Extracellular vesicles containing miR-181a-5p as a novel therapy for experimental autoimmune encephalomyelitis-induced demyelination.

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system. Recent research has revealed that mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), containing specific miRNAs, possess immunomodulatory properties and have demonstrated therapeutic potential in the treatment of MS. This study aimed to investigate the role MSC-EVs, containing microRNA-181a-5p (miR-181a-5p) in both experimental autoimmune encephalomyelitis (EAE), an established animal model of MS, and lipopolysaccharide-stimulated BV2 microglia. We evaluated clinical symptoms and inflammatory responses in EAE mice following intrathecal injections of MSC-EVs. MSC-EVs containing miR-181a-5p were co-cultured with microglia to explore their impact on inflammation and cell pyroptosis. We validated the interaction between miR-181a-5p and its downstream regulators and conducted in vivo verification by injecting manipulated EVs containing miR-181a-5p into EAE mice. Our results demonstrated that MSC-EVs, containing miR-181a-5p reduced the clinical symptoms of EAE mice. Furthermore, we observed downregulation of miR-181a-5p in EAE model mice, and its expression was restored after treatment with MSC-EVs, which corresponded to suppressed microglial inflammation and pyroptosis. Additionally, EVs containing miR-181a-5p mitigated spinal cord injury and demyelination in EAE mice. Mechanistically, ubiquitin-specific protease 15 (USP15) exhibited high expression in EAE mice, and miR-181a-5p was specifically targeted and bound to USP15, thereby regulating the RelA/NEK7 axis. In conclusion, MSC-EVs containing miR-181a-5p inhibit microglial inflammation and pyroptosis through the USP15-mediated RelA/NEK7 axis, thus alleviating the clinical symptoms of EAE. These findings present a potential therapeutic approach for the treatment of MS.

Swimming behavior indicates stress and adaptations to exercise.

Introduction: Behaviors of swimming rodents are not uniform, exhibiting large variations, which may underlie the individual differences in swimming exercise-induced benefits. The study aimed to monitor individualized swimming behavior and evaluate its biological significance. Methods: A swimming tank which can monitor individualized rodent swimming behavior during exercise was established. A total of 45 mice were subjected to swimming training for 1 month (1 h per day) and the swimming behaviors of each mouse were recorded. Results: The swimming behaviors of mice displayed considerable variations in aspects of distance, velocity, and area preference. For example, nearly one-third of mice preferred to swim in central area and most of the mice exhibited an even area distribution. Long-term exercise training improved cardiac systolic function and decreased blood pressure in mice, but hardly changed swimming behaviors. Analyses of the relationship between swimming behavior and cardiovascular adaptations to exercise training revealed that swimming behavior indicated the biological effects of swimming training. Specifically, mice which preferred swimming at the central zone or were trainable in behavior during 1-month training exhibited better outcomes in cardiac function and blood pressure post long-term exercise. Mechanistically, a centralized swimming behavior indicated a smaller stress during exercise, as evidenced by a milder activation of hypothalamic-pituitary-adrenal axis. Discussion: These results suggest that swimming behavior during training indicates individualized adaptations to long-term exercise, and highlight a biological significance of swimming behavior monitoring in animal studies.

Gh4CL20/20A involved in flavonoid biosynthesis is essential for male fertility in cotton (Gossypium hirsutum L.).

Flavonoids have been shown to play an essential role in plant growth and fertility. 4-Coumarate CoA ligase (4CL) is one of the indispensable enzymes involved in the biosynthesis of flavonoids. However, the role of 4CL and flavonoids in impact on cotton fertility is still unknown. In this study, on the basis of identification of an additional Gh4CL gene, Gh4CL20A, by using an updated G. hirsutum genome, we found that Gh4CL20A and its homologous Gh4CL20 were preferentially expressed in petals and stamens. The petals of the loss-of-function Gh4CL20/Gh4CL20A mutant generated by CRISPR/Cas9 gene editing remained white until wilting. Notably, the mutant showed indehiscent anthers, reduced number of pollen grains and pollen viability, leading to male sterility. Histological analysis revealed that abnormal degradation of anther tapetum at the tetrad stage and abnormal pollen grain development at the mature stage caused male sterility of the gene editing mutant. Analysis of the anther transcriptome identified a total of 10574 and 11962 genes up- and down-regulated in the mutant, respectively, compared to the wild-type. GO, KEGG, and WGCNA analyses linked the abnormality of the mutant anthers to the defective flavonoid biosynthetic pathway, leading to decreased activity of 4CL and chalcone isomerase (CHI) and reduced accumulation of flavonoids in the mutant. These results imply a role of Gh4CL20/Gh4CL20A in assuring proper development of cotton anthers by regulating flavonoid metabolism. This study elucidates a molecular mechanism underlying cotton anther development and provides candidate genes for creating cotton male sterile germplasm that has the potential to be used in production of hybrid seeds.

Extraordinary preservation of gene collinearity over three hundred million years revealed in homosporous lycophytes.

Homosporous lycophytes (Lycopodiaceae) are a deeply diverged lineage in the plant tree of life, having split from heterosporous lycophytes (Selaginella and Isoetes) ~400 Mya. Compared to the heterosporous lineage, Lycopodiaceae has markedly larger genome sizes and remains the last major plant clade for which no chromosome-level assembly has been available. Here, we present chromosomal genome assemblies for two homosporous lycophyte species, the allotetraploid Huperzia asiatica and the diploid Diphasiastrum complanatum. Remarkably, despite that the two species diverged ~350 Mya, around 30% of the genes are still in syntenic blocks. Furthermore, both genomes had undergone independent whole genome duplications, and the resulting intragenomic syntenies have likewise been preserved relatively well. Such slow genome evolution over deep time is in stark contrast to heterosporous lycophytes and is correlated with a decelerated rate of nucleotide substitution. Together, the genomes of H. asiatica and D. complanatum not only fill a crucial gap in the plant genomic landscape but also highlight a potentially meaningful genomic contrast between homosporous and heterosporous species.

Bifidobacteria in disease: from head to toe.

Bifidobacteria as a strictly anaerobic gram-positive bacteria, is widely distributed in the intestine, vagina and oral cavity, and is one of the first gut flora to colonize the early stages of life. Intestinal flora is closely related to health, and dysbiosis of intestinal flora, especially Bifidobacteria, has been found in a variety of diseases. Numerous studies have shown that in addition to maintaining intestinal homeostasis, Bifidobacteria may be involved in diseases covering all parts of the body, including the nervous system, respiratory system, genitourinary system and so on. This review collects evidence for the variation of Bifidobacteria in typical diseases among various systems, provides mild and effective therapeutic options for those diseases that are difficult to cure, and moves Bifidobacteria from basic research to further clinical applications.

Multiomics comparison among populations of three plant sources of Amomi Fructus.

Amomi Fructus (Sharen, AF) is a traditional Chinese medicine (TCM) from three source species (or varieties), including Wurfbainia villosa var. villosa (WVV), W. villosa var. xanthioides (WVX), or W. longiligularis (WL). Among them, WVV has been transplanted from its top-geoherb region, Guangdong, to its current main production area, Yunnan, for >50 years in China. However, the genetic and transcriptomic differentiation among multiple AF source species (or varieties) and between the origin and transplanted populations of WVV is unknown. In our study, the observed overall higher expression of terpenoid biosynthesis genes in WVV than in WVX provided possible evidence for the better pharmacological effect of WVV. We also screened six candidate borneol dehydrogenases (BDHs) that potentially catalyzed borneol into camphor in WVV and functionally verified them. Highly expressed genes at the P2 stage of WVV, Wv05G1424 and Wv05G1438, were capable of catalyzing the formation of camphor from (+)-borneol, (-)-borneol and DL-isoborneol. Moreover, the BDH genes may experience independent evolution after acquiring the ancestral copies, and the following tandem duplications might account for the abundant camphor content in WVV. Furthermore, four populations of WVV, WVX, and WL are genetically differentiated, and the gene flow from WVX to WVV in Yunnan contributed to the greater genetic diversity in the introduced population (WVV-JH) than in its top-geoherb region (WVV-YC), which showed the lowest genetic diversity and might undergo genetic degradation. In addition, terpene synthesis (TPS) and BDH genes were selected among populations of multiple AF source species (or varieties) and between the top- and non-top-geoherb regions, which might explain the difference in metabolites between these populations. Our findings provide important guidance for the conservation, genetic improvement, and industrial development of the three source species (or varieties) and for identifying top-geoherbalism with molecular markers, and proper clinical application of AF.

Unraveling Prevalence and Effects of Deleterious Mutations in Maize Elite Lines across Decades of Modern Breeding.

Future breeding is likely to involve the detection and removal of deleterious alleles, which are mutations that negatively affect crop fitness. However, little is known about the prevalence of such mutations and their effects on phenotypic traits in the context of modern crop breeding. To address this, we examined the number and frequency of deleterious mutations in 350 elite maize inbred lines developed over the past few decades in China and the United States. Our findings reveal an accumulation of weakly deleterious mutations and a decrease in strongly deleterious mutations, indicating the dominant effects of genetic drift and purifying selection for the two types of mutations, respectively. We also discovered that slightly deleterious mutations, when at lower frequencies, were more likely to be heterozygous in the developed hybrids. This is consistent with complementation as a potential explanation for heterosis. Subsequently, we found that deleterious mutations accounted for more of the variation in phenotypic traits than nondeleterious mutations with matched minor allele frequencies, especially for traits related to leaf angle and flowering time. Moreover, we detected fewer deleterious mutations in the promoter and gene body regions of differentially expressed genes across breeding eras than in nondifferentially expressed genes. Overall, our results provide a comprehensive assessment of the prevalence and impact of deleterious mutations in modern maize breeding and establish a useful baseline for future maize improvement efforts.

Manipulating Attosecond Charge Migration in Molecules by Optical Cavities.

The ultrafast electronic charge dynamics in molecules upon photoionization while the nuclear motions are frozen is known as charge migration. In a theoretical study of the quantum dynamics of photoionized 5-bromo-1-pentene, we show that the charge migration process can be induced and enhanced by placing the molecule in an optical cavity, and can be monitored by time-resolved photoelectron spectroscopy. The collective nature of the polaritonic charge migration process is investigated. We find that, unlike spectroscopy, molecular charge dynamics in a cavity is local and does not show many-molecule collective effects. The same conclusion applies to cavity polaritonic chemistry.

Photoelectron spectroscopy with entangled photons; enhanced spectrotemporal resolution.

In this theoretical study, we show how photoelectron signals generated by time-energy entangled photon pairs can monitor ultrafast excited state dynamics of molecules with high joint spectral and temporal resolutions, not limited by the Fourier uncertainty of classical light. This technique scales linearly, rather than quadratically, with the pump intensity, allowing the study of fragile biological samples with low photon fluxes. Since the spectral resolution is achieved by electron detection and the temporal resolution by a variable phase delay, this technique does not require scanning the pump frequency and the entanglement times, which significantly simplifies the experimental setup, making it feasible with current instrumentation. Application is made to the photodissociation dynamics of pyrrole calculated by exact nonadiabatic wave packet simulations in a reduced two nuclear coordinate space. This study demonstrates the unique advantages of ultrafast quantum light spectroscopy.

Scalar Breit interaction for molecular calculations.

Variational treatment of the Dirac-Coulomb-Gaunt or Dirac-Coulomb-Breit two-electron interaction at the Dirac-Hartree-Fock level is the starting point of high-accuracy four-component calculations of atomic and molecular systems. In this work, we introduce, for the first time, the scalar Hamiltonians derived from the Dirac-Coulomb-Gaunt and Dirac-Coulomb-Breit operators based on spin separation in the Pauli quaternion basis. While the widely used spin-free Dirac-Coulomb Hamiltonian includes only the direct Coulomb and exchange terms that resemble nonrelativistic two-electron interactions, the scalar Gaunt operator adds a scalar spin-spin term. The spin separation of the gauge operator gives rise to an additional scalar orbit-orbit interaction in the scalar Breit Hamiltonian. Benchmark calculations of Aun (n = 2-8) show that the scalar Dirac-Coulomb-Breit Hamiltonian can capture 99.99% of the total energy with only 10% of the computational cost when real-valued arithmetic is used, compared to the full Dirac-Coulomb-Breit Hamiltonian. The scalar relativistic formulation developed in this work lays the theoretical foundation for the development of high-accuracy, low-cost correlated variational relativistic many-body theory.

Mesenchymal stem cell-derived exosomal microRNA-367-3p alleviates experimental autoimmune encephalomyelitis via inhibition of microglial ferroptosis by targeting EZH2.

Multiple sclerosis (MS) is an autoimmune, inflammatory demyelinating disorder of the central nervous system. Accumulating evidence has underscored the therapeutic potential of bone marrow mesenchymal stem cells (BMSCs)-derived exosomes (BMSC-Exos) containing bioactive compounds in MS. Herein, the current study sought to characterize the mechanism of BMSC-Exos harboring miR-367-3p both in BV2 microglia by Erastin-induced ferroptosis and in experimental autoimmune encephalomyelitis (EAE), a typical animal model of MS. Exosomes were firstly isolated from BMSCs and identified for further use. BV2 microglia were co-cultured with miR-367-3p-containing BMSC-Exos, followed by an assessment of cell ferroptosis. Mechanistic exploration was furthered by the interaction of miR-367-3p and its downstream regulators. Lastly, BMSC-Exos harboring miR-367-3p were injected into EAE mice for in vivo validation. BMSC-Exos carrying miR-367-3p restrained microglial ferroptosis in vitro. Mechanistically, miR-367-3p could bind to Enhancer of zeste homolog 2 (EZH2) and restrain EZH2 expression, leading to the over-expression of solute carrier family 7 member 11 (SLC7A11). Meanwhile, over-expression of SLC7A11 resulted in Glutathione Peroxidase 4 (GPX4) activation and ferroptosis suppression. Ectopic expression of EZH2 in vitro negated the protective effects of BMSC-Exos. Furthermore, BMSC-Exos containing miR-367-3p relieved the severity of EAE by suppressing ferroptosis and restraining EZH2 expression in vivo. Collectively, our findings suggest that BMSC-Exos carrying miR-367-3p brings about a significant decline in microglia ferroptosis by repressing EZH2 and alleviating the severity of EAE in vivo, suggesting a possible role of miR-367-3p overexpression in the treatment strategy of EAE. AVAILABILITY OF DATA AND MATERIALS: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Exosomal miR-23b-3p from bone mesenchymal stem cells alleviates experimental autoimmune encephalomyelitis by inhibiting microglial pyroptosis.

Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system and is marked by inflammation and damage to the myelin sheath surrounding nerve fibers. Recent studies have highlighted the therapeutic value of exosomes (Exos) obtained from bone marrow mesenchymal stem cells (BMSCs) in MS treatment. These BMSC-Exos contain biologically active molecules that show promising results in preclinical evaluations. The aim of this study was to investigate the mechanism of BMSC-Exos containing miR-23b-3p in both LPS-stimulated BV2 microglia and in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Exos were isolated from BMSCs, and their effects were evaluated in vitro by co-culturing with BV2 microglia. The interaction between miR-23b-3p and its downstream targets was also explored. The efficacy of BMSC-Exos was further verified in vivo by injecting the Exos into EAE mice. The results showed that BMSC-Exos containing miR-23b-3p reduced microglial pyroptosis in vivo by specifically binding to and suppressing the expression of NEK7. In vivo, BMSC-Exos containing miR-23b-3p alleviated the severity of EAE by decreasing microglial inflammation and pyroptosis via the repression of NEK7. These findings provide new insights into the therapeutic potential of BMSC-Exos containing miR-23b-3p for MS.

Correlated Dirac-Coulomb-Breit multiconfigurational self-consistent-field methods.

The fully correlated frequency-independent Dirac-Coulomb-Breit Hamiltonian provides the most accurate description of electron-electron interaction before going to a genuine relativistic quantum electrodynamics theory of many-electron systems. In this work, we introduce a correlated Dirac-Coulomb-Breit multiconfigurational self-consistent-field method within the frameworks of complete active space and density matrix renormalization group. In this approach, the Dirac-Coulomb-Breit Hamiltonian is included variationally in both the mean-field and correlated electron treatment. We also analyze the importance of the Breit operator in electron correlation and the rotation between the positive- and negative-orbital space in the no-virtual-pair approximation. Atomic fine-structure splittings and lanthanide contraction in diatomic fluorides are used as benchmark studies to understand the contribution from the Breit correlation.

Attosecond Charge Migration in Molecules Imaged by Combined X-ray and Electron Diffraction.

We show how ultrafast gas-phase X-ray and electron diffraction signals can be combined to generate real-space movies of charge migration dynamics in molecules. Charge migration denotes short time electronic charge redistribution upon photoexcitation of molecules where the nuclei are frozen. In this regime, we identify a mixed electronic-nuclear interference term that can be cleanly singled out. Using the ground-state nuclear structure as a reference, the phase information in this signal allows its inversion to real space and the capture of electronic charge density movies on the attosecond time scale.

A Programmable, DNA-Exclusively-Guided Argonaute DNase and Its Higher Cleavage Specificity Achieved by 5'-Hydroxylated Guide.

Argonaute proteins exist widely in eukaryotes and prokaryotes, and they are of great potential for molecular cloning, nucleic acid detection, DNA assembly, and gene editing. However, their overall properties are not satisfactory and hinder their broad applications. Herein, we investigated a prokaryotic Argonaute nuclease from a mesophilic bacterium Clostridium disporicum (CdAgo) and explored its overall properties, especially with 5'-hydroxylated (5'-OH) guides. We found that CdAgo can exclusively use single-stranded DNA (ssDNA) as guide to cleave ssDNA and plasmid targets. Further, we found the length of the efficient guide is narrower for the 5'-OH guide (17-20 nt) than for the 5'-phosphorylated guide (5'-P, 14-21 nt). Furthermore, we discovered that the 5'-OH guides can generally offer stronger mismatch discrimination than the 5'-P ones. The 5'-OH guides offer the narrower length range, higher mismatch discrimination and more accurate cleavage than the 5'-P guides. Therefore, 5'-OH-guide-directed CdAgo has great potential in biological and biomedical applications.

The chromosome-level genome of female ginseng (Angelica sinensis) provides insights into molecular mechanisms and evolution of coumarin biosynthesis.

Coumarins are natural products with important medicinal values, and include simple coumarins, furanocoumarins and pyranocoumarins. Female ginseng (Angelica sinensis) is a renowned herb with abundant coumarins, originated in China and known for the treatment of female ailments for thousands of years. The molecular basis of simple coumarin biosynthesis in A. sinensis and the evolutionary history of the genes involved in furanocoumarin biosynthesis are largely unknown. Here, we generated the first chromosome-scale genome of A. sinensis. It has a genome size of 2.37 Gb, which was generated by combining PacBio and Hi-C sequencing technologies. The genome was predicted to contain 43 202 protein-coding genes dispersed mainly on 11 pseudochromosomes. We not only provided evidence for whole-genome duplication (WGD) specifically occurring in the Apioideae subfamily, but also demonstrated the vital role of tandem duplication for phenylpropanoid biosynthesis in A. sinensis. Combined analyses of transcriptomic and metabolomic data revealed key genes and candidate transcription factors regulating simple coumarin biosynthesis. Furthermore, phylogenomic synteny network analyses suggested prenyltransferase genes involved in furanocoumarin biosynthesis evolved independently in the Moraceae, Fabaceae, Rutaceae and Apiaceae after ζ and ε WGD. Our work sheds light on coumarin biosynthesis, and provides a benchmark for accelerating genetic research and molecular breeding in A. sinensis.

Synergizing Cobalt Ruthenium Alloy with Chromium Oxyhydroxide for Highly Efficient Electrocatalytic Water Splitting.

Constructing a coupling interface of multicomponents with different functions is of considerable importance for designing an advanced bifunctional water splitting electrode. Particularly, designing and developing alloy/oxyhydroxide-integrated electrodes have emerged as a tendency yet remain a considerable challenge. In this work, a novel 3D nanostructure electrocatalyst assembled from CoRu nanoalloy and CrOOH nanosheets (denoted as CoRu-CrOOH/NF) was directly grown on nickel foam via a successive hydrothermal method. The unique synergy in CoRu-CrOOH/NF heterostructures is not only conducive to strengthening charge transfer capability and accelerating the reaction kinetics but also favors the redistribution of charge within the interface, thus improving the electrocatalytic performance. In view of the above-mentioned points, the resultant CoRu-CrOOH/NF displays outstanding catalytic performance with overpotentials of 26 and 272 mV at 10 mA cm-2 for hydrogen evolution reaction (HER) and 50 mA cm-2 for oxygen evolution reaction (OER). Remarkably, the symmetrical two-electrode cell using CoRu-CrOOH/NF only acquires 1.47 V at 10 mA cm-2 in 1.0 M KOH, which is superior to many other state-of-the-art overall water-splitting electrocatalysts. This holistic work provides a new insight to designing alloy/oxyhydroxide-integrated electrodes for high-efficiency overall water splitting.

Coherent ring-current migration of Mg-phthalocyanine probed by time-resolved X-ray circular dichroism.

The coherent ring current of Mg-phthalocyanine created by a broad band UV-visible pump pulse shows variation with time, where the ring currents at the corner benzene rings, around the Mg cation and on the outer ring oscillate with different time periods and the current density migrates among these regions. The 7 pairs of E u degenerate excited states populated upon photoexcitation, generate 21 distinct coherent ring currents. We further calculate the time-resolved X-ray circular dichroism (TRXCD) spectrum of the coherences contributing to the ring current obtained by an attosecond X-ray probe pulse resonant with the nitrogen K-edge. A frequency domain TRXCD signal obtained by a Fourier transform of the signal with respect to the pump-probe delay time clearly separates the currents induced by different state pairs.

Efficient evaluation of the Breit operator in the Pauli spinor basis.

The frequency-independent Coulomb-Breit operator gives rise to the most accurate treatment of two-electron interaction in the non-quantum-electrodynamics regime. The Breit interaction in the Coulomb gauge consists of magnetic and gauge contributions. The high computational cost of the gauge term limits the application of the Breit interaction in relativistic molecular calculations. In this work, we apply the Pauli component integral-density matrix contraction scheme for gauge interaction with a maximum spin- and component separation scheme. We also present two different computational algorithms for evaluating gauge integrals. One is the generalized Obara-Saika algorithm, where the Laplace transformation is used to transform the gauge operator into Gaussian functions and the Obara-Saika recursion is used for reducing the angular momentum. The other algorithm is the second derivative of Coulomb interaction evaluated with Rys-quadrature. This work improves the efficiency of performing Dirac-Hartree-Fock with the variational treatment of Breit interaction for molecular systems. We use this formalism to examine relativistic trends in the Periodic Table and analyze the relativistic two-electron interaction contributions in heavy-element complexes.

Metal-Organic Framework-Derived Three-Dimensional Macropore Nitrogen-Doped Carbon Frameworks Decorated with Ultrafine Ru-Based Nanoparticles for Overall Water Splitting.

Hydrogen energy with the advantages of green, sustainability, and high energy density has been considered as an alternative to fossil fuel energy. Water electrolysis to produce hydrogen is a promising energy conversion technology but limited to the large overpotential; thus, a highly efficient electrocatalyst is urgently needed. Herein, Ru-based electrocatalysts including an ultrathin Ru/three-dimensional (3D) macropore N-doped carbon framework (Ru/3DMNC) and ultrathin RuO2/3D macropore N-doped carbon framework (RuO2/3DMNC) are first prepared using a Zn-centered metal-organic framework (MOF, ZIF-8) as the precursor. The ultrathin 3D macropore framework structure together with N doping endows the as-synthesized Ru-based electrocatalysts with abundant exposed catalytic active sites, good electroconductivity, and excellent electron/mass transport, accomplishing improved activities for hydrogen evolution reaction (HER), oxygen evolution reaction (OER), and overall water splitting. The Ru/3DMNC and RuO2/3DMNC present low overpotentials of 50.96 and 216.74 mV to reach a current density of 10 mA cm-2. Moreover, the overall water splitting device constructed by Ru/3DMNC and RuO2/3DMNC as the cathode and anode catalysts, respectively, affords a current density of 10 mA cm-2 only at 1.51 V, which is superior to the Pt/C||RuO2 cell (1.573 V). This work provides a rational strategy to design and construct the efficient framework structure electrocatalysts for water splitting using MOFs as the precursor.