Synapse density is reduced in postmortem cortical tissue from schizophrenia patients, which is suggestive of increased synapse elimination. Using a reprogrammed in vitro model of microglia-mediated ...synapse engulfment, we demonstrate increased synapse elimination in patient-derived neural cultures and isolated synaptosomes. This excessive synaptic pruning reflects abnormalities in both microglia-like cells and synaptic structures. Further, we find that schizophrenia risk-associated variants within the human complement component 4 locus are associated with increased neuronal complement deposition and synapse uptake; however, they do not fully explain the observed increase in synapse uptake. Finally, we demonstrate that the antibiotic minocycline reduces microglia-mediated synapse uptake in vitro and its use is associated with a modest decrease in incident schizophrenia risk compared to other antibiotics in a cohort of young adults drawn from electronic health records. These findings point to excessive pruning as a potential target for delaying or preventing the onset of schizophrenia in high-risk individuals.
Pharmacological strategies that boost intracellular NAD
are highly coveted for their therapeutic potential. One approach is activation of nicotinamide phosphoribosyltransferase (NAMPT) to increase ...production of nicotinamide mononucleotide (NMN), the predominant NAD
precursor in mammalian cells. A high-throughput screen for NAMPT activators and hit-to-lead campaign yielded SBI-797812, a compound that is structurally similar to active-site directed NAMPT inhibitors and blocks binding of these inhibitors to NAMPT. SBI-797812 shifts the NAMPT reaction equilibrium towards NMN formation, increases NAMPT affinity for ATP, stabilizes phosphorylated NAMPT at His247, promotes consumption of the pyrophosphate by-product, and blunts feedback inhibition by NAD
. These effects of SBI-797812 turn NAMPT into a "super catalyst" that more efficiently generates NMN. Treatment of cultured cells with SBI-797812 increases intracellular NMN and NAD
. Dosing of mice with SBI-797812 elevates liver NAD
. Small molecule NAMPT activators such as SBI-797812 are a pioneering approach to raise intracellular NAD
and realize its associated salutary effects.
The clinical success of tissue-engineered constructs commonly requires mechanical properties that closely mimic those of the human tissue. Determining the viscoelastic properties of such biomaterials ...and the factors governing their failure profiles, however, has proven challenging, although collecting extensive data regarding their tensile behavior is straightforward. The easily calculated Young's modulus remains the most reported mechanical measure, regardless of its limitations, even though single-relaxation-time (SRT) models can provide much more information, which remain scarce due to a lack of manageable tools for implementing these models. We developed an easy-to-use algorithm for applying the Zener SRT model and determining the elastic moduli, viscosity, and failure profiles of materials under different mechanical tests in a user-independent manner. The algorithm was validated on the data resulting from tensile tests on native and decellularized porcine cardiac tissue, previously suggested as a promising scaffold material for cardiac tissue engineering. This analysis yields new and more accurate measurements such as the elastic moduli and viscosity, the model's relaxation time, and information on the factors governing the materials' failure profiles. These measurements indicate that the viscoelasticity and strength of the decellularized acellular extracellular matrix (ECM) are similar to those of native tissue, although its elasticity and apparent viscosity are higher. Nonetheless, reseeding and culturing the ECM with mesenchymal stem cells was shown to partially restore the mechanical properties lost after decellularization. We propose this algorithm as a platform for soft-tissue analysis that can provide comparable and unbiased measures for characterizing viscoelastic biomaterials commonly used in tissue engineering.
Multi-carrier continuous-variable quantum key distribution (CV-QKD) is considered to be a promising way to boost the secret key rate (SKR) over the existing single-carrier CV-QKD scheme. However, the ...extra excess noise induced in the imperfect multi-carrier quantum state preparation process of N subcarriers will limit the performance of the system. Here, a systematic modulation noise model is proposed for the multi-carrier CV-QKD based on the orthogonal frequency division multiplexing (OFDM). Subsequently, the performance of multi-carrier CV-QKD with arbitrary modulation protocol (e.g. QPSK, 256QAM and Gaussian modulation protocol) can be quantitatively evaluated by combining the security analysis method of the single-carrier CV-QKD. Under practical system parameters, the simulation results show that the SKR of the multi-carrier CV-QKD can still be significantly improved by increasing the carrier number N even with imperfect practical modulations. Specifically, the total SKR of multi-carrier CV-QKD can be optimized by carefully choosing N. The proposed model provides a feasible theoretical framework for the future multi-carrier CV-QKD experimental implementation.
We report the discovery of a multi-planetary system transiting the M0 V dwarf HD 260655 (GJ 239, TOI-4599). The system consists of at least two transiting planets, namely HD 260655 b, with a period ...of 2.77 d, a radius of R\(_b\) = 1.240\(\pm\)0.023 R\(_\oplus\), a mass of M\(_b\) = 2.14\(\pm\)0.34 M\(_\oplus\), and a bulk density of \(\rho_b\) = 6.2\(\pm\)1.0 g cm\(^{-3}\), and HD 260655 c, with a period of 5.71 d, a radius of R\(_c\) = 1.533\(^{+0.051}_{-0.046}\) R\(_\oplus\), a mass of M\(_c\) = 3.09\(\pm\)0.48 M\(_\oplus\), and a bulk density of \(\rho_c\) = 4.7\(^{+0.9}_{-0.8}\) g cm\(^{-3}\). The planets were detected in transit by the TESS mission and confirmed independently with archival and new precise radial velocities obtained with the HIRES and CARMENES instruments since 1998 and 2016, respectively. At a distance of 10 pc, HD 260655 becomes the fourth closest known multi-transiting planet system after HD 219134, LTT 1445 A, and AU Mic. Due to the apparent brightness of the host star (J = 6.7 mag), both planets are among the most suitable rocky worlds known today for atmospheric studies with the JWST, both in transmission and emission.
Cellular lipid requirements are achieved through a combination of biosynthesis and import programs. Using isotope tracer analysis, we show that type I interferon (IFN) signaling shifts the balance of ...these programs by decreasing synthesis and increasing import of cholesterol and long chain fatty acids. Genetically enforcing this metabolic shift in macrophages is sufficient to render mice resistant to viral challenge, demonstrating the importance of reprogramming the balance of these two metabolic pathways in vivo. Unexpectedly, mechanistic studies reveal that limiting flux through the cholesterol biosynthetic pathway spontaneously engages a type I IFN response in a STING-dependent manner. The upregulation of type I IFNs was traced to a decrease in the pool size of synthesized cholesterol and could be inhibited by replenishing cells with free cholesterol. Taken together, these studies delineate a metabolic-inflammatory circuit that links perturbations in cholesterol biosynthesis with activation of innate immunity.
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•Identification of a cholesterol metabolism-type I interferon (IFN) inflammatory circuit•Type I interferon reprograms cholesterol homeostasis•Perturbing cholesterol synthesis engages type I IFN signaling•STING/TBK1 links cholesterol metabolism with type I interferon pathway
Cholesterol metabolism and type I interferon response are co-regulated in macrophages, creating an immuno-metabolic circuit that allows innate immune cells to coordinate metabolism changes with immune activation required for antiviral responses.
The nucleotide-binding domain and leucine-rich-repeat-containing (NLR) proteins regulate innate immunity. Although the positive regulatory impact of NLRs is clear, their inhibitory roles are not well ...defined. We showed that
Nlrx1
−/−
mice exhibited increased expression of antiviral signaling molecules IFN-β, STAT2, OAS1, and IL-6 after influenza virus infection. Consistent with increased inflammation,
Nlrx1
−/−
mice exhibited marked morbidity and histopathology. Infection of these mice with an influenza strain that carries a mutated NS-1 protein, which normally prevents IFN induction by interaction with RNA and the intracellular RNA sensor RIG-I, further exacerbated IL-6 and type I IFN signaling. NLRX1 also weakened cytokine responses to the 2009 H1N1 pandemic influenza virus in human cells. Mechanistically,
Nlrx1 deletion led to constitutive interaction of MAVS and RIG-I. Additionally, an inhibitory function is identified for NLRX1 during LPS activation of macrophages where the MAVS-RIG-I pathway was not involved. NLRX1 interacts with TRAF6 and inhibits NF-κB activation. Thus, NLRX1 functions as a checkpoint of overzealous inflammation.
► NLRX1 attenuates IFN induction by preventing the interaction between RIG-I and MAVS ► NLRX1 functions as a negative regulator of IFN-I and IL-6 during influenza infection ► NLRX1 attenuates inflammation by intersecting the TRAF6 pathway to affect NF-κB
Inflammatory bowel diseases involve the dynamic interaction of host genetics, the microbiome and inflammatory responses. Here we found lower expression of NLRP12 (which encodes a negative regulator ...of innate immunity) in human ulcerative colitis, by comparing monozygotic twins and other patient cohorts. In parallel, Nlrp12 deficiency in mice caused increased basal colonic inflammation, which led to a less-diverse microbiome and loss of protective gut commensal strains (of the family Lachnospiraceae) and a greater abundance of colitogenic strains (of the family Erysipelotrichaceae). Dysbiosis and susceptibility to colitis associated with Nlrp12 deficency were reversed equally by treatment with antibodies targeting inflammatory cytokines and by the administration of beneficial commensal Lachnospiraceae isolates. Fecal transplants from mice reared in specific-pathogen-free conditions into germ-free Nlrp12-deficient mice showed that NLRP12 and the microbiome each contributed to immunological signaling that culminated in colon inflammation. These findings reveal a feed-forward loop in which NLRP12 promotes specific commensals that can reverse gut inflammation, while cytokine blockade during NLRP12 deficiency can reverse dysbiosis.
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