Therapeutic drug monitoring of azole antifungal agents.

Deep-seated mycoses are generally opportunistic infections that are difficult to diagnose and treat. They are expected to increase with the spread of advanced medical care and aging populations, thus highlighting the need for safe, effective, and rapid drug-based treatments. Depending on a patient's age, sex, underlying diseases, and immune system status, therapeutic drug monitoring (TDM) may be important for assessing variable pharmacokinetic parameters, as well as preventing drug-drug interactions, adverse events, and breakthrough infections caused by fungal resistance. Azole antifungal agents play an important role in the prevention and treatment of deep-seated fungal infections, with each azoles having its own unique pharmacokinetic properties and specific adverse events. Therefore, it is necessary to use national and international guidelines to build evidence for the expansion of TDM indications. This review focuses on the clinical utility and future perspectives of TDM using azole antifungal agents, in the context of recent evidence in the literature.

Optimized Antifungal Therapy for Chronic Pulmonary Aspergillosis.

Chronic pulmonary aspergillosis (CPA) represents a spectrum of lung disorders caused by local proliferation of Aspergillus hyphae in individuals with non-systemic or mildly systemic immunodepression or altered pulmonary integrity due to underlying disease. While long-term systemic antifungal treatment is still the mainstay for management, surgery is considered mainly in rarer invasive disease manifestations such as sinusitis and osteomyelitis. Optimal application of existing antifungal agents with suitable pharmacokinetic properties is important for the treatment of diseases such as CPA, which requires long-term use. Appropriate management of side effects by therapeutic drug monitoring, maintenance of adherence, and assessment of drug resistance to Aspergillus can provide safe and effective treatment in the future. Most available antifungal agents for the management of mycoses in humans have disadvantages that can limit their use in clinical practice. By contrast, second generation antifungals such as triazoles have advantages of extended antifungal spectrum and availability in both oral and intravenous formulations. Isavuconazole, a new extended spectrum triazole, has been shown to be effective against Aspergillus. The safety profile and excellent pharmacokinetic characteristics of isavuconazole make it an attractive option for treatment of invasive fungal infections including CPA. With this drug now available in Japan, new evidence is expected to expand treatment options. This review focuses on the selection of antifungal agents based on national and international guidelines and the characteristics of each agent for their appropriate use in CPA.

Outcome evaluation of pharmacist-physician collaborative protocol-based antimicrobial treatment for hospitalized stroke patients with aspiration pneumonia.

OBJECTIVES: To evaluate the efficacy and patient outcomes of pharmacist-physician collaborative protocol-based antimicrobial treatment regimens for antimicrobial stewardship. METHODS: Patients treated for aspiration pneumonia due to stroke within 48 h after admission to Kochi Medical School Hospital (January 2019 to December 2022) were included. Primary outcomes were the cumulative number of days of antimicrobial treatment and length of hospital stay. Secondary outcomes included the percentage of patients under-dosed with first-choice antimicrobial agents and inpatient mortality. RESULTS: Group A (66 patients) did not receive the antimicrobial treatment protocol, whereas group B (46 patients) did. There were no differences in the patient backgrounds. Group B had a significantly lower percentage of patients who were undertreated with the first-choice antimicrobial agent (9.1 % vs. 42.9 %). There was no significant difference in inpatient mortality between group A and group B (6.1 % vs. 4.3 %). The cumulative number of days of antimicrobial administration and the length of hospital stay were significantly lower in group B: 7.0 days (95 % CI, 6.0-8.0) vs. 9.0 days (95 % CI, 8.0-11.0) for antimicrobial administration, and 28.5 days (95 % CI, 22.0-35.0) vs. 43.0 days (95 % CI, 28.0-55.0) for hospital stay. CONCLUSIONS: Protocol-based antimicrobial treatment for aspiration pneumonia supports appropriate antimicrobial usage and improves patient quality of life. These findings will assist in the effective treatment of aspiration pneumonia in an aging society.

Management of a Large Cerebral Abscess in Children Caused by Campylobacter gracilis: A Case Report and Review of the Literature.

Campylobacter gracilis inhabits the gingival sulcus and has been reported to cause various periodontal diseases; it has rarely been reported to cause bacteremia. We describe a case of a two-year-old boy who presented with a consciousness disorder and was transferred to our hospital for treatment of a brain abscess. Magnetic resonance imaging (MRI) showed a 6-cm brain abscess in the right frontal lobe. Urgent drainage and antibiotic administration resulted in a favorable clinical course, and the patient was discharged on the 34th day of hospitalization. Streptococcus anginosus and C. gracilis were identified in the pus. Brain abscesses caused by C. gracilis have rarely been reported, which makes this a valuable case.

Epidemiological Study on Case Definition of Methicillin-Resistant Staphylococcus aureus Enteritis.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) enteritis is a condition in which MRSA grows abnormally in the intestine after administration of antimicrobial agents, resulting in enteritis. Patients with MRSA detected in stool culture tests are often diagnosed with MSRA enteritis. However, uncertainty remains in the diagnostic criteria; therefore, we conducted epidemiological studies to define these cases. Patients and Methods: Patients who tested positive for MRSA by stool culture using selective media 48 h after admission to Kochi Medical School Hospital between April 1, 2012, and December 31, 2022, and did not meet the exclusion criteria were included. We defined MRSA enteritis (Group A) as cases that were responsive to treatment with vancomycin hydrochloride powder, had a Bristol Stool Scale of ≥ 5, and a stool frequency of at least three times per day; all others were MRSA carriers (Group B). Multivariate analysis was performed to risk factors associated with MRSA enteritis. Results: Groups A and B included 18 (25.4%) and 53 (74.6%) patients, respectively. Multivariate logistic regression analysis showed that a white blood cell count of > 10000/µL (odds ratio [OR], 5.50; 95% confidence interval [CI], 1.12-26.9), MRSA count of ≥ 2+ in stool cultures (OR, 8.91; 95% CI, 1.79-44.3), and meropenem administration within 1 month of stool specimen submission (OR, 7.47; 95% CI, 1.66-33.6) were risk factors of MRSA enteritis. Conclusion: The case definitions reviewed for MRSA enteritis may be useful as diagnostic criteria.

Translational enhancement of target endogenous mRNA in mammalian cells using programmable RNA-binding pentatricopeptide repeat proteins.

Programmable protein scaffolds are invaluable in the development of genome engineering tools. The pentatricopeptide repeat (PPR) protein is an attractive platform for RNA manipulation because of its programmable RNA-binding selectivity, which is determined by the combination of amino acid species at three specific sites in the PPR motif. Translation is a key RNA regulatory step that determines the final gene expression level and is involved in various human diseases. In this study, designer PPR protein was used to develop a translational enhancement technique by fusion with the translation initiation factor eIF4G. The results showed that the PPR-eIF4G fusion protein could activate the translation of endogenous c-Myc and p53 mRNAs and control cell fate, indicating that PPR-based translational enhancement is a versatile technique applicable to various endogenous mRNAs in mammalian cells. In addition, the translational enhancement was dependent on both the target position and presence of eIF4G, suggesting the presence of an unknown translation activation mechanism.

Synthesis and Biological Evaluation of a Novel Sugar-Conjugated Platinum(II) Complex Having a Tumor-Targeting Effect.

We designed and synthesized a novel platinum complex conjugated with 2-fluorinated 2-deoxyglucoside, named FGC-Pt, to capitalize on the Warburg effect and metabolic trapping properties of [18F]2-deoxy-2-fluoro-d-glucose ([18F]FDG). Then, we conducted comprehensive in vitro and in vivo studies to evaluate the effects of FGC-Pt. In vitro cytotoxicity assays using HeLa cells revealed that FGC-Pt exhibited concentration-dependent cytotoxicity, even though its cytotoxic effect was less pronounced than that of cisplatin. In the evaluation of in vivo biodistribution in mice, platinum concentration in tumors and major organs (muscle, bone, blood, liver, and kidney) and the ratio of platinum concentration in tumors to major organs following the tail vein injection of FGC-Pt and cisplatin suggest that FGC-Pt is more retained in tumors than in other organs and tends to accumulate in tumors more than cisplatin. Furthermore, an in vivo assessment of the antitumor effect conducted in A549 cell-bearing mice demonstrated that FGC-Pt possesses substantial potential as an antitumor agent. It exhibited a tumor growth-inhibitory effect comparable to that of cisplatin while inducing lower toxicity, as evidenced by lower weight loss after administration. Herein, we successfully produced a novel compound with a tumor-growth-inhibitory effect comparable to that of cisplatin and low toxicity.

Production and synthesis of a novel 191Pt-labeled platinum complex and evaluation of its biodistribution in healthy mice.

We previously reported that our sugar-conjugated platinum complex (cis-dichloro [(2-fluoro-α-d-glucopylanosidyl) propane-1,3-diamine] platinum: FGC-Pt) has low toxicity and tumor growth inhibitory effect comparable to that of cisplatin. We focused on radioactive Pt isotopes in order to analyze the kinetics of FGC-Pt using gamma-ray imaging techniques, assuming that FGC-Pt could be used for chemotherapy in the future. Therefore, in this study, we aimed to develop a non-invasive method to analyze the biodistribution of FGC-Pt using 191Pt-labeled FGC-Pt ([191Pt]FGC-Pt). 191Pt was produced via the (n,2n) reaction induced by accelerator neutrons. [191Pt]FGC-Pt was prepared using two different methods. In the first method, [191Pt]FGC-Pt (method A) was obtained through the accelerator neutron irradiation of FGC-Pt. In the second method, [191Pt]FGC-Pt (method B) was synthesized using [191Pt]K2PtCl4, which was obtained by the accelerator neutron irradiation of K2PtCl4. Highly purified [191Pt]FGC-Pt was obtained using the latter method, which suggests that the synthetic method using a 191Pt-labeled platinum reagent is suitable for the radioactivation of platinum complexes. We also aimed to investigate whether a significant correlation existed between the biodistribution of FGC-Pt and [191Pt]FGC-Pt in healthy mice 24 h after tail vein administration. FGC-Pt and [191Pt]FGC-Pt were similarly distributed in healthy mice, with a higher accumulation in the liver and kidney 24 h post injection. In addition, a significant correlation (p < 0.05, r = 0.92) between the 191Pt radioactivity concentration (%ID/g (gamma counter)) and platinum concentration (%ID/g (ICP-MS)) was observed in 13 organs. These results suggest that 191Pt-labeled compounds, synthesized using radioactive platinum reagents, can be used to confirm the biodistribution of platinum compounds. Our study on the biodistribution of [191Pt]FGC-Pt is expected to contribute to the development of novel platinum-based drugs in the future.

Effect of Water on Direct Radioiodination of Small Molecules/Peptides Using Copper-Mediated Iododeboronation in Water-Alcohol Solvent.

Direct radioiodination of peptides using copper-mediated iododeboronation is a promising radiosynthetic method for solving issues of classical direct radiolabeling, such as toxicity of the organotin precursor (iododestannylation) or formation of radio byproducts (by electrophilic iodination of a tyrosine residue). However, the parameters for optimizing the reaction conditions for various peptides are not completely understood. In particular, considering peptide solubility, the effects of water-containing solvents on labeling efficiency should be thoroughly investigated. Herein, we describe the effect of water on copper-mediated radioiododeboronation and the key factors for ensuring the successful radiolabeling of small molecules and peptides in water-organic solvents. 125I-labeled substrates containing peptides ([125I]m/p-IBTA) were obtained with high radiochemical conversions (RCCs: >95%) using an alcohol solvent, and a decrease in these RCCs was observed with increasing water content in the methanol solvent. Additionally, when using water-methanol solvents, a difference in RCC due to the substituent effect was also observed. However, the RCCs can be improved without the use of other additives by adjusting the copper catalyst and time of the labeling reaction or by utilizing substituent effects. This study contributes to the improvement of the design of boronic peptide precursors and radiolabeling protocols using copper-mediated iododeboronation.

First case of bacteremia caused by Cetobacterium somerae following necrotizing cholecystitis.

Cetobacterium somerae, a gram-negative anaerobic rod, first identified in the feces of children with autism, also colonize freshwater fish intestinal tract. However there have been no reports of human C. somerae infection. Here, we describe the first case of C. somerae bacteremia in a patient with necrotizing cholecystitis. A 72-year-old male presented to the emergency department with chills, vomiting, and fever and was diagnosed with acute necrotizing cholecystitis. An emergency cholecystectomy was performed and the following day, two sets of blood culture were positive for gram-negative bacilli. Identification of C. somerae from the biochemical profile was difficult but possible by mass spectrometry and 16s rRNA sequence.

Novel [ 111 In]In-BnDTPA-EphA2-230-1 Antibody for Single-Photon Emission Computed Tomography Imaging Tracer Targeting of EphA2.

Erythropoietin-producing hepatocellular receptor A2 (EphA2) is overexpressed in cancer cells and causes abnormal cell proliferation. Therefore, it has attracted attention as a target for diagnostic agents. In this study, the EphA2-230-1 monoclonal antibody (EphA2-230-1) was labeled with [111In]In and evaluated as an imaging tracer for single-photon emission computed tomography (SPECT) of EphA2. EphA2-230-1 was conjugated with 2-(4-isothiocyanatobenzyl)-diethylenetriaminepentaacetic acid (p-SCN-BnDTPA) and then labeled with [111In]In. [111In]In-BnDTPA-EphA2-230-1 was evaluated in cell-binding, biodistribution, and SPECT/computed tomography (CT) studies. The cellular uptake ratio of [111In]In-BnDTPA-EphA2-230-1 was 14.0 ± 2.1%/mg protein at 4 h in the cell-binding study. In the biodistribution study, a high uptake of [111In]In-BnDTPA-EphA2-230-1 was observed in tumor tissue (14.6 ± 3.2% injected dose/g at 72 h). The superior accumulation of [111In]In-BnDTPA-EphA2-230-1 in tumors was also confirmed using SPECT/CT. Therefore, [111In]In-BnDTPA-EphA2-230-1 has potential as a SPECT imaging tracer for EphA2.

Construction of a Versatile, Programmable RNA-Binding Protein Using Designer PPR Proteins and Its Application for Splicing Control in Mammalian Cells.

RNAs play many essential roles in gene expression and are involved in various human diseases. Although genome editing technologies have been established, the engineering of sequence-specific RNA-binding proteins that manipulate particular cellular RNA molecules is immature, in contrast to nucleotide-based RNA manipulation technology, such as siRNA- and RNA-targeting CRISPR/Cas. Here, we demonstrate a versatile RNA manipulation technology using pentatricopeptide-repeat (PPR)-motif-containing proteins. First, we developed a rapid construction and evaluation method for PPR-based designer sequence-specific RNA-binding proteins. This system has enabled the steady construction of dozens of functional designer PPR proteins targeting long 18 nt RNA, which targets a single specific RNA in the mammalian transcriptome. Furthermore, the cellular functionality of the designer PPR proteins was first demonstrated by the control of alternative splicing of either a reporter gene or an endogenous CHK1 mRNA. Our results present a versatile protein-based RNA manipulation technology using PPR proteins that facilitates the understanding of unknown RNA functions and the creation of gene circuits and has potential for use in future therapeutics.

U-to-C RNA editing by synthetic PPR-DYW proteins in bacteria and human culture cells.

Programmable RNA editing offers significant therapeutic potential for a wide range of genetic diseases. Currently, several deaminase enzymes, including ADAR and APOBEC, can perform programmable adenosine-to-inosine or cytidine-to-uridine RNA correction. However, enzymes to perform guanosine-to-adenosine and uridine-to-cytidine (U-to-C) editing are still lacking to complete the set of transition reactions. It is believed that the DYW:KP proteins, specific to seedless plants, catalyze the U-to-C reactions in mitochondria and chloroplasts. In this study, we designed seven DYW:KP domains based on consensus sequences and fused them to a designer RNA-binding pentatricopeptide repeat (PPR) domain. We show that three of these PPR-DYW:KP proteins edit targeted uridine to cytidine in bacteria and human cells. In addition, we show that these proteins have a 5' but not apparent 3' preference for neighboring nucleotides. Our results establish the DYW:KP aminase domain as a potential candidate for the development of a U-to-C editing tool in human cells.

Copper-mediated radioiodination and radiobromination via aryl boronic precursor and its application to 125I/77Br-labeled prostate-specific membrane antigen imaging probes.

Prostate-specific membrane antigen (PSMA), expressed in prostate cancer cells, is being investigated extensively worldwide as a target for imaging and therapy of prostate cancer. Various radioiodinated PSMA imaging probes have been developed, and their structure has a peptidomimetic urea-based skeleton as a pharmacophore. For direct radioiodination of molecules containing these peptidomimetic structures, prior studies performed radioiododestannylation or electrophilic radioiodination of tyrosine residues. However, although these radiolabeling methods are frequently used, there are some issues with precursor toxicity and by-product production. Therefore, it is required to investigate a radiolabeling method that can be used for the radiosynthesis of radioiodinated PSMA imaging probes with urea-based peptidomimetic structures. We recently reported that copper-mediated radioiodination via a boronic precursor is an effective method for directly labeling a peptide. This radiohalogenation method was expected to be an effective method for radiosynthesis of PSMA imaging probes with a peptidomimetic structure. In this study, to confirm that this labeling method applies to the synthesis of the PSMA imaging probe, we synthesized PSMA imaging probes labeled with 125I and 77Br ([125I]mIB-PS and [77Br]mBrB-PS) using a copper-mediated radiohalogenation via common boronic precursors and investigated optimal boronic precursor and labeling conditions. As a result, the radiochemical yields of [125I]mIB-PS and [77Br]mBrB-PS were improved to > 93% at room temperature by optimizing the structure of the boronic precursor. We demonstrate that copper-mediated nucleophilic radiochemistry using a boronic precursor is a promising radiosynthetic method of PSMA imaging probes. Although we focused on the synthesis of PSMA imaging probes, the results in this study will also be useful for the synthesis of various radioiodine or radiobromine-labeled bioactive molecules.

Development of novel radioiodinated exendin-4 derivatives targeting GLP-1 receptor for detection of ß-cell mass.

In subjects with type 2 diabetes mellitus (T2DM), pancreatic ß-cell mass decreases; however, it is unknown to what extent this decrease contributes to the pathophysiology of T2DM. Therefore, the development of a method for noninvasive detection of ß-cell mass is underway. We previously reported that glucagon-like peptide-1 receptor (GLP-1R) is a promising target molecule for ß-cell imaging. In this study, we attempted to develop a probe targeting GLP-1R for ß-cell imaging using single-photon emission computed tomography (SPECT). For this purpose, we selected exendin-4 as the lead compound and radiolabeled lysine at residue 12 in exendin-4 or additional lysine at the C-terminus using [123I]iodobenzoylation. To evaluate in vitro receptor specificity, binding assay was performed using dispersed mouse islet cells. Biodistribution study was performed in normal ddY mice. Ex vivo autoradiography was performed in transgenic mice expressing green fluorescent protein under control of the mouse insulin I gene promoter. Additionally, SPECT imaging was performed in normal ddY mice. The affinity of novel synthesized derivatives toward pancreatic ß-cells was not affected by iodobenzoylation. The derivatives accumulated in the pancreas after intravenous administration specifically via GLP-1R expressed on the pancreatic ß-cells. Extremely high signal-to-noise ratio was observed during evaluation of biodistribution of [123I]IB12-Ex4. SPECT images using normal mice showed that [123I]IB12-Ex4 accumulated in the pancreas with high contrast between the pancreas and background. These results indicate that [123I]IB12-Ex4 for SPECT is useful for clinical applications because of its preferable kinetics in vivo.

A Putative Single-Photon Emission CT Imaging Tracer for Erythropoietin-Producing Hepatocellular A2 Receptor.

Erythropoietin-producing hepatocellular (Eph) receptors are receptor tyrosine kinases involved in cell-cell contact. The EphA2 receptor is associated with cancer proliferation and migration. Therefore, EphA2 receptor imaging has the potential for cancer diagnosis. Here, we synthesized N-(5-((4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)-2-methylphenyl)-5-[123I]iodonicotinamide ([123I]ETB) and evaluated it as an imaging tracer for single-photon emission computed tomography (SPECT) imaging of the EphA2 receptor. [123I]ETB was designed on the basis of ALW-II-41-27, an inhibitor of EphA2 receptor kinase. Nonradioactive ETB was also synthesized and has been shown to efficiently inhibit EphA2 receptor kinase activity in vitro (IC50: ETB, 90.2 ± 18.9 nM). A cell-binding assay demonstrated that [125I]ETB binds specifically to the EphA2 receptor. The ex vivo biodistribution study of [125I]ETB in U87MG tumor-bearing mice also revealed tumor uptake (2.2% ID/g at 240 min). In addition, [123I]ETB uptake in tumors was visualized via SPECT/CT imaging. On the basis of the above, [123I]ETB can be considered a potential SPECT imaging tracer for the EphA2 receptor.

Copper-mediated radioiodination reaction through aryl boronic acid or ester precursor and its application to direct radiolabeling of a cyclic peptide.

A copper-mediated radioiodination using aryl boronic precursors is attracting attention as a solution to oxidative iododestannylation and nickel-mediated radioiodination drawbacks. The copper-mediated radiolabeling method allows radioiodination at room temperature with stable aryl boronic precursors without preparing complex starting materials or reagents and can be performed in a reaction vessel exposed to air. This method has good potential in radiochemistry; however, studies on the scope of copper-mediated radioiodination through boronic precursors are insufficient. In particular, few reports have demonstrated the effect of protecting groups on radiolabeling efficiency. Therefore, the effect of the protecting group of aryl boronic acids on the copper-mediated radioiodination was investigated. In addition, this method, which does not require heating, is expected to be useful for direct radiolabeling of peptides. Thus, we attempted direct radioiodination of c(RGDyk) as an example. The resulting radioiodination method was well tolerated in various substrates and was unaffected by the pinacol ester-type protecting group. Also, c(RGDyk) was labeled with 125 I via copper-mediated radioiodination using an aryl boronic acid precursor. The reaction time and yield were improved, compared with the indirect method. Furthermore, the large difference in polarity between the boronic acid precursor and the radiolabeled compound facilitated purification.

Daptomycin for the successful treatment of postoperative methicillin-resistant Staphylococcus aureus empyema: a case report.

Empyema is typically treated using pleural space drainage and systemic treatment with antimicrobials, and specific antimicrobial agents in the case of methicillin-resistant Staphylococcus aureus (MRSA) infections. A 57-year-old man underwent segmental resection of the left lung owing to multiple lung metastases and developed MRSA-related empyema postoperatively. Although the patient received chest drainage and linezolid, the inflammation caused by the infection persisted. Consequently, linezolid was replaced by daptomycin, and his empyema was accordingly resolved. Our findings indicate that daptomycin could be an effective treatment for postoperative MRSA-related empyema.

Temperature-dependent fasciation mutants provide a link between mitochondrial RNA processing and lateral root morphogenesis.

Although mechanisms that activate organogenesis in plants are well established, much less is known about the subsequent fine-tuning of cell proliferation, which is crucial for creating properly structured and sized organs. Here we show, through analysis of temperature-dependent fasciation (TDF) mutants of Arabidopsis, root redifferentiation defective 1 (rrd1), rrd2, and root initiation defective 4 (rid4), that mitochondrial RNA processing is required for limiting cell division during early lateral root (LR) organogenesis. These mutants formed abnormally broadened (i.e. fasciated) LRs under high-temperature conditions due to extra cell division. All TDF proteins localized to mitochondria, where they were found to participate in RNA processing: RRD1 in mRNA deadenylation, and RRD2 and RID4 in mRNA editing. Further analysis suggested that LR fasciation in the TDF mutants is triggered by reactive oxygen species generation caused by defective mitochondrial respiration. Our findings provide novel clues for the physiological significance of mitochondrial activities in plant organogenesis.

Aicardi-Goutières syndrome-like encephalitis in mutant mice with constitutively active MDA5.

MDA5 is a cytoplasmic sensor of viral RNA, triggering type I interferon (IFN-I) production. Constitutively active MDA5 has been linked to autoimmune diseases such as systemic lupus erythematosus, Singleton-Merten syndrome (SMS) and Aicardi-Goutières syndrome (AGS), a genetically determined inflammatory encephalopathy. However, AGS research is challenging due to the lack of animal models. We previously reported lupus-like nephritis and SMS-like bone abnormalities in adult mice with constitutively active MDA5 (Ifih1G821S/+), and herein demonstrate that these mice also exhibit high lethality and spontaneous encephalitis with high IFN-I production during the early postnatal period. Increases in the number of microglia were observed in MDA5/MAVS signaling- and IFN-I-dependent manners. Furthermore, microglia showed an activated state with an increased phagocytic capability and reduced expression of neurotrophic factors. Although multiple auto-antibodies including lupus-related ones were detected in the sera of the mice as well as AGS patients, Ifih1G821S/+Rag2-/- mice also exhibited up-regulation of IFN-I, astrogliosis and microgliosis, indicating that auto-antibodies or lymphocytes are not required for the development of the encephalitis. The IFN-I signature without lymphocytic infiltration observed in Ifih1G821S/+ mice is a typical feature of AGS. Collectively, our results suggest that the Ifih1G821S/+ mice are a model recapitulating AGS and that microglia are a potential target for AGS therapy.