Airway epithelial CD47 plays a critical role in inducing influenza virus-mediated bacterial super-infection.

Respiratory viral infection increases host susceptibility to secondary bacterial infections, yet the precise dynamics within airway epithelia remain elusive. Here, we elucidate the pivotal role of CD47 in the airway epithelium during bacterial super-infection. We demonstrated that upon influenza virus infection, CD47 expression was upregulated and localized on the apical surface of ciliated cells within primary human nasal or bronchial epithelial cells. This induced CD47 exposure provided attachment sites for Staphylococcus aureus, thereby compromising the epithelial barrier integrity. Through bacterial adhesion assays and in vitro pull-down assays, we identified fibronectin-binding proteins (FnBP) of S. aureus as a key component that binds to CD47. Furthermore, we found that ciliated cell-specific CD47 deficiency or neutralizing antibody-mediated CD47 inactivation enhanced in vivo survival rates. These findings suggest that interfering with the interaction between airway epithelial CD47 and pathogenic bacterial FnBP holds promise for alleviating the adverse effects of super-infection.

Cell-adhesive double network self-healing hydrogel capable of cell and drug encapsulation: New platform to construct biomimetic environment with bottom-up approach.

This study presents the development and characterization of a novel double-network self-healing hydrogel based on N-carboxyethyl chitosan (CEC) and oxidized dextran (OD) with the incorporation of crosslinked collagen (CEC-OD/COL-GP) to enhance its biological and physicochemical properties. The hydrogel formed via dynamic imine bond formation exhibited efficient self-healing within 30 min, and a compressive modulus recovery of 92 % within 2 h. In addition to its self-healing ability, CEC-OD/COL-GP possesses unique physicochemical characteristics including transparency, injectability, and adhesiveness to various substrates and tissues. Cell encapsulation studies confirmed the biocompatibility and suitability of the hydrogel as a cell-culture scaffold, with the presence of a collagen network that enhances cell adhesion, spreading, long-term cell viability, and proliferation. Leveraging their unique properties, we engineered assemblies of self-healing hydrogel modules for controlled spatiotemporal drug delivery and constructed co-culture models that simulate angiogenesis in tumor microenvironments. Overall, the CEC-OD/COL-GP hydrogel is a versatile and promising material for biomedical applications, offering a bottom-up approach for constructing complex structures with self-healing capabilities, controlled drug release, and support for diverse cell types in 3D environments. This hydrogel platform has considerable potential for advancements in tissue engineering and therapeutic interventions.

Improved physical and structural properties of high-protein powders by fluidized-bed agglomeration.

High-protein powders (milk protein isolate (MPI) and soybean protein isolate (SPI)) were treated with maltodextrin solution (10% or 20%) or water as a binder and then subjected to fluidized-bed agglomeration. The MPI agglomerates were compared with the SPI agglomerates as a function of maltodextrin (MD) concentration. The particle size, wettability, and porosity values of SPI agglomerates were much higher than those of the raw powder when compared to the MPI agglomerates. The agglomerated protein powders with MD binder showed significantly higher solubility values than the raw powders. These tendencies were discernible in the morphological examination via SEM analysis. The dynamic modulus values of SPI agglomerates decreased with an increase in MD concentration from 10 to 20% whereas those of MPI agglomerates increased. These findings indicate that the physical, structural, and rheological properties of agglomerated high-protein powders are greatly influenced by the type of protein and the addition of MD binder.

Effect of platelet-rich plasma in Achilles tendon allograft in rabbits.

BACKGROUND: Achilles tendon is composed of dense connective tissue and is one of the largest tendons in the body. In veterinary medicine, acute ruptures are associated with impact injury or sharp trauma. Healing of the ruptured tendon is challenging because of poor blood and nerve supply as well as the residual cell population. Platelet-rich plasma (PRP) contains numerous bioactive agents and growth factors and has been utilized to promote healing in bone, soft tissue, and tendons. OBJECTIVE: The purpose of this study was to evaluate the healing effect of PRP injected into the surrounding fascia of the Achilles tendon after allograft in rabbits. METHODS: Donor rabbits (n = 8) were anesthetized and 16 lateral gastrocnemius tendons were fully transected bilaterally. Transected tendons were decellularized and stored at -80°C prior to allograft. The allograft was placed on the partially transected medial gastrocnemius tendon in the left hindlimb of 16 rabbits. The allograft PRP group (n = 8) had 0.3 mL of PRP administered in the tendon and the allograft control group (n = 8) did not receive any treatment. After 8 weeks, rabbits were euthanatized and allograft tendons were transected for macroscopic, biomechanical, and histological assessment. RESULTS: The allograft PRP group exhibited superior macroscopic assessment scores, greater tensile strength, and a histologically enhanced healing process compared to those in the allograft control group. CONCLUSIONS: Our results suggest administration of PRP on an allograft tendon has a positive effect on the healing process in a ruptured Achilles tendon.

Harnessing microRNA-enriched extracellular vesicles for liquid biopsy.

Extracellular microRNAs (miRNAs) can be detected in body fluids and hold great potential as cancer biomarkers. Extracellular miRNAs are protected from degradation by binding various proteins and through their packaging into extracellular vesicles (EVs). There is evidence that the diagnostic performance of cancer-associated extracellular miRNAs can be improved by assaying EV-miRNA instead of total cell-free miRNA, but several challenges have hampered the advancement of EV-miRNA in liquid biopsy. Because almost all types of cells release EVs, cancer cell-derived EVs might constitute only a minor fraction of EVs in body fluids of cancer patients with low volume disease. Furthermore, a given cell type can release several subpopulations of EVs that vary in their cargo, and there is evidence that the majority of EVs contain low copy numbers of miRNAs. In this mini-review, we discuss the potential of several candidate EV membrane proteins such as CD147 to define cancer cell-derived EVs, and approaches by which subpopulations of miRNA-rich EVs in body fluids might be identified. By integrating these insights, we discuss strategies by which EVs that are both cancer cell-derived and miRNA-rich could be isolated to enhance the diagnostic performance of extracellular miRNAs.

Clinical Characteristics, Diagnosis, and Treatment of Thyroid Stimulating Hormone-Secreting Pituitary Neuroendocrine Tumor (TSH PitNET): A Single-Center Experience.

BACKGRUOUND: Thyroid-stimulating hormone (TSH)-secreting pituitary neuroendocrine tumor (TSH PitNET) is a rare subtype of PitNET. We investigated the comprehensive characteristics and outcomes of TSH PitNET cases from a single medical center. Also, we compared diagnostic methods to determine which showed superior sensitivity. METHODS: A total of 17 patients diagnosed with TSH PitNET after surgery between 2002 and 2022 in Samsung Medical Center was retrospectively reviewed. Data on comprehensive characteristics and treatment outcomes were collected. The sensitivities of diagnostic methods were compared. RESULTS: Seven were male (41%), and the median age at diagnosis was 42 years (range, 21 to 65); the median follow-up duration was 37.4 months. The most common (59%) initial presentation was hyperthyroidism-related symptoms. Hormonal co-secretion was present in four (23%) patients. Elevated serum alpha-subunit (α-SU) showed the greatest diagnostic sensitivity (91%), followed by blunted response at thyrotropin-releasing hormone (TRH) stimulation (80%) and elevated sex hormone binding globulin (63%). Fourteen (82%) patients had macroadenoma, and a specimen of one patient with heavy calcification was negative for TSH. Among 15 patients who were followed up for more than 6 months, 10 (67%) achieved hormonal and structural remission within 6 months postoperatively. A case of growth hormone (GH)/TSH/prolactin (PRL) co-secreting mixed gangliocytoma-pituitary adenoma (MGPA) was discovered. CONCLUSION: The majority of the TSH PitNET cases was macroadenoma, and 23% showed hormone co-secretion. A rare case of GH/TSH/PRL co-secreting MGPA was discovered. Serum α-SU and TRH stimulation tests showed great diagnostic sensitivity. Careful consideration is needed in diagnosing TSH PitNET. Achieving remission requires complete tumor resection. In case of nonremission, radiotherapy or medical therapy can improve the long-term remission rate.

Chiral recognition and discrimination studies of tyrosine enantiomers on (-)-18-crown-6-tetracarboxylic acid as a chiral selector by nuclear magnetic resonance spectroscopy and docking simulations.

Considering the substantial significance of chiral biomolecules, such as amino acids, in our daily routines, we performed chiral recognition and discrimination of tyrosine (Tyr) enantiomers on (-)-(18-crown-6)-2,3,11,12-tetracarboxylic acid [(-)-18-C-6-TA] as crown-ether type chiral selector (CS) by nuclear magnetic resonance (NMR) spectroscopy and docking simulations. In this study, successful discrimination of the enantiomers of Tyr was achieved, as evidenced by the proton chemical shift differences (ΔΔδ) of Tyr enantiomers observed in the 1 H NMR spectra with (-)-18-C-6-TA CS. We compared the results of these two techniques with the findings obtained from high performance liquid chromatography (HPLC) investigations. In both NMR and HPLC experimental and docking simulation studies, a stronger interaction between the L-Tyr enantiomer with (-)-18-C-6-TA CS than the D-Tyr was consistently observed. Also, the binding energy differences (ΔΔEL-D ) found in simulation data that correspond to enantioselectivity aligned well with the NMR experimental result.

Skin microbe-dependent TSLP-ILC2 priming axis in early life is co-opted in allergic inflammation.

Although early life colonization of commensal microbes contributes to long-lasting immune imprinting in host tissues, little is known regarding the pathophysiological consequences of postnatal microbial tuning of cutaneous immunity. Here, we show that postnatal exposure to specific skin commensal Staphylococcus lentus (S. lentus) promotes the extent of atopic dermatitis (AD)-like inflammation in adults through priming of group 2 innate lymphoid cells (ILC2s). Early postnatal skin is dynamically populated by discrete subset of primed ILC2s driven by microbiota-dependent induction of thymic stromal lymphopoietin (TSLP) in keratinocytes. Specifically, the indole-3-aldehyde-producing tryptophan metabolic pathway, shared across Staphylococcus species, is involved in TSLP-mediated ILC2 priming. Furthermore, we demonstrate a critical contribution of the early postnatal S. lentus-TSLP-ILC2 priming axis in facilitating AD-like inflammation that is not replicated by later microbial exposure. Thus, our findings highlight the fundamental role of time-dependent neonatal microbial-skin crosstalk in shaping the threshold of innate type 2 immunity co-opted in adulthood.

Ethnic Differences in Thrombotic Profiles of Acute Coronary Syndrome Patients and Relationship to Cardiovascular Outcomes: A Comparison of East Asian and White subjects.

BACKGROUND: East Asians (EAs), compared to white Caucasians (W), have a lower risk of ischemic heart disease and a higher risk of bleeding with antithrombotic medications. The underlying mechanisms are incompletely understood. OBJECTIVES: We sought to compare thrombotic profiles of EA and W patients with myocardial infarction (MI) and relate these to cardiovascular outcomes. METHODS: In a prospective study in the United Kingdom and Korea, blood samples from patients (n = 515) with ST- or non-ST-elevation MI (STEMI and NSTEMI) were assessed using the Global Thrombosis Test, measuring thrombotic occlusion (OT) and endogenous fibrinolysis (lysis time [LT]). Patients were followed for 1 year for major adverse cardiovascular events (MACE) and bleeding. RESULTS: EA patients showed reduced OT (longer OT) compared to W (646 seconds [470-818] vs. 436 seconds [320-580], p < 0.001), with similar LT. In STEMI, OT (588 seconds [440-759] vs. 361 seconds [274-462], p < 0.001) and LT (1,854 seconds [1,389-2,729] vs. 1,338 seconds [1,104-1,788], p < 0.001) were longer in EA than W. In NSTEMI, OT was longer (OT: 734 seconds [541-866] vs. 580 seconds [474-712], p < 0.001) and LT shorter (1519 seconds [1,058-2,508] vs. 1,898 seconds [1,614-2,806], p = 0.004) in EA than W patients. MACE was more frequent in W than EA (6.3 vs. 1.9%, p = 0.014) and bleeding infrequent. While OT was unrelated, LT was a strong independent predictor of MACE event after adjustment for risk factors (hazard ratio: 3.70, 95% confidence interval: 1.43-9.57, p = 0.007), predominantly in W patients, and more so in STEMI than NSTEMI patients. CONCLUSION: EA patients exhibit different global thrombotic profiles to W, associated with a lower rate of cardiovascular events.

Do political parties always prefer loyalists? Evidence from South Korea.

This paper examines the relationship between ideological polarization and party disloyalty, focusing on the moderating role of the status of a political party in the legislature, i.e., the ruling party or the opposition party. It hypothesizes that the ruling party is willing to endorse disloyal candidates whose issue positions are not close to their own party's platform, whereas the opposition party is likely to punish disloyal candidates to demonstrate party unity in the nomination process. The present study tests this hypothesis, using data from South Korea, where the nomination process for the parliamentary election is dominated by party leaders. The results are by and large consistent with the hypotheses. In line with previous studies, our results suggest that party loyalty is one of the driving forces of polarization in politics. In order to fully understand party polarization at the level of political elites, it is necessary to consider heterogeneous effects of party members' behavior on candidate selection, varying across the party's status, either the ruling party or the opposition party.

Cardiovascular and Respiratory Effects of Increased Intra-Abdominal Pressure with and without Dexmedetomidine in Anesthetized Dogs.

Intra-abdominal pressure (IAP) elevation during capnoperitoneum can cause adverse cardiovascular and respiratory effects. This study aimed to determine if a sequentially increased IAP affects cardiovascular and respiratory variables in anesthetized dogs and evaluate the effects of the constant-rate infusion of dexmedetomidine (Dex) on cardiovascular and respiratory variables with increased IAP. Five dogs were anesthetized and instrumented, and a Veress needle was equipped to adjust the IAP using a carbon dioxide insufflator. Stabilization was conducted for 1 h, and physiological variables were measured at IAPs of 0, 5, 10, 15, and 20 mmHg and after desufflation. After the washout period, the dogs underwent similar procedures along with a constant-rate infusion of dexmedetomidine. The cardiovascular effects of increased IAP up to 20 mmHg were not significant in healthy beagle dogs and those administered with dexmedetomidine. When comparing the control and dexmedetomidine groups, the overall significant effects of dexmedetomidine were noted on heart rate, cardiac output, and systemic vascular resistance during the experiment. Respiratory effects were not observed during abdominal insufflation when compared between different IAPs and between the two groups. Overall, an increased IAP of up to 20 mmHg did not significantly affect cardiovascular and respiratory variables in both the control and dexmedetomidine groups. This study suggests that the administration of a dexmedetomidine infusion is applicable in laparoscopic procedures in healthy dogs.

Insensitive Effects of Inflammatory Cytokines on the Reference Genes of Synovial Fluid Resident-Mesenchymal Stem Cells Derived from Rheumatoid Arthritis Patients.

Mesenchymal stem cells derived from rheumatoid arthritis patients (RA-MSCs) provide an understanding of a variety of cellular and immunological responses within the inflammatory milieu. Sustained exposure of MSCs to inflammatory cytokines is likely to exert an influence on genetic variations, including reference genes (RGs). The sensitive effect of cytokines on the reference genes of RA-SF-MSCs may be a variation factor affecting patient-derived MSCs as well as the accuracy and reliability of data. Here, we comparatively evaluated the stability levels of nine RG candidates, namely GAPDH, ACTB, B2M, EEF1A1, TBP, RPLP0, PPIA, YWHAZ, and HPRT1, to find the most stable ones. Alteration of the RG expression was evaluated in MSCs derived from the SF of healthy donors (H-SF-MSCs) and in RA-SF-MSCs using the geNorm and NormFinder software programs. The results showed that TBP, PPIA, and YWHAZ were the most stable RGs for the normalization of H-SF-MSCs and RA-SF-MSCs using RT-qPCR, whereas ACTB, the most commonly used RG, was less stable and performed poorly. Additionally, the sensitivity of RG expression upon exposure to proinflammatory cytokines (TNF-α and IL-1ß) was evaluated. RG stability was sensitive in the H-SF-MSCs exposed to TNF-α and IL-1ß but insensitive in the RA-SF-MSCs. Furthermore, the normalization of IDO expression using ACTB falsely diminished the magnitude of biological significance, which was further confirmed with a functional analysis and an IDO activity assay. In conclusion, the results suggest that TBP, PPIA, and YWHAZ can be used in SF-MSCs, regardless of their exposure to inflammatory cytokines.

The pattern of intra-/inter-hemispheric interactions of left and right hemispheres in visual word processing.

This study aimed to investigate the intra-/inter-hemispheric interactions during visual word processing, by manipulating stimulus onset asynchrony (SOA) in a primed-lateralized lexical decision task. To assess intra-/inter-hemispheric priming effects, identical prime-target pairs were presented in the same or opposite unilateral visual fields. The study found that the right visual field advantage (RVFA) was observed when Korean words were presented sequentially within hemispheres, indicating that the inherent characteristics of the two hemispheres, rather than differences in memory or linguistic aspects of lexical processing, contributed to the hemispheric asymmetry. Additionally, intra-hemispheric priming effects were symmetrical in both hemispheres, with similar increases in priming for words and nonwords from SOA 120 ms to SOA 600 ms. Furthermore, inter-hemispheric priming effects were asymmetrical, with stronger priming when stimuli were presented in a sequence of LH→RH than in RH→LH. These findings suggest that the intrinsic differences in lexical processing between the two hemispheres may be related to the asymmetric pattern of hemispheric interactions in visual word processing.

Left-superiority in lexical processing was maintained in sequential presentation.Recency memory of lexical processing does not lead to hemispheric asymmetry.Symmetrical pattern in intra-hemispheric repetition primings was shown.Asymmetry pattern in inter-hemispheric repetition primings was observed.Hemispheric asymmetry of lexical processing have relevance to these patterns.

Diagnostic Value of a Wearable Continuous Electrocardiogram Monitoring Device (AT-Patch) for New-Onset Atrial Fibrillation in High-Risk Patients: Prospective Cohort Study.

BACKGROUND: While conventional electrocardiogram monitoring devices are useful for detecting atrial fibrillation, they have considerable drawbacks, including a short monitoring duration and invasive device implantation. The use of patch-type devices circumvents these drawbacks and has shown comparable diagnostic capability for the early detection of atrial fibrillation. OBJECTIVE: We aimed to determine whether a patch-type device (AT-Patch) applied to patients with a high risk of new-onset atrial fibrillation defined by the congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke, vascular disease, age 65-74 years, sex scale (CHA2DS2-VASc) score had increased detection rates. METHODS: In this nonrandomized multicenter prospective cohort study, we enrolled 320 adults aged ≥19 years who had never experienced atrial fibrillation and whose CHA2DS2-VASc score was ≥2. The AT-Patch was attached to each individual for 11 days, and the data were analyzed for arrhythmic events by 2 independent cardiologists. RESULTS: Atrial fibrillation was detected by the AT-Patch in 3.4% (11/320) of patients, as diagnosed by both cardiologists. Interestingly, when participants with or without atrial fibrillation were compared, a previous history of heart failure was significantly more common in the atrial fibrillation group (n=4/11, 36.4% vs n=16/309, 5.2%, respectively; P=.003). When a CHA2DS2-VASc score ≥4 was combined with previous heart failure, the detection rate was significantly increased to 24.4%. Comparison of the recorded electrocardiogram data revealed that supraventricular and ventricular ectopic rhythms were significantly more frequent in the new-onset atrial fibrillation group compared with nonatrial fibrillation group (3.4% vs 0.4%; P=.001 and 5.2% vs 1.2%; P<.001), respectively. CONCLUSIONS: This study detected a moderate number of new-onset atrial fibrillations in high-risk patients using the AT-Patch device. Further studies will aim to investigate the value of early detection of atrial fibrillation, particularly in patients with heart failure as a means of reducing adverse clinical outcomes of atrial fibrillation. TRIAL REGISTRATION: ClinicalTrials.gov NCT04857268; https://classic.clinicaltrials.gov/ct2/show/NCT04857268.

Chiral LC-MS/MS method for the discrimination of triiodothyronine enantiomers on a crown ether-based chiral stationary phase.

Considering the greater pharmaceutical and clinical interest of triiodothyronine (T3 ) thyroid hormone, an effective D/L-T3 enantiomer separation was performed on a crown ether-based chiral stationary phase by LC-MS/MS. In optimal analytical condition and selected reaction monitoring mode, the two enantiomers of T3 were baseline separated within 10 min. The limit of detection and limit of quantitation were found to be 0.05 and 0.10 ng/µl; 0.20 and 0.50 ng/µl for D- and L-T3 , respectively. During validation, this method proved to be feasible, accurate as well as enantioselective and sensitive for the resolution of T3 enantiomers. For commercial D- and L-T3 chemicals, the enantiomeric impurities as the other enantiomer were 0.11% and 4.61%. On the other hand, the impurity as D-T3 for commercial pharmaceutical products (liothyronine sodium tablets, two suppliers) was 0.68% and 6.57%.

Antibacterial and biofilm-inhibiting cotton fabrics decorated with copper nanoparticles grown on graphene nanosheets.

Infectious pathogens can be transmitted through textiles. Therefore, additional efforts are needed to develop functional fabrics containing antimicrobial substances to prevent the growth of antibiotic-resistant bacteria and their biofilms. Here, we developed a cotton fabric coated with reduced graphene oxide (rGO) and copper nanoparticles (Cu NPs), which possessed hydrophobic, antimicrobial, and anti-biofilm properties. Once the graphene oxide was dip-coated on a cellulose cotton fabric, Cu NPs were synthesized using a chemical reduction method to fabricate an rGO/Cu fabric, which was analyzed through FE-SEM, EDS, and ICP-MS. The results of our colony-forming unit assays indicated that the rGO/Cu fabric possessed high antibacterial and anti-biofilm properties against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermidis, Corynebacterium xerosis, and Micrococcus luteus. Particularly, the fabric could inhibit the growth of E. coli, C. xerosis, and M. luteus with a 99% efficiency. Furthermore, our findings confirmed that the same concentrations of rGO/Cu had no cytotoxic effects against CCD-986Sk and Human Dermal Fibroblast (HDF), human skin cells, and NIH/3T3, a mouse skin cell. The developed rGO/Cu fabric thus exhibited promising applicability as a cotton material that can maintain hygienic conditions by preventing the propagation of various bacteria and sufficiently suppressing biofilm formation while also being harmless to the human body.

Impact of dementia and drug compliance on patients with acute myocardial infarction.

BACKGROUND: In South Korea, the number of people with dementia is rising at a worrisome rate, and many of them also have acute myocardial infarction (AMI), a disease with a high mortality rate. HYPOTHESIS: We speculated that dementia and drug compliance have significant impact on the mortality of patients with AMI. METHODS: The study derived data from the National Health Insurance Service-Senior for a retrospective cohort study. The total number of patients diagnosed with AMI for the first time between 2007 and 2013 was 16 835, among whom 2021 had dementia. Medication possession ratio (MPR) was used to assess medication adherence. RESULTS: AMI patients with dementia had unfavorable baseline characteristics; they had significantly higher risk of all-cause mortality (hazard ratio [HR]: 2.49; 95% confidence interval [CI]: 2.34-2.66; p < .001) and lower MPR (aspirin: 21.9% vs. 42.8%; p < .001). AMI patients were stratified by presence of dementia and medication adherence, and the survival rate was the highest among those with no dementia and good adherence, followed by those with no dementia and poor adherence, those with dementia and good adherence, and those with dementia and poor adherence. The multivariable analysis revealed that dementia (HR: 1.64; 95% CI: 1.53-1.75; p < .001) and poor adherence to medication (HR: 1.60; 95% CI: 1.49-1.71; p < .001) had a significant association with all-cause mortality in AMI patients. CONCLUSIONS: AMI patients with dementia have a higher mortality rate. Their prognosis is negatively affected by their poorer medication adherence than patients without dementia.

Statins suppress cell-to-cell propagation of α-synuclein by lowering cholesterol.

Cell-to-cell propagation of protein aggregates has been implicated in the progression of neurodegenerative diseases. However, the underlying mechanism and modulators of this process are not fully understood. Here, we screened a small-molecule library in a search for agents that suppress the propagation of α-synuclein and mutant huntingtin (mHtt). These screens yielded several molecules, some of which were effective against both α-synuclein and mHtt. Among these molecules, we focused on simvastatin and pravastatin. Simvastatin administration in a transgenic model of synucleinopathy effectively ameliorated behavioral deficits and α-synuclein accumulation, whereas pravastatin had no effect. Because only simvastatin enters the brain effectively, these results suggest that inhibition of brain cholesterol synthesis is important in simvastatin effects. In cultured cells, accumulation of intracellular cholesterol, induced by genetic ablation of the NPC1 gene or by pharmacological treatment with U18666A, increased α-synuclein aggregation and secretion. In contrast, lowering cholesterol using methyl-ß-cyclodextrin or statins reversed α-synuclein aggregation and secretion in NPC1-knockout cells. Consistent with these observations, feeding a high-fat diet aggravated α-synuclein pathology and behavioral deficits in the preformed fibril-injected mouse model, an effect that was also reversed by simvastatin administration. These results suggest that statins suppress propagation of protein aggregates by lowering cholesterol in the brain.

Secreted Akkermansia muciniphila threonyl-tRNA synthetase functions to monitor and modulate immune homeostasis.

Commensal bacteria are critically involved in the establishment of tolerance against inflammatory challenges, the molecular mechanisms of which are just being uncovered. All kingdoms of life produce aminoacyl-tRNA synthetases (ARSs). Thus far, the non-translational roles of ARSs have largely been reported in eukaryotes. Here, we report that the threonyl-tRNA synthetase (AmTARS) of the gut-associated bacterium Akkermansia muciniphila is secreted and functions to monitor and modulate immune homeostasis. Secreted AmTARS triggers M2 macrophage polarization and orchestrates the production of anti-inflammatory IL-10 via its unique, evolutionary-acquired regions, which mediates specific interactions with TLR2. This interaction activates the MAPK and PI3K/AKT signaling pathways, which converge on CREB, leading to an efficient production of IL-10 and suppression of the central inflammatory mediator NF-κB. AmTARS restores IL-10-positive macrophages, increases IL-10 levels in the serum, and attenuates the pathological effects in colitis mice. Thus, commensal tRNA synthetases can act as intrinsic mediators that maintain homeostasis.