Impact of stabilizing mutations on the antigenic profile and glycosylation of membrane-expressed HIV-1 envelope glycoprotein.

Recent HIV-1 vaccine development has centered on "near native" soluble envelope glycoprotein (Env) trimers that are artificially stabilized laterally (between protomers) and apically (between gp120 and gp41). These mutations have been leveraged for use in membrane-expressed Env mRNA vaccines, although their effects in this context are unclear. To address this question, we used virus-like particle (VLP) produced in 293T cells. Uncleaved (UNC) trimers were laterally unstable upon gentle lysis from membranes. However, gp120/gp41 processing improved lateral stability. Due to inefficient gp120/gp41 processing, UNC is incorporated into VLPs. A linker between gp120 and gp41 neither improved trimer stability nor its antigenic profile. An artificially introduced enterokinase cleavage site allowed post-expression gp120/gp41 processing, concomitantly increasing trimer stability. Gp41 N-helix mutations I559P and NT1-5 imparted lateral trimer stability, but also reduced gp120/gp41 processing and/or impacted V2 apex and interface NAb binding. I559P consistently reduced recognition by HIV+ human plasmas, further supporting antigenic differences. Mutations in the gp120 bridging sheet failed to stabilize membrane trimers in a pre-fusion conformation, and also reduced gp120/gp41 processing and exposed non-neutralizing epitopes. Reduced glycan maturation and increased sequon skipping were common side effects of these mutations. In some cases, this may be due to increased rigidity which limits access to glycan processing enzymes. In contrast, viral gp120 did not show glycan skipping. A second, minor species of high mannose gp160 was unaffected by any mutations and instead bypasses normal folding and glycan maturation. Including the full gp41 cytoplasmic tail led to markedly reduced gp120/gp41 processing and greatly increased the proportion of high mannose gp160. Remarkably, monoclonal antibodies were unable to bind to this high mannose gp160 in native protein gels. Overall, our findings suggest caution in leveraging stabilizing mutations in nucleic acid-based immunogens to ensure they impart valuable membrane trimer phenotypes for vaccine use.

pH-sensitive release of nitric oxide gas using peptide-graphene co-assembled hybrid nanosheets.

Nitric oxide (NO) donating drugs such as organic nitrates have been used to treat cardiovascular diseases for more than a century. These donors primarily produce NO systemically. It is however sometimes desirable to control the amount, location, and time of NO delivery. We present the design of a novel pH-sensitive NO release system that is achieved by the synthesis of dipeptide diphenylalanine (FF) and graphene oxide (GO) co-assembled hybrid nanosheets (termed as FF@GO) through weak molecular interactions. These hybrid nanosheets were characterised by using X-ray diffraction, Raman spectroscopy, Fourier transform infrared spectroscopy, zeta potential measurements, X-ray photoelectron spectroscopy, scanning and transmission electron microscopies. The weak molecular interactions, which include electrostatic, hydrogen bonding and π-π stacking, are pH sensitive due to the presence of carboxylic acid and amine functionalities on GO and the dipeptide building blocks. Herein, we demonstrate that this formulation can be loaded with NO gas with the dipeptide acting as an arresting agent to inhibit NO burst release at neutral pH; however, at acidic pH it is capable of releasing NO at the rate of up to 0.6 µM per minute, comparable to the amount of NO produced by healthy endothelium. In conclusion, the innovative conjugation of dipeptide with graphene can store and release NO gas under physiologically relevant concentrations in a pH-responsive manner. pH responsive NO-releasing organic-inorganic nanohybrids may prove useful for the treatment of cardiovascular diseases and other pathologies.

Improved high-performance liquid chromatography tandem mass spectrometry method for quantification of infliximab in pediatric plasma and its application in therapeutic drug monitoring.

RATIONALE: The application of infliximab (IFX) to immune-mediated disease is limited by the significant individual variability and associated clinical nonresponse, emphasizing the importance of therapeutic drug monitoring (TDM). Because of the cross-reactivity, limited linear range, and high costs, the clinical application of the previous reported methods was limited. Here, an improved high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method was developed to address the issues. METHODS: This study developed an improved bioanalytical HPLC-MS/MS method coupling nanosurface and molecular-orientation limited proteolysis technology. The commercially available compound P14R was selected as the internal standard. This method was developed with fewer volume of reagents and was thoroughly validated. The validated method was applied to TDM in pediatric inflammatory bowel disease (IBD). RESULTS: Chromatography was performed using a Shim-pack GISS-HP C18 metal-free column (3 µm, 2.1 × 100 mm) with a gradient elution of 0.1% formic acid in water and acetonitrile at 0.4 mL/min. Detection and quantitation were performed using electrospray ionization (ESI) and multiple reaction monitoring in the positive ion mode. The method was validated to demonstrate its selectivity, linearity, accuracy, precision, recovery, matrix effect, and stability. The method exhibited a linear dynamic range of 0.3-100 µg/mL, with intra- and inter-day precision and relative errors below 15%. The recovery and matrix effect were measured as 87.28%-89.72% and 41.98%-67.17%, respectively, which were effectively compensated by the internal standard. A total of 32 samples collected from 24 pediatric patients with IBD were analyzed using the validated method, and only 46.9% achieved the reported targeted trough level. CONCLUSION: This study developed an improved HPLC-MS/MS method for the quantitative determination of IFX concentration in human plasma. The accurate, reliable, and cost-effective method was validated and utilized in the analysis of clinical samples. The results confirmed the importance of TDM on IFX and the clinical application prospects of the improved method.

Real-Time Imaging of Interfacial Copper(II) Ion-Initiated Selective Etching in the Core Region of Single Cuprous Oxide-Bismoclite Core-Shell Microcrystals.

The core-shell microstructures are attracting much interest, most notably for their superior performance compared with their pure counterparts because of the interfacial effect. Comprehensively understanding the mechanism of the interfacial effect is critical but still elusive. Here, we report real-time dark-field optical microscopy (DFM) imaging of the selective etching in the core region of single cuprous oxide-bismoclite (Cu2O@BiOCl) core-shell microcrystals by I-. In situ DFM observations reveal that the reaction activity of Cu2O is significantly improved after coating the BiOCl shell layer, and the I- diffuses through the BiOCl shell and approaches the interface region, followed by etching the Cu2O core. During the etching process, two distinct reaction pathways, such as interfacial Cu2+-driven redox etching and confinement-governed dissolution, are identified. The interfacial Cu2+ is generated due to the coordination number difference at the core-shell interface. Moreover, according to the in situ DFM single-crystal imaging results, the ensemble adsorption capacity improvement for I- is also demonstrated in Cu2O@BiOCl core-shell microcrystals. These findings provide deep insights into the interfacial effect of core-shell microcrystals and establish a bridge between microscopic imaging and macroscopic practical application.

Independent and joint associations of monocyte to high-density lipoprotein-cholesterol ratio and body mass index with cardiorenal syndrome: insights from NHANES 2003-2020.

BACKGROUND: With the development of pathophysiology, cardiorenal syndrome (CRS), a complex and severe disease, has received increasing attention. Monocyte to high-density lipoprotein-cholesterol ratio (MHR) and body mass index (BMI) are independent risk factors for cardiovascular diseases, but their association with CRS remains unexplored. This study aims to explore the independent and joint effects of MHR and BMI on CRS. METHODS: We included 42,178 NHANES participants. The determination of CRS referred to the simultaneous presence of cardiovascular disease (identified through self-report) and chronic kidney disease (eGFR < 60 mL/min per 1.73 m²). We employed multivariate weighted logistic regression to evaluate the odds ratio (OR) and 95% confidence interval (CI) for the independent and joint associations of MHR and BMI with CRS. We also conducted restricted cubic spines to explore nonlinear associations. RESULTS: The prevalence of CRS was 3.45% among all participants. An increase in both MHR and BMI is associated with a higher risk of CRS (MHR: OR = 1.799, 95% CI = 1.520-2.129, P < 0.001, P-trend < 0.001; BMI: OR = 1.037, 95% CI = 1.023-1.051, P < 0.001). Individuals who simultaneously fall into the highest quartile of MHR and have a BMI of 30 or more face the highest risk of CRS compared to those in the lowest MHR quartile with a BMI of less than 25 (OR = 3.45, 95% CI = 2.40-4.98, P < 0.001). However, there is no interactive association between MHR and BMI with CRS. CONCLUSIONS: Higher MHR and BMI are associated with higher odds of CRS. MHR and BMI can serve as tools for early prevention and intervention of CRS, respectively.

Unconditional and Robust Quantum Metrological Advantage beyond N00N States.

Quantum metrology employs quantum resources to enhance the measurement sensitivity beyond that can be achieved classically. While multiphoton entangled N00N states can in principle beat the shot-noise limit and reach the Heisenberg limit, high N00N states are difficult to prepare and fragile to photon loss which hinders them from reaching unconditional quantum metrological advantages. Here, we combine the idea of unconventional nonlinear interferometers and stimulated emission of squeezed light, previously developed for the photonic quantum computer Jiuzhang, to propose and realize a new scheme that achieves a scalable, unconditional, and robust quantum metrological advantage. We observe a 5.8(1)-fold enhancement above the shot-noise limit in the Fisher information extracted per photon, without discounting for photon loss and imperfections, which outperforms ideal 5-N00N states. The Heisenberg-limited scaling, the robustness to external photon loss, and the ease-of-use of our method make it applicable in practical quantum metrology at a low photon flux regime.

Solving Graph Problems Using Gaussian Boson Sampling.

Gaussian boson sampling (GBS) is not only a feasible protocol for demonstrating quantum computational advantage, but also mathematically associated with certain graph-related and quantum chemistry problems. In particular, it is proposed that the generated samples from the GBS could be harnessed to enhance the classical stochastic algorithms in searching some graph features. Here, we use Jiǔzhang, a noisy intermediate-scale quantum computer, to solve graph problems. The samples are generated from a 144-mode fully connected photonic processor, with photon click up to 80 in the quantum computational advantage regime. We investigate the open question of whether the GBS enhancement over the classical stochastic algorithms persists-and how it scales-with an increasing system size on noisy quantum devices in the computationally interesting regime. We experimentally observe the presence of GBS enhancement with a large photon-click number and a robustness of the enhancement under certain noise. Our work is a step toward testing real-world problems using the existing noisy intermediate-scale quantum computers and hopes to stimulate the development of more efficient classical and quantum-inspired algorithms.

Gaussian Boson Sampling with Pseudo-Photon-Number-Resolving Detectors and Quantum Computational Advantage.

We report new Gaussian boson sampling experiments with pseudo-photon-number-resolving detection, which register up to 255 photon-click events. We consider partial photon distinguishability and develop a more complete model for the characterization of the noisy Gaussian boson sampling. In the quantum computational advantage regime, we use Bayesian tests and correlation function analysis to validate the samples against all current classical spoofing mockups. Estimating with the best classical algorithms to date, generating a single ideal sample from the same distribution on the supercomputer Frontier would take ∼600 yr using exact methods, whereas our quantum computer, Jiǔzhang 3.0, takes only 1.27 µs to produce a sample. Generating the hardest sample from the experiment using an exact algorithm would take Frontier∼3.1×10^{10} yr.

Mettl3-mediated m6 A modification of Lrp2 facilitates neurogenesis through Ythdc2 and elicits antidepressant-like effects.

N6 -methyladenosine (m6 A) is the most abundant mRNA modification affecting diverse biological processes. However, the functions and precise mechanisms of m6 A signaling in adult hippocampal neurogenesis and neurogenesis-related depression remain largely enigmatic. We found that depletion of Mettl3 or Mettl14 in neural stem cells (NSCs) dramatically reduced m6 A abundance, proliferation, and neuronal genesis, coupled with enhanced glial differentiation. Conversely, overexpressing Mettl3 promoted proliferation and neuronal differentiation. Mechanistically, the m6 A modification of Lrp2 mRNA by Mettl3 enhanced its stability and translation efficiency relying on the reader protein Ythdc2, which in turn promoted neurogenesis. Importantly, mice lacking Mettl3 manifested reduced hippocampal neurogenesis, which could contribute to spatial memory decline, and depression-like behaviors. We found that these defective behaviors were notably reversed by Lrp2 overexpression. Moreover, Mettl3 overexpression in the hippocampus of depressive mice rescues behavioral defects. Our findings uncover the biological role of m6 A modification in Lrp2-mediated neurogenesis via m6 A-binding protein Ythdc2, and propose a rationale that targeting Mettl3-Ythdc2-Lrp2 axis regulation of neurogenesis might serve as a promising antidepressant strategy.

Preparation and Evaluation of Co-Doped Fe7S8/C Composites for Lithium Storage.

Fe7S8 has a high theoretical capacity (663 mAh g-1) and can be prepared at a low cost, making it advantageous for production. However, Fe7S8 has two disadvantages as a lithium-ion battery anode material. The first is that the conductivity of Fe7S8 is not good. The second is that when the lithium ion is embedded, the volume expansion of the Fe7S8 electrode is serious. That is why Fe7S8 has not been used in real life yet. In this paper, Co-Fe7S8/C composites were prepared by doping Co into Fe7S8 through a one-pot simple hydrothermal method. In situ Co is doped into Fe7S8 to produce a more disordered microstructure to improve ion and electron transport performance, thereby reducing the activation barrier of the main material. The Co-Fe7S8/C electrode presents a high specific discharge capacity of 1586 mAh g-1 and a Coulombic efficiency (CE) of 71.34% at an initial cycle at 0.1 A g-1. After 1500 cycles, the specific discharge capacity remains at 436 mAh g-1 (5 A g-1). When the current density returns to 0.1 A g-1, the capacity almost returns to the initial level, showing excellent rate performance.

Highly Efficient Coremoval of Nitrate and Phosphate Driven by a Sulfur-Siderite Composite Reactive Filler toward Secondary Effluent Polishing.

Reactive fillers consisting of reduced sulfur and iron species (SFe-ReFs) have received increasing attention in tertiary wastewater treatment for nitrate and phosphate coremoval. However, the existing SFe-ReFs suffer from either low performance (e.g., pyrrhotite and pyrite) or unsatisfactory use in terms of combustible risk and residual nonreactive impurities (e.g., sulfur mixing with natural iron ores). Here, we developed a new type of sulfur-siderite composite ReF (SSCReF) with a structure of natural siderite powders eventually embedded into sulfur. SSCReFs exhibited many excellent properties, including higher mechanical strengths and hardness and especially much poorer ignitability compared to pure sulfur. By using SSCReF to construct packed-bed reactors, the highest denitrification and dephosphorization rates reached 829.70 gN/m3/d (25 wt % siderite) and 36.70 gP/m3/d (75 wt % siderite), respectively. Dephosphorization was demonstrated to be dependent on sulfur-driven denitrification, in which the acid produced from the later process promoted Fe(II) dissolution, which then directly combined with phosphate to form vivianite or further converted into phosphate adsorbents (ferrihydrite, a green rust-like compound). Water flush was an effective way to finally wash out these surface deposited Fe-P compounds, as well as those nonreactive impurities (Si and Al-bearing compounds) detached from SSCReF. Such a highly efficient and safe SSCReF holds considerable application potential in secondary effluent polishing.

The Effect of Nitrogen Annealing on the Resistive Switching Characteristics of the W/TiO2/FTO Memory Device.

In this paper, the effect of nitrogen annealing on the resistive switching characteristics of the rutile TiO2 nanowire-based W/TiO2/FTO memory device is analyzed. The W/TiO2/FTO memory device exhibits a nonvolatile bipolar resistive switching behavior with a high resistance ratio (RHRS/RLRS) of about two orders of magnitude. The conduction behaviors of the W/TiO2/FTO memory device are attributed to the Ohmic conduction mechanism and the Schottky emission in the low resistance state and the high resistance state, respectively. Furthermore, the RHRS/RLRS of the W/TiO2/FTO memory device is obviously increased from about two orders of magnitude to three orders of magnitude after the rapid nitrogen annealing treatment. In addition, the change in the W/TiO2 Schottky barrier depletion layer thickness and barrier height modified by the oxygen vacancies at the W/TiO2 interface is suggested to be responsible for the resistive switching characteristics of the W/TiO2/FTO memory device. This work demonstrates the potential applications of the rutile TiO2 nanowire-based W/TiO2/FTO memory device for high-density data storage in nonvolatile memory devices.

A Facile Hydrothermal Synthesis and Resistive Switching Behavior of α-Fe2O3 Nanowire Arrays.

A facile hydrothermal process has been developed to synthesize the α-Fe2O3 nanowire arrays with a preferential growth orientation along the [110] direction. The W/α-Fe2O3/FTO memory device with the nonvolatile resistive switching behavior has been achieved. The resistance ratio (RHRS/RLRS) of the W/α-Fe2O3/FTO memory device exceeds two orders of magnitude, which can be preserved for more than 103s without obvious decline. Furthermore, the carrier transport properties of the W/α-Fe2O3/FTO memory device are dominated by the Ohmic conduction mechanism in the low resistance state and trap-controlled space-charge-limited current conduction mechanism in the high resistance state, respectively. The partial formation and rupture of conducting nanofilaments modified by the intrinsic oxygen vacancies have been suggested to be responsible for the nonvolatile resistive switching behavior of the W/α-Fe2O3/FTO memory device. This work suggests that the as-prepared α-Fe2O3 nanowire-based W/α-Fe2O3/FTO memory device may be a potential candidate for applications in the next-generation nonvolatile memory devices.

Experimental self-testing for photonic graph states.

Graph states-one of the most representative families of multipartite entangled states-are important resources for multiparty quantum communication, quantum error correction, and quantum computation. Device-independent certification of highly entangled graph states plays a prominent role in quantum information processing tasks. Here we have experimentally demonstrated device-independent certification for multipartite graph states by adopting the robust self-testing scheme based on scalable Bell inequalities. Specifically, the prepared multi-qubit Greenberger-Horne-Zeilinger (GHZ) states and linear cluster states achieve a high degree of Bell violation, which are beyond the nontrivial bounds of the robust self-testing scheme. Furthermore, our work paves the way to the device-independent certification of complex multipartite quantum states.

Experimental Demonstration of Quantum Pseudotelepathy.

Quantum pseudotelepathy is a strong form of nonlocality. Different from the conventional nonlocal games where quantum strategies win statistically, e.g., the Clauser-Horne-Shimony-Holt game, quantum pseudotelepathy in principle allows quantum players to with probability 1. In this Letter, we report a faithful experimental demonstration of quantum pseudotelepathy via playing the nonlocal version of Mermin-Peres magic square game, where Alice and Bob cooperatively fill in a 3×3 magic square. We adopt the hyperentanglement scheme and prepare photon pairs entangled in both the polarization and the orbital angular momentum degrees of freedom, such that the experiment is carried out in a resource-efficient manner. Under the locality and fair-sampling assumption, our results show that quantum players can simultaneously win all the queries over any classical strategy.

Hong-Ou-Mandel Interference between Two Hyperentangled Photons Enables Observation of Symmetric and Antisymmetric Particle Exchange Phases.

Two-photon Hong-Ou-Mandel (HOM) interference is a fundamental quantum effect with no classical counterpart. The existing research on two-photon interference was mainly limited in one degree of freedom (DOF); hence, it is still a challenge to realize quantum interference in multiple DOFs. Here, we demonstrate HOM interference between two hyperentangled photons in two DOFs of polarization and orbital angular momentum (OAM) for all 16 hyperentangled Bell states. We observe hyperentangled two-photon interference with a bunching effect for ten symmetric states (nine boson-boson states and one fermion-fermion state) and an antibunching effect for six antisymmetric states (three boson-fermion states and three fermion-boson states). More interestingly, expanding the Hilbert space by introducing an extra DOF for two photons enables one to transfer the unmeasurable external phase in the initial DOF to a measurable internal phase in the expanded two DOFs. We directly measured the symmetric exchange phases being 0.012±0.002, 0.025±0.002, and 0.027±0.002 in radian for the three boson states in OAM and the antisymmetric exchange phase being 0.991π±0.002 in radian for the other fermion state, as theoretical predictions. Our Letter may not only pave the way for more wide applications of quantum interference, but also develop new technologies by expanding Hilbert space in more DOFs.

PPARß mediates mangiferin-induced neuronal differentiation of neural stem cells through DNA demethylation.

Adult hippocampal neurogenesis (AHN) is heavily implicated in the pathogenesis of various neuropsychiatric disorders. The mangiferin (MGF), a bioactive compound of the mango, reportedly produces biological effects on a variety of neuropsychiatric disorders. However, the function and underlying mechanisms of MGF in regulating hippocampal neurogenesis remain unknown. Here we discovered that the transcriptome and methylome of MGF-induced neural stem cells (NSCs) are distinct from the control. RNA-seq analysis revealed that the diferentially expressed genes (DEGs) were signifcantly enriched in the PPARs. Furthermore, we found that MGF enhanced neuronal differentiation and proliferation of neural stem cells (NSCs) via PPARß but not PPARα and PPARγ. The combination of WGBS and RNA-seq analysis showed that the expression of some neurogenesis genes was negatively correlated with the DNA methylation level generally. We further found that PPARß increased demethylation of Mash1 promoter by modulating the expressions of active and passive DNA demethylation enzymes in MGF-treated NSCs. Importantly, genetic deficiency of PPARß decreased hippocampal neurogenesis in the adult mice, whereas the defective neurogenesis was notably rescued by Mash1 overexpression. Our findings uncover a model that PPARß-mediated DNA demethylation of Mash1 contributes to MGF-induced neuronal genesis, and advance the concept that targeting PPARß-TET1/DNMT3a-Mash1 axis regulation of neurogenesis might serve as a novel neurotherapeutic strategy.

Health-related quality of life questionnaires used in primary biliary cholangitis: a systematic review.

OBJECTIVE: The purpose of this systematic review was to assess the suitability of health-related quality of life (HRQOL) questionnaires in patients with primary biliary cholangitis. METHODS: Relevant studies were compiled from a search of five electronic databases. The properties under investigation included the validity of the translated questionnaires, floor and ceiling effects, internal consistency and test-retest reliability. RESULTS: Forty-four studies were included, from which fifteen HRQOL questionnaires were identified. The most frequently used instruments were the PBC-40 (n = 22), the SF-36 (n = 19), the PBC-27 (n = 4), the CLDQ (n = 3) and the NIDDK-QA (n = 2). The remaining instruments were used only once. Twenty-six studies used a translated HRQOL questionnaire, but only six reported or referenced validating the translated questionnaire. CONCLUSIONS: PBC-specific HRQOL questionnaires generally have good psychometric properties. However, many studies have directly applied HRQOL tools without verifying their validity and reliability in PBC patients. There was no clear indication that one HRQOL tool was superior to another, although the PBC-40 is the most well-studied. Thus, more robust psychometric studies are needed to investigate the measurement properties of HRQOL questionnaires.

Vascular Analysis of Soft Tissues Around the Bone Lesion in Osteoradionecrosis, Medication-Related Osteonecrosis, and Infectious Osteomyelitis of the Jaw.

OBJECTIVE: The histopathological differences of the surrounding soft tissues in osteoradionecrosis of the jaw, medication-related osteonecrosis of the jaw as well as infectious osteomyelitis of the jaw patients were rarely investigated. Here, we focused on the vascular microarchitecture of the soft tissues around bone lesion and compared the microvessel difference of ORNJ, MRONJ, and IOMJ in a quantitative fashion. METHODS: A series of consecutive patients diagnosed as ORNJ, MRONJ, and acute/chronic IOMJ was retrospectively reviewed. All cases received preoperative cone bean computed tomography scans. Immunohistochemistry of CD34 was performed with the streptavidin-peroxidase method and the variables including vascular density, vascular area fraction, mean vessel lumen area, perimeter and diameter of the vessels as well as percentage of lumen less than 400 µm2 were analyzed. RESULTS: The results showed that the vascular-like structures were visible in more cases of acute/chronic IOMJ compared with ORNJ and MRONJ by hematoxylin-eosin staining. Quantitively, our results demonstrated the decreased vascular density, mean perimeter and diameter of the vessels but increased percentage of small vessels in ORNJ and MRONJ patients in contrast with IOMJ patients. CONCLUSIONS: Hypovascularity of surrounding soft tissues could play important roles in the etiology of IOMJ, ORNJ, and MRONJ, and microvessel profile may be a useful pathological diagnostic indicator to differentiate these 3 types of OMJ.

The Firing of Theta State-Related Septal Cholinergic Neurons Disrupt Hippocampal Ripple Oscillations via Muscarinic Receptors.

The septo-hippocampal cholinergic system is critical for hippocampal learning and memory. However, a quantitative description of the in vivo firing patterns and physiological function of medial septal (MS) cholinergic neurons is still missing. In this study, we combined optogenetics with multichannel in vivo recording and recorded MS cholinergic neuron firings in freely behaving male mice for 5.5-72 h. We found that their firing activities were highly correlated with hippocampal theta states. MS cholinergic neurons were highly active during theta-dominant epochs, such as active exploration and rapid eye movement sleep, but almost silent during non-theta epochs, such as slow-wave sleep (SWS). Interestingly, optogenetic activation of these MS cholinergic neurons during SWS suppressed CA1 ripple oscillations. This suppression could be rescued by muscarinic M2 or M4 receptor antagonists. These results suggest the following important physiological function of MS cholinergic neurons: maintaining high hippocampal acetylcholine level by persistent firing during theta epochs, consequently suppressing ripples and allowing theta oscillations to dominate.SIGNIFICANCE STATEMENT The major source of acetylcholine in the hippocampus comes from the medial septum. Early experiments found that lesions to the MS result in the disappearance of hippocampal theta oscillation, which leads to speculation that the septo-hippocampal cholinergic projection contributing to theta oscillation. In this article, by long-term recording of MS cholinergic neurons, we found that they show a theta state-related firing pattern. However, optogenetically activating these neurons shows little effect on theta rhythm in the hippocampus. Instead, we found that activating MS cholinergic neurons during slow-wave sleep could suppress hippocampal ripple oscillations. This suppression is mediated by muscarinic M2 and M4 receptors.