectional conversion with efficiencies on the order of 10-5 has been realized. In this article, we demonstrate the bidirectional electro-optic conversion in TFLN-superconductor hybrid system, with conversion efficiency improved by more than three orders of magnitude. Our air-clad device architecture boosts the sustainable intracavity pump power at cryogenic temperatures by suppressing the prominent photorefractive effect that limits cryogenic performance of TFLN, and reaches an efficiency of 1.02% (internal efficiency of 15.2%). This work firmly establishes the TFLN-superconductor hybrid EO system as a highly competitive transduction platform for future quantum network applications.

Quantum Microwave Radiometry with a Superconducting Qubit.

The interaction of photons and coherent quantum systems can be employed to detect electromagnetic radiation with remarkable sensitivity. We introduce a quantum radiometer based on the photon-induced dephasing process of a superconducting qubit for sensing microwave radiation at the subunit photon level. Using this radiometer, we demonstrate the radiative cooling of a 1 K microwave resonator and measure its mode temperature with an uncertainty ∼0.01 K. We thus develop a precise tool for studying the thermodynamics of quantum microwave circuits, which provides new solutions for calibrating hybrid quantum systems and detecting candidate particles for dark matter.

Cascade diversification directs generation of neuronal diversity in the hypothalamus.

The hypothalamus contains an astounding heterogeneity of neurons that regulate endocrine, autonomic, and behavioral functions. However, its molecular developmental trajectory and origin of neuronal diversity remain unclear. Here, we profile the transcriptome of 43,261 cells derived from Rax+ hypothalamic neuroepithelium to map the developmental landscape of the mouse hypothalamus and trajectory of radial glial cells (RGCs), intermediate progenitor cells (IPCs), nascent neurons, and peptidergic neurons. We show that RGCs adopt a conserved strategy for multipotential differentiation but generate Ascl1+ and Neurog2+ IPCs. Ascl1+ IPCs differ from their telencephalic counterpart by displaying fate bifurcation, and postmitotic nascent neurons resolve into multiple peptidergic neuronal subtypes. Clonal analysis further demonstrates that single RGCs can produce multiple neuronal subtypes. Our study reveals that multiple cell types along the lineage hierarchy contribute to fate diversification of hypothalamic neurons in a stepwise fashion, suggesting a cascade diversification model that deconstructs the origin of neuronal diversity.

Cavity piezo-mechanics for superconducting-nanophotonic quantum interface.

Hybrid quantum systems are essential for the realization of distributed quantum networks. In particular, piezo-mechanics operating at typical superconducting qubit frequencies features low thermal excitations, and offers an appealing platform to bridge superconducting quantum processors and optical telecommunication channels. However, integrating superconducting and optomechanical elements at cryogenic temperatures with sufficiently strong interactions remains a tremendous challenge. Here, we report an integrated superconducting cavity piezo-optomechanical platform where 10 GHz phonons are resonantly coupled with photons in a superconducting cavity and a nanophotonic cavity at the same time. Taking advantage of the large piezo-mechanical cooperativity (Cem ~7) and the enhanced optomechanical coupling boosted by a pulsed optical pump, we demonstrate coherent interactions at cryogenic temperatures via the observation of efficient microwave-optical photon conversion. This hybrid interface makes a substantial step towards quantum communication at large scale, as well as novel explorations in microwave-optical photon entanglement and quantum sensing mediated by gigahertz phonons.

Radiative Cooling of a Superconducting Resonator.

Cooling microwave resonators to near the quantum ground state, crucial for their operation in the quantum regime, is typically achieved by direct device refrigeration to a few tens of millikelvin. However, in quantum experiments that require high operation power such as microwave-to-optics quantum transduction, it is desirable to operate at higher temperatures with non-negligible environmental thermal excitations, where larger cooling power is available. In this Letter, we present a radiative cooling protocol to prepare a superconducting microwave mode near its quantum ground state in spite of warm environment temperatures for the resonator. In this proof-of-concept experiment, the mode occupancy of a 10 GHz superconducting resonator thermally anchored at 1.02 K is reduced to 0.44±0.05 from 1.56 by radiatively coupling to a 70 mK cold load. This radiative cooling scheme allows high-operation-power microwave experiments to work in the quantum regime, and opens possibilities for routing microwave quantum states to elevated temperatures.

Proposal for Heralded Generation and Detection of Entangled Microwave-Optical-Photon Pairs.

Quantum state transfer between microwave and optical frequencies is essential for connecting superconducting quantum circuits to optical systems and extending microwave quantum networks over long distances. However, establishing such a quantum interface is extremely challenging because the standard direct quantum transduction requires both high coupling efficiency and small added noise. We propose an entanglement-based scheme-generating microwave-optical entanglement and using it to transfer quantum states via quantum teleportation-which can bypass the stringent requirements in direct quantum transduction and is robust against loss errors. In addition, we propose and analyze a counterintuitive design-suppress the added noise by placing the device at a higher temperature environment-which can improve both the device quality factor and power handling capability. We systematically analyze the generation and verification of entangled microwave-optical-photon pairs. The parameter for entanglement verification favors the regime of cooperativity mismatch and can tolerate certain thermal noises. Our scheme is feasible given the latest advances on electro-optomechanics, and can be generalized to various physical systems.

Maternal exposure to swainsonine impaired the early postnatal development of mouse dentate gyrus of offspring.

Neurogenesis in the dentate gyrus (DG) plays a key role in the normal of structure and function of the hippocampus-learning and memory. After eating the locoweeds, animals develop a chronic neurological disease called "locoism". Swainsonine (SW) is the main toxin in locoweeds. Studies have shown that SW induces neuronal apoptosis in vitro and impairs learning and memory in adult mouse. The present study explored effects of SW exposure to dams on the postnatal neurogenesis of DG of offspring. Pregnant ICR mice were orally gavaged with SW at a dose of 0, 5.6 or 8.4 mg/kg/day from gestation day 10 to postnatal day (PND) 21, respectively. We found that SW impaired the proliferation capacity of neural progenitor cells in the DG so that the number of newborn cells was reduced at PND 8. Using the postnatal in vivo electroporation, we showed that the dendritic branching and total length of granule cells were significantly decreased due to SW exposure. In addition, on PND 21, the density of NeuN-positive and Reelin-positive interneurons increased in the hilus, implying the disorder of neuronal migration. These results suggest that maternal exposure to SW, the neurogenesis of DG on offspring was disrupted, finally leading to the functional disorder of DG.

Soliton microcomb generation at 2 µm in z-cut lithium niobate microring resonators.

Chip-based soliton frequency combs have been demonstrated on various material platforms, offering broadband, mutually coherent, and equally spaced frequency lines desired for many applications. Lithium niobate (LN), possessing both second- and third-order optical nonlinearities, as well as integrability on insulating substrates, has emerged as a novel source for microcomb generation and controlling. Here we demonstrate mode-locked soliton microcombs generated around 2 µm in a high-Q z-cut LN microring resonator. The intracavity photorefractive effect is found to be still dominant over the thermal effect in the 2 µm region, which facilitates direct accessing soliton states in the red-detuned regime, as reported in the telecom band. We also find that intracavity stimulated Raman scattering is greatly suppressed when moving the pump wavelength from the telecom band to 2 µm, thus alleviating Raman-Kerr comb competition. This Letter expands mode-locked LN microcombs to 2 µm, and could enable a variety of potential applications based on LN nanophotonic platform.

Effects of chronic mild stress induced depression on synaptic plasticity in mouse hippocampus.

Chronic mild stress (CMS) model is most similar to the depression human suffered in daily life. Strong evidence proved the important role of hippocampal synaptic plasticity in the mechanism of depression. This study investigated the effect of CMS on synaptic plasticity in hippocampus. Our results showed that CMS impaired spatial memory and exploring ability, disturbed the release of neurotransmitters including 5-hydroxytryptamine (5-HT) and dopamine (DA), reduced the density of synaptic vesicle in inner molecular layer, increased the number of thin spines in inner and outer molecular layer, whereas did not affect the density of spine apparatus, the above mentioned were probably related to the reduction of astrocytes and activation of microglial cells.