Controllable Chiral Light Generation and Vortex Field Investigation Using Plasmonic Holes Revealed by Cathodoluminescence.

Control of the angular momentum of light is a key technology for next-generation nano-optical devices and optical communications, including quantum communication and encoding. We propose an approach to controllably generate circularly polarized light from a circular hole in a metal film using an electron beam by coherently exciting transition radiation and light scattering from the hole through surface plasmon polaritons. The circularly polarized light generation is confirmed by fully polarimetric four-dimensional cathodoluminescence mapping, where angle-resolved spectra are simultaneously obtained. The obtained intensity and Stokes maps show clear interference fringes as well as almost fully circularly polarized light generation with controllable parities by the electron beam position. By applying this approach to a three-hole system, a vortex field with a phase singularity is visualized in the middle of three holes.

Myocardin-related transcription factor contributes to renal fibrosis through the regulation of extracellular microenvironment surrounding fibroblasts.

Fibroblast accumulation and extracellular matrix (ECM) deposition are common critical steps for the progression of organ fibrosis, but the precise molecular mechanisms remain to be fully investigated. We have previously demonstrated that lysophosphatidic acid contributes to organ fibrosis through the production of connective tissue growth factor (CTGF) via actin cytoskeleton-dependent signaling, myocardin-related transcription factor family (MRTF) consisting of MRTF-A and MRTF-B-serum response factor (SRF) pathway. In this study, we investigated the role of the MRTF-SRF pathway in the development of renal fibrosis, focusing on the regulation of ECM-focal adhesions (FA) in renal fibroblasts. Here we showed that both MRTF-A and -B were required for the expressions of ECM-related molecules such as lysyl oxidase family members, type I procollagen and fibronectin in response to transforming growth factor (TGF)-ß1 . TGF-ß1 -MRTF-SRF pathway induced the expressions of various components of FA such as integrin α subunits (αv , α2 , α11 ) and ß subunits (ß1 , ß3 , ß5 ) as well as integrin-linked kinase (ILK). On the other hand, the blockade of ILK suppressed TGF-ß1 -induced MRTF-SRF transcriptional activity, indicating a mutual relationship between MRTF-SRF and FA. Myofibroblast differentiation along with CTGF expression was also dependent on MRTF-SRF and FA components. Finally, global MRTF-A deficient and inducible fibroblast-specific MRTF-B deficient mice (MRTF-AKO BiFBKO mice) are protected from renal fibrosis with adenine administration. Renal expressions of ECM-FA components and CTGF as well as myofibroblast accumulation were suppressed in MRTF-AKO BiFBKO mice. These results suggest that the MRTF-SRF pathway might be a therapeutic target for renal fibrosis through the regulation of components forming ECM-FA in fibroblasts.

Newer parameters of the octreotide test in patients with acromegaly.

PURPOSE: Predicting the therapeutic effects of first-generation somatostatin receptor ligands (fg-SRLs) is important when assessing or planning effective treatment strategies in patients with acromegaly. The oft-used maximum growth hormone (GH) suppression rate parameter of the octreotide test has a suboptimal predictive value. Therefore, this study explored newer parameters of the octreotide test for predicting the therapeutic effect of long-acting fg-SRLs. METHODS: In this single-center retrospective study, the octreotide test parameters and the therapeutic effects of fg-SRL at 3 months were investigated in 45 consecutive treatment-naïve patients with acromegaly between April 2008 and March 2023. Additionally, the relationship between the octreotide test parameters and the therapeutic effects of fg-SRLs was investigated. Tumor shrinkage was evaluated based on changes in the longitudinal diameter of the macroadenomas. The area GH suppression rate-time under the curve (AUC) and the time to nadir GH level were calculated and compared with the maximum GH suppression rate. RESULTS: The AUC estimated reductions in serum insulin-like growth factor I, and tumor shrinkage. The time to nadir GH level predicted tumor shrinkage more robustly than the maximum GH suppression rate in patients with macroadenoma. CONCLUSION: The AUC and time to nadir GH level may potentially be newer parameters of the octreotide test for estimating the therapeutic effect of fg-SRLs.

Optical Biopsies Using Probe-Based Confocal Laser Endomicroscopy for Autoimmune Pulmonary Alveolar Proteinosis.

INTRODUCTION: Increasing numbers of cases of mild asymptomatic pulmonary alveolar proteinosis (PAP) are being reported with the recent increase in chest computed tomography (CT). Bronchoscopic diagnosis of mild PAP is challenging because of the patchy distribution of lesions, which makes it difficult to obtain sufficient biopsy samples. Additionally, the pathological findings of mild PAP, particularly those that differ from severe PAP, have not been fully elucidated. This study aimed to clarify the pathological findings of mild PAP and the usefulness of optical biopsy using probe-based confocal laser endomicroscopy (pCLE). METHODS: We performed bronchoscopic optical biopsy using pCLE and tissue biopsy in 5 consecutive patients with PAP (three with mild PAP and two with severe PAP). We compared the pCLE images of mild PAP with those of severe PAP by integrating clinical findings, tissue pathology, and chest CT images. RESULTS: pCLE images of PAP showed giant cells with strong fluorescence, amorphous substances, and thin alveolar walls. Images of affected lesions in mild PAP were equivalent to those obtained in arbitrary lung lesions in severe cases. All 3 patients with mild PAP spontaneously improved or remained stable after ≥3 years of follow-up. Serum autoantibodies to granulocyte-macrophage colony-stimulating factor were detected in all 5 cases. CONCLUSION: Optical biopsy using pCLE can yield specific diagnostic findings, even in patients with mild PAP. pCLE images of affected areas in mild and severe PAP showed similar findings, indicating that the dysfunction level of pathogenic alveolar macrophages in affected areas is similar between both disease intensities.

A case of meningoencephalitis caused by multisystem inflammatory syndrome in adult SARS-CoV-2 infection.

A 37-year-old woman was hospitalized with fever and consciousness disturbance. She showed systemic inflammation with stress cardiomyopathy. Brain computed tomography showed diffuse brain edema. Cerebrospinal fluid (CSF) findings revealed markedly elevated cerebrospinal fluid pressure with pleocytosis, elevated protein, and elevated interleukin 6. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nicking enzyme amplification reaction test using a nasopharyngeal swab was positive, and the patient was diagnosed with SARS-CoV-2 infection. From the negative result of the CSF SARS-CoV-2 polymerase chain reaction test and no findings of bacterial or viral infection, we diagnosed meningoencephalitis by multisystem inflammation syndrome in adults (MIS-A). Intravenous methylprednisolone pulse therapy improved her symptoms and brain edema. There have been no cases of MIS-A with meningoencephalitis, and no initial treatment strategy has been established, especially in emergency cases of suspected MIS-A. The present case suggested Early intravenous methylprednisolone pulse with anti-coronaviral therapies after the exclusion of bacterial infection would be useful in suspected MIS-A with emergent meningoencephalitis cases.

The aortic knob index as a novel predictor of new-onset atrial fibrillation after off-pump coronary artery bypass grafting.

PURPOSE: To validate the predictive value of the aortic knob index for identifying new-onset postoperative atrial fibrillation (POAF) after off-pump coronary artery bypass grafting (OPCAB). METHODS: Among 156 patients who underwent isolated OPCAB, 138 consecutive patients without a history of atrial fibrillation were enrolled in this retrospective observational cohort study. The patients were divided into two groups based on the development of POAF. We compared the baseline clinical characteristics; preoperative radiographic characteristics of the aorta, including aortic knob measurements; and perioperative data, between the groups. Logistic regression analysis was performed to identify the predictors of new-onset POAF. RESULTS: New-onset POAF developed in 35 (25.4%) patients. Multivariate logistic regression analysis revealed that the aortic knob index was an independent predictor of POAF and yielded that the risk of POAF increased by 1.85 times when the aortic knob index increased by 0.1 (odds ratio, 1.853; confidence interval, 1.326-2.588; P < 0.001). Receiver operating characteristic analysis revealed that an aortic knob index of 1.364 constituted a cutoff value for new-onset POAF with 80.0% sensitivity and 65.0% specificity. CONCLUSIONS: The aortic knob index on preoperative chest radiography was a significant and independent predictor of new-onset POAF following OPCAB.

Gene co-expression modules behind the three-pistil formation in wheat.

Multi-pistil trait in wheat is of great potential value in plant development research and crop breeding. Our previous studies identified the Pis1 locus that causes three pistils in wheat by genetic mapping using multiple DNA marker systems. However, there are still 26 candidate genes on the locus, and the causal gene remains to be found. In this study, we aimed to approach the molecular mechanism of multi-pistil formation. Comparative RNA sequencing (RNA-Seq) during the pistil formation was undertaken in four wheat lines: a three-pistil mutant TP, a single-pistil TILLING mutant of TP (SP), a three-pistil near-isogenic line CM28TP with the background of cultivar Chunmai 28 (CM28), and CM28. Electron microscopic analysis specified probable developmental stages of young spikes for the three-pistil formation. mRNA sequencing in the young spikes of the four lines represented 253 down-regulated genes and 98 up-regulated genes in both three-pistil lines, which included six potential genes for ovary development. Weighted gene co-expression analysis represented three-pistil trait-associated transcription factor-like genes, among which one hub gene, ARF5, was the most highlighted. ARF5 is on the Pis1 locus and an orthologue of MONOPTEROS which mediates tissue development in Arabidopsis. qRT-PCR validation implies that the deficiency of ARF5 underlies the three-pistil formation in wheat.

Effects of tumor-infiltrating CD8+ T cells, PD1/PD-L1 axis, and expression patterns of HLA class I on the prognosis of patients with malignant pleural mesothelioma who underwent extra-pleural pneumonectomy.

Programmed cell death protein-1 (PD1), PD1 ligand 1 (PD-L1), and human leukocyte antigen (HLA) class I molecule play pivotal roles in T cell-induced anti-tumor immunity; however, the clinical impact of these parameters in resected malignant pleural mesothelioma (MPM) cases is unknown. We immunohistochemically evaluated the tumor infiltrated lymphocytes (TILs), PD1/PD-L1 axis, and expression of HLA class I in resected specimens from 58 patients with MPM who underwent extra-pleural pneumonectomy (EPP). Higher infiltration of CD3-TIL, CD8-TIL, and PD1-TIL, loss of HLA class I, and overexpression of PD-L1 by tumor cells (PD-L1 TC) or immune cells (PD-L1 IC) were observed in 34 (58.6%), 27 (46.6%), 41 (70.7%), 45 (77.6%), 29 (50.0%), and 33 (56.4%) of 58 cases, respectively. Interestingly, the CD3-TIL score positively correlated with PD-L1 TC and PD1-TIL scores. HLA class I expression level was inversely correlated with the expression levels of PD-L1 TC and PD-L1 IC. Multivariate analysis showed that age, histology, and node metastasis were independent prognostic factors for 5-year overall survival (OS) and loss of HLA class I coincided with a positive prognosis (p = 0.011). The concomitant lack of infiltrating CD8+ T cells with no loss of HLA class I predicted worse 5-year OS (p = 0.007). Moreover, cluster classifications among multiple immunoparameters showed that categories among CD3/PD-L1 TC/HLA class I (p = 0.043), CD8/PD1/HLA class I (p = 0.032), CD8/PD-L1 TC/HLA class I (p = 0.011), and PD1/PD-L1 TC/HLA class I (p = 0.032) predicted 5-year OS in EPP cases for MPM. These immunoparameters could guide surgical indications for patients with MPM.

Red-light receptor phytochrome B inhibits BZR1-NAC028-CAD8B signaling to negatively regulate rice resistance to sheath blight.

Phytochrome (Phy)-regulated light signalling plays important roles in plant growth, development, and stress responses. However, its function in rice defence against sheath blight disease (ShB) remains unclear. Here, we found that PhyB mutation or shade treatment promoted rice resistance to ShB, while resistance was reduced by PhyB overexpression. Further analysis showed that PhyB interacts with phytochrome-interacting factor-like 15 (PIL15), brassinazole resistant 1 (BZR1), and vascular plant one-zinc-finger 2 (VOZ2). Plants overexpressing PIL15 were more susceptible to ShB in contrast to bzr1-D-overexpressing plants compared with the wild-type, suggesting that PhyB may inhibit BZR1 to negatively regulate rice resistance to ShB. Although BZR1 is known to regulate brassinosteroid (BR) signalling, the observation that BR signalling negatively regulated resistance to ShB indicated an independent role for BZR1 in controlling rice resistance. It was also found that the BZR1 ligand NAC028 positively regulated resistance to ShB. RNA sequencing showed that cinnamyl alcohol dehydrogenase 8B (CAD8B), involved in lignin biosynthesis was upregulated in both bzr1-D- and NAC028-overexpressing plants compared with the wild-type. Yeast-one hybrid, ChIP, and transactivation assays demonstrated that BZR1 and NAC028 activate CAD8B directly. Taken together, the analyses demonstrated that PhyB-mediated light signalling inhibits the BZR1-NAC028-CAD8B pathway to regulate rice resistance to ShB.

Effective Chiral Magnetic Effect from Neutrino Radiation.

We develop an approach to chiral kinetic theories for electrons close to equilibrium and neutrinos away from equilibrium based on a systematic power counting scheme for different timescales of electromagnetic and weak interactions. Under this framework, we derive electric and energy currents along magnetic fields induced by neutrino radiation in general nonequilibrium states. This may be regarded as an effective chiral magnetic effect (CME), which is present without a chiral chemical potential, unlike the conventional CME. We also consider the so-called gain region of core-collapse supernovae as an example and find that the effective CME enhanced by persistent neutrino emission in time is sufficiently large to lead to the inverse cascade of magnetic and fluid kinetic energies and observed magnitudes of pulsar kicks. Our framework may also be applicable to other dense-matter systems involving nonequilibrium neutrinos.

Piezo1 channel causes lens sclerosis via transglutaminase 2 activation.

Presbyopia is caused by age-related lenticular hardening, resulting in near vision loss, and it occurs in almost every individual aged ≥50 years. The lens experiences mechanical pressure during for focal adjustment to change its thickness. As lenticular stiffening results in incomplete thickness changes, near vision is reduced, which is known as presbyopia. Piezo1 is a mechanosensitive channel that constantly senses pressure changes during the regulation of visual acuity, and changes in Piezo1 channel activity may contribute to presbyopia. However, no studies have reported on Piezo1 activation or the onset of presbyopia. To elucidate the relevance of Piezo1 activation and cross-linking in the development of presbyopia, we analysed the function of Piezo1 in the lens. The addition of Yoda1, a Piezo1 activator, induced an increase in transglutaminase 2 (TGM2) mRNA expression and activity through the extra-cellular signal-regulated kinase (ERK) 1/2 and c-Jun-NH2-terminal kinase1/2 pathways. In ex vivo lenses, Yoda1 treatment induced γ-crystallin cross-linking via TMG2 activation. Furthermore, Yoda1 eye-drops in mice led to lenticular hardening via TGM2 induction and activation in vivo, suggesting that Yoda1-treated animals could serve as a model for presbyopia. Our findings indicate that this presbyopia-animal model could be useful for screening drugs for lens-stiffening inhibition.

Kif26b contributes to the progression of interstitial fibrosis via migration and myofibroblast differentiation in renal fibroblast.

Kinesin family member 26b (Kif26b) is essential for kidney development, and its deletion in mice leads to kidney agenesis. However, the roles of this gene in adult settings remain elusive. Thus, this study aims to investigate the role of Kif26b in the progression of renal fibrosis. A renal fibrosis model with adenine administration using Kif26b heterozygous mice and wild-type mice was established. Renal fibrosis and the underlying mechanism were investigated. The underlying pathways and functions of Kif26b were evaluated in an in vitro model using primary renal fibroblasts. Kif26b heterozygous mice were protected from renal fibrosis with adenine administration. Renal expressions of connective tissue growth factor (CTGF) and myofibroblast accumulation were reduced in Kif26b heterozygous mice. The expression of nonmuscle myosin heavy chain II (NMHCII), which binds to the C-terminus of Kif26b protein, was also suppressed in Kif26b heterozygous mice. The in vitro study revealed reduced expressions of CTGF, α-smooth muscle actin, and myosin heavy chain 9 (Myh9) via transfection with siRNAs targeting Kif26b in renal fibroblasts (RFB). RFBs, which were transfected by the expression vector of Kif26b, demonstrated higher expressions of these genes than non-transfected cells. Finally, Kif26b suppression and NMHCII blockage led to reduced abilities of migration and collagen gel contraction in renal fibroblasts. Taken together, Kif26b contributes to the progression of interstitial fibrosis via migration and myofibroblast differentiation through Myh9 in the renal fibrosis model. Blockage of this pathway at appropriate timing might be a therapeutic approach for renal fibrosis.

One-day systemic corticosteroid administration for asthma and future "short bursts" risk in real clinical practice.

OBJECTIVE: Systemic corticosteroid administration, also called short bursts (SB), is harmful for patients with asthma; however, the actual burden of one-day SB remains unsolved. This study aimed to elucidate the characteristics of patients requiring one-day SB against asthma in clinical practice. METHODS: Consecutive patients who regularly visited our hospital for asthma treatment between January 2019 and December 2020 were reviewed and followed for one year. SB was defined as ≥3 days of systemic corticosteroid treatment for an exacerbation. One-day SB was defined as one-day of systemic corticosteroid to treat an exacerbation. The one-day SB group included patients who received only one-day SB but no SB during the preceding year. Frequent SB was defined as that occurring ≥2 times/year. RESULTS: Data on 229 patients were analyzed. Among them, 2.6% (95% confidence interval 1.2-5.6%) were in the one-day SB group. The one-day SB group was female-dominant, obese, non-eosinophilic, and non-atopic. The median one-day SB was 1.5 times/year and almost half of one-day SB were performed by patients themselves. Independent of the low pulmonary function, high blood eosinophil count, and inhaled corticosteroid dose, one-day SB was associated with future frequent SB (adjusted odds ratio = 18.2, 95% confidence interval 1.1-288, P = 0.040, compared to the no SB group). CONCLUSIONS: Although one-day SB was not frequently experienced, even one-day SB without conventional SB was associated with future frequent SB. It is important to grasp the actual condition of one-day SB and to reinforce the treatment used.

Survey of glucocorticoid dose escalation in patients with adrenal insufficiency during the peri-COVID-19 vaccination period.

There is uncertainty regarding the need for COVID-19 peri-vaccination glucocorticoid coverage in patients with adrenal insufficiency. In this survey conducted in a single tertiary medical institution, 167 consecutive outpatients taking physiological glucocorticoids because of adrenal insufficiency were included. The patients declared if they developed an adrenal crisis after vaccination, and the amount and duration of an increase in their glucocorticoid dosage, if any. None of the patients without preventive glucocorticoid increase suffered an adrenal crisis after COVID-19 vaccination. Only 8.3% (14 cases) and 27.5% (46 cases) of the patients needed to escalate the dose of glucocorticoids when systemic symptoms appeared after the first and second injections, respectively. Glucocorticoids were increased in patients <60 years of age more than in patients ≥60 years of age at the time of both the first (p = 0.026) and second injections (p = 0.005). Sex and the causes of adrenal insufficiency were not associated with the frequency of the patients who needed glucocorticoid dose escalation. In the cases with increased glucocorticoids, the median dosage for escalation was 10 mg (hydrocortisone equivalent). In conclusion, even without prophylactic glucocorticoid administration, adrenal crisis did not occur during the peri-COVID-19 vaccination period. The dose escalation of steroid was more frequent in younger patients following the second vaccination. Careful monitoring of adverse effects and the appropriate management of glucocorticoids when necessary are essential following COVID-19 vaccinations.

Geriatric nutrition risk index predicts prolonged post-stroke dysphagia in acute ischemic stroke.

BACKGROUND: Post-stroke dysphagia (PSD) is a common complication after stroke. Malnutrition inhibits stroke recovery and is associated with stroke mortality. However, no studies have investigated the effects of nutritional state at admission on prolonged PSD. METHODS: We retrospectively analyzed ischemic stroke patients in our institute from January 2018 to December 2020. Swallowing function was assessed using the Food Oral Intake Scale; prolonged PSD was defined as levels 1-3 at 14 days after admission. The Geriatric Nutritional Risk Index (GNRI) was used to assess nutritional risks, which were classified as follows: >98, no nutritional risk; 92-98, mild nutritional risk; 82-92, moderate nutritional risk; and <82, severe nutritional risk. The association between GNRI and prolonged PSD was assessed. RESULTS: Of 580 patients (median age, 81 years; male, 53%), prolonged PSD was detected in 117 patients. Patients with severe dysphagia had older age, higher pre-stroke modified Rankin Scale score, lower GNRI, and higher National Institutes of Health Stroke Scale score. Logistic regression analysis revealed that lower GNRI was independently associated with prolonged PSD (continuous value; adjusted odds ratio [OR] 1.03, 95% confidence interval [CI] 1.00-1.05). In addition, when "severe" and "moderate" nutritional risk was analyzed as a single class, moderate or severe nutritional risk (GNRI < 92) was independently associated with prolonged PSD (adjusted OR 2.50, 95% CI 1.29-4.87), compared with no nutritional risk patients (GNRI > 98). CONCLUSIONS: In acute ischemic stroke, lower GNRI at admission was independently associated with prolonged PSD, suggesting that GNRI at admission might identify patients at risk of prolonged PSD.

Aquaporins contribute to vacuoles formation in Nile grass type II diabetic rats.

Regulation of ion and water microcirculation within the lens is tightly controlled through aquaporin channels and connexin junctions. However, cataracts can occur when the lens becomes cloudy. Various factors can induce cataracts, including diabetes which is a well-known cause. The most common phenotype of diabetic cataracts is a cortical and/or posterior subcapsular opacity. In addition to the three main types and two subtypes of cataracts, a vacuole formation is frequently observed; however, their origin remains unclear. In this study, we focused on the aquaporins and connexins involved in diabetes-induced cataracts and vacuoles in Nile grass type II diabetes. The results showed that the expression of aquaporin 0 and aquaporin 5 increased, and that of connexin 43 decreased in diabetic rat lenses. Additionally, aquaporin 0 and 5 were strongly localized in peripheral of vacuoles, suggesting that aquaporins are involved in vacuoles formation. Transillumination photography revealed large vacuoles at the tip of the Y-suture in the anterior capsule of the diabetic lens, and several small vacuoles were observed in the posterior capsule. Within the vacuoles, cytoplasmic degradation and aggregation of fibrous material were observed. Our findings suggest that aquaporins are potential candidate proteins for preventing vacuole formation.

Flexural and Cell Adhesion Characteristic of Phakic Implantable Lenses.

Background and Objectives: In this study, we aimed to compare the physical properties of hole-implantable collamer lenses (H-ICLs) and implantable phakic contact lenses (IPCLs) and investigate their flexural and cell adhesion characteristics. Materials and Methods: Transverse compression load to achieve lens flexion and static Young's modulus were measured in H-ICLs and IPCLs using designated equipment. Load was measured both with and without restraining the optic section of the lenses. Adhesion of iHLEC-NY2 cells to the lens surfaces was examined using phase-contrast microscopy, and cell proliferation activity was evaluated using WST-8 assay. Results: The H-ICL showed a greater tendency for transverse compression load compared to IPCL, while the IPCL showed a higher Young's modulus with respect to the force exerted on the center of the anterior surface of the optic section. The joint between the optic section and haptic support in the IPCL was found to mitigate the effects of transverse compression load. Both lens types showed minimal cell adhesion. Conclusions: Our findings indicate that H-ICLs and IPCLs exhibit distinct physical properties and adhesive characteristics. The IPCL demonstrated higher Young's modulus and unique structural features, while the H-ICL required greater transverse compression load to achieve the flexion required to tuck the haptic supports into place behind the iris to fix the lens. The observed cell non-adhesive properties for both lens types are promising in terms of reducing complications related to cell adhesion. However, further investigation and long-term observation of IPCL are warranted to assess its stability and potential impact on the iris. These findings contribute to a better understanding of the performance and potential applications of H-ICLs and IPCLs in ophthalmology.

Poly(I:C) promotes neurotoxic amyloid ß accumulation through reduced degradation by decreasing neprilysin protein levels in astrocytes.

Inflammation associated with viral infection of the nervous system has been involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD) and multiple sclerosis. Polyinosinic:polycytidylic acid (poly[I:C]) is a Toll-like receptor 3 (TLR3) agonist that mimics the inflammatory response to systemic viral infections. Despite growing recognition of the role of glial cells in AD pathology, their involvement in the accumulation and clearance of amyloid ß (Aß) in the brain of patients with AD is poorly understood. Neprilysin (NEP) and insulin-degrading enzyme (IDE) are the main Aß-degrading enzymes in the brain. This study investigated whether poly(I:C) regulated Aß degradation and neurotoxicity by modulating NEP and IDE protein levels through TLR3 in astrocytes. To this aim, primary rat primary astrocyte cultures were treated with poly(I:C) and inhibitors of the TLR3 signaling. Protein levels were assessed by Western blot. Aß toxicity to primary neurons was measured by lactate dehydrogenase release. Poly(I:C) induced a significant decrease in NEP levels on the membrane of astrocytes as well as in the culture medium. The degradation of exogenous Aß was markedly delayed in poly(I:C)-treated astrocytes. This delay significantly increased the neurotoxicity of exogenous Aß1-42. Altogether, these results suggest that viral infections induce Aß neurotoxicity by decreasing NEP levels in astrocytes and consequently preventing Aß degradation.

Differential genetic associations and expression of PAPST1/SLC35B2 in bipolar disorder and schizophrenia.

Lithium's inhibitory effect on enzymes involved in sulfation process, such as inhibition of 3'(2')-phosphoadenosine 5'-phosphate (PAP) phosphatase, is a possible mechanism of its therapeutic effect for bipolar disorder (BD). 3'-Phosphoadenosine 5'-phosphosulfate (PAPS) is translocated from cytosol to Golgi lumen by PAPS transporter 1 (PAPST1/SLC35B2), where it acts as a sulfa donor. Since SLC35B2 was previously recognized as a molecule that facilitates the release of D-serine, a co-agonist of N-methyl-D-aspartate type glutamate receptor, altered function of SLC35B2 might be associated with the pathophysiology of BD and schizophrenia (SCZ). We performed genetic association analyses of the SLC35B2 gene using Japanese cohorts with 366 BD cases and 370 controls and 2012 SCZ cases and 2170 controls. We then investigated expression of SLC35B2 mRNA in postmortem brains by QPCR using a Caucasian cohort with 33 BD and 34 SCZ cases and 34 controls and by in situ hybridization using a Caucasian cohort with 37 SCZ and 29 controls. We found significant associations between three SNPs (rs575034, rs1875324, and rs3832441) and BD, and significantly reduced SLC35B2 mRNA expression in postmortem dorsolateral prefrontal cortex (DLPFC) of BD. Moreover, we observed normalized SLC35B2 mRNA expression in BD subgroups who were medicated with lithium. While there was a significant association of SLC35B2 with SCZ (SNP rs2233437), its expression was not changed in SCZ. These findings indicate that SLC35B2 might be differentially involved in the pathophysiology of BD and SCZ by influencing the sulfation process and/or glutamate system in the central nervous system.

ldhA-induced persister in Escherichia coli is formed through accidental SOS response via intracellular metabolic perturbation.

Persisters are a subpopulation that exhibit growth suppression, antibiotic tolerance, and regrowth after antibiotic removal, without any genetic mutations, which causes the recalcitrance and recurrence of infectious diseases. Persisters are majorly induced through the repression of energy metabolism, but some exceptions have been reported. We have previously shown that ldhA, which encodes lactate dehydrogenase, induces Escherichia coli persisters, resulting in a state of high-energy metabolism. However, the detailed mechanism of persister formation upon ldhA expression remains elusive. In the present study, we focused on the SOS response pathway via the DNA repair pathway that consumes adenosine triphosphate and revealed that the SOS response pathway is activated upon ldhA expression even before antimicrobial treatment. Metabolome analysis of ldhA-overexpressing cells revealed that nucleotide metabolic pathways, such as de novo purine biosynthesis, were activated to prepare a nucleotide pool, as substrate for repairing ofloxacin-induced DNA damage. We provide a novel persister model that contributes to survival as a species by "accidentally" activating the SOS response even before receiving antimicrobial stress.