Search

In this work the nuclear reaction routes 70 Zn(p,x) 64,67 Cu, 66,67 Ga, and 65,69m Zn, induced by a high-energy proton beam up to 100 MeV have been investigated. Demand for 67 Cu is increasing worldwide because it is known to be one of the best radionuclides having theranostic properties. Thus, efforts to improve its global production are underway. In previous studies, experimental data about nuclear cross-section measurements on 70 Zn-enriched targets induced by proton beams were limited to an energy range of up to 70 MeV. Our goal was to extend nuclear data on 70 Zn over a wider and unexplored so far region from 42 MeV to 98 MeV. As a result, our data turned out to be in good agreement with the literature ones in the overlapping energy range. In addition, to the best of our knowledge, new nuclear data exceeding 70 MeV were provided, demonstrating an excellent analytical method for producing 67 Cu in the extended energy range., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease caused by Bandavirus dabieense (SFTS virus [SFTSV]). Recently, at least 6 different genotypes of SFTSV have been identified, with genotypes A, D, and F dominant in China and B dominant in Japan and Korea. This study investigated the effect of SFTSV genotypes circulating in South Korea on disease severity, viral load, and cytokine profile., Methods: We prospectively enrolled 70 patients with SFTS from July 2015 to June 2022. Serial plasma samples were obtained during hospitalization and analyzed. Viral load was measured by real-time reverse-transcription polymerase chain reaction. Partial sequences of the viral genome were analyzed for genotyping. Plasma concentrations of 17 cytokines were measured by multiplex-bead immunoassay., Results: Of 70 samples, 51 could be genotyped. Genotype B was predominant (80.4%) and other genotypes were uncommon. Intensive care unit admission rates (51.2% vs 50.0%) and mortality rates (26.8% vs 40.0%) did not show any significant differences between genotype B and non-B genotypes. The initial viral load did not show any significant differences (3.59 vs 3.64 log copies/μL), whereas viral load measured at hospital day 3-4 tended to be higher in genotype B than non-B genotypes (3.83 vs 1.83 log copies/μL, P = .07). Additionally, the plasma concentrations of interferon-α, interleukin 10, and interferon-γ-induced protein 10, which are closely related to mortality in cases of SFTS, did not show any significant differences., Conclusions: SFTSV genotype B was the prevalent genotype in South Korea, with no genotype-specific difference in clinical outcomes, initial viral load, or cytokine profiles., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The pathophysiological mechanisms underlying the post-acute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC) are not well understood. Our study aimed to investigate various aspects of theses mechanisms, including viral persistence, immunological responses, and laboratory parameters in patients with and without PASC., Methods: We prospectively enrolled adults aged ≥ 18 years diagnosed with coronavirus disease 2019 (COVID-19) between August 2022 and July 2023. Blood samples were collected at three time-points: within one month of diagnosis (acute phase) and at 1 month, and 3 months post-diagnosis. Following a recent well-designed definition of PASC, PASC patients were defined as those with a questionnaire-based PASC score ≥ 12 persisting for at least 4 weeks after the initial COVID-19 diagnosis., Results: Of 57 eligible COVID-19 patients, 29 (51%) had PASC, and 28 (49%) did not. The PASC group had significantly higher nucleocapsid protein (NP) antigenemia 3 months after COVID-19 diagnosis ( P = 0.022). Furthermore, several cytokines, including IL-2, IL-17A, VEGF, RANTES, sCD40L, IP-10, I-TAC, and granzyme A, were markedly elevated in the PASC group 1 and/or 3 month(s) after COVID-19 diagnosis. In contrast, the median values of several serological markers, including thyroid markers, autoimmune indicators, and stress-related hormones, were within the normal range., Conclusion: Levels of NP antigen and of various cytokines involved in immune responses become significantly elevated over time after COVID-19 diagnosis in PASC patients compared to non-PASC patients. This suggests that PASC is associated with prolonged immune dysregulation resulting from heightened antigenic stimulation., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Radioisotopes are widely used in the fields of medicine, science, and industry. The growing demand for medical radioisotopes has driven research on alternative production methods. In particular, both isotopes of 67 Cu and 68 Ge play vital roles in the medical environment in many countries to be used in the radio-immunotherapy and the positron emission tomography imaging, respectively. This study designed a multi-target system consisting of two Zn and one Ga 2 O 3 plates to enable simultaneous production of the medical radioisotopes 67 Cu and 68 Ge using 100 MeV proton beams. To understand the thermal effect on the multi-targets, we examined the distribution of energy absorbed in each solid plate target when exposed to an accelerated proton beam through the thermal-fluid analysis based on ANSYS simulation. For confirming thermal stability for two Zn targets and one Ga 2 O 3 target, the modified water flow path inside the multi-target system was designed effectively with the controlled distribution of multiple sub-holes between main inlet and the following four channels. It was confirmed that the newly designed multi-target system of Zn and Ga 2 O 3 solid plates shows higher thermal stability than the case of uniform distribution of water inlet, which means it could be exposed to a higher current beam of 7.57% to decrease the processing time., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Although research on aspergillosis and mucormycosis confection is important to optimize antifungal therapy, data on this issue is scarce. Thus, we systematically investigated aspergillosis coinfection in patients with proven mucormycosis. Medical records of adult patients with proven mucormycosis whose formalin-fixed paraffin-embedded (FFPE) tissue sections were available, in a tertiary hospital from August 2007 to July 2023 were retrospectively reviewed to assess coinfection with aspergillosis. We noted cultures of fungi from sterile and non-sterile sites and performed polymerase chain reaction (PCR) assays on FFPE tissues to detect Aspergillus- and Mucorales-specific DNA. Sixty-seven patients with proven mucormycosis, including 12 (18%) with a positive culture of the mucormycosis agent from sterile site cultures, were enrolled. Fungal cultures from sterile and non-sterile sites revealed Aspergillus spp. growth in nine (13%) of the 67 patients, including two sterile and seven non-sterile cultures. The fungal PCR analysis from the FFPE sections was positive for Aspergillus-specific PCR in five (7%) and positive for both Aspergillus- and Mucorales-specific PCR results in eight (12%). Overall, 21 (31%) of the 67 patients with proven mucormycosis had microbiologic and/or molecular evidence of aspergillosis coinfection. Positive blood or bronchoalveolar lavage fluid galactomannan results were more common in the coinfection group (67% [14/21]) than in the mucormycosis group (37% [17/46], P = .024). No significant difference in mortality between the two groups was observed. Approximately one-third of patients with proven mucormycosis exhibited molecular and/or microbiologic evidence of aspergillosis coinfection. Further research is needed to identify patients with aspergillosis and mucormycosis coinfections, for optimal antifungal therapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Pueraria lobata root and Glycine max ( L. ) Merrill are rich in phytoestrogens. However, these bioactive ingredients have limited bioavailability due to their high molecular weight. In this study, we extracted two natural products and fermented with Lactiplantibacillus plantarum before mixing the fermented extracts (FPE-FGE). To understand whether FPE-FGE could alleviate menopause with dyslipidemia, we examined their effects on ovariectomy (OVX)-induced dyslipidemia in mice. Oral administration of the FPE-FGE (1:9, 3:7, and 9:1) did not affect safety-related biomarkers, such as uterus index (%), vagina index (%), aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine. Furthermore, FPE-FGE (1:9, 3:7, and 9:1) increased the levels of 17β-estradiol (E2) and expression of uterus estrogen receptor β (ERβ); there was little effect on the expression of uterus estrogen receptor α (ERα), and reduced the levels of gonadotropins, such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH). However, only the FPE-FGE (3:7) reduced the levels of blood lipids, including total cholesterol (TC) and LDL-cholesterol (LDL-C). Accordingly, FPE-FGE (3:7) upregulated endothelial nitric oxide synthase (eNOS), nitric oxide (NO), cyclic guanosine monophosphate (cGMP), and protein kinase G (PKG). In conclusion, FPE-FGE (3:7) attenuated the menopausal dyslipidemia by upregulating eNOS-NO-cGMP signaling pathway., Competing Interests: The authors declare that they have no competing interests., (© 2024 The Author(s). Food Science & Nutrition published by Wiley Periodicals LLC.)

The seropositivity of measles antibodies among 261 autologous stem cell transplant recipients (ASCTs) in Korea, assessed approximately 1-2 years after transplant (median, 11 months; interquartile range, 9-14), was significantly lower than age- and sex-matched control healthcare workers (83.1% [217/261] vs. 90.3% [539/597], P = 0.002). The findings underscore the vulnerability of adult ASCT recipients to measles. Clinicians should prioritize testing for measles IgG after ASCT and consider vaccination for ASCT recipients who remain seronegative 2 years after ASCT., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Cytochrome P450s (CYPs) regulate plant growth and stress responses by producing diverse primary and secondary metabolites. However, the function of many plant CYPs remains unknown because, despite their structural similarity, predicting the enzymatic activity of CYPs is difficult. In this study, one member of the CYP736A subfamily (CYP736A61) from tomatoes was isolated and characterized its enzymatic functions. CYP736A61 was successfully expressed in Escherichia coli through co-expression with molecular chaperones. The purified CYP736A61 showed hydroxylation activity toward 7-ethoxycoumarin, producing 7-hydroxycoumarin or 3-hydroxy 7-ethoxycoumarin. Further substrate screening revealed that dihydrochalcone and stilbene derivates (resveratrol and polydatin) are the substrates of CYP736A61. CYP736A61 also mediated the hydroxylation of resveratrol and polydatin, albeit with low activity. Importantly, CYP736A61 mediated the cleavage of resveratrol and polydatin as well as pinostilbene and pterostilbene. Interestingly, CY736A61 also converted phloretin to naringenin chalcone. These results suggest that CYP736A61 is a novel CYP enzyme with stilbene cleavage activity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Our study analyzed 95 solid organ transplant (SOT) and 78 hematopoietic stem cell transplant (HSCT) recipients with prior coronavirus disease 2019 (COVID-19). Patients who underwent transplantation within 30 days of COVID-19 infection comprised the early group, and those who underwent transplantation post-30 days of COVID-19 infection comprised the delayed group. In the early transplantation group, no patient, whether undergoing SOT and HSCT, experienced COVID-19-associated complications. In the delayed transplantation group, one patient each from SOT and HSCT experienced COVID-19-associated complications. Additionally, among early SOT and HSCT recipients, two and six patients underwent transplantation within seven days of COVID-19 diagnosis, respectively. However, no significant differences were observed in the clinical outcomes of these patients compared to those in other patients. Early transplantation following severe acute respiratory syndrome coronavirus 2 infection can be performed without increased risk of COVID-19-associated complications. Therefore, transplantation needs not be delayed by COVID-19 infection., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, caused by a complex interplay of genetic and environmental factors. This study aimed to evaluate the combined efficacy of multi-polygenic risk scores and pooled cohort equations (PCE) for predicting future CVD risks in the Korean population. In this longitudinal study, 7,612 individuals from the Ansan and Ansung cohorts were analyzed over a 17-year follow-up period. The participants were genotyped using the Korea Biobank Array, and quality-controlled genetic data were subjected to imputation analysis. The weighted sum of the PRSs (wPRSsum) was calculated using PRS-CS with summary statistics from myocardial infarction, ischemic stroke, coronary artery disease, and hypertension genome-wide association studies. The recalibrated PCE was used to assess clinical risk, and the participants were stratified into risk groups based on the wPRSsum and PCE. Associations between these risk scores and incident CVD were evaluated using Cox proportional hazards models and Kaplan-Meier analysis. The wPRSsum approach showed a significant association with incident CVD (HR = 1.15, p = 7.49 × 10 -5 ), and the top 20% high-risk genetic group had an HR of 1.50 ( p = 5.04 × 10 -4 ). The recalibrated PCE effectively differentiated between the low and high 10-year CVD risk groups, with a marked difference in survival rates. The predictive models constructed using the wPRSsum and PCE demonstrated a slight improvement in prediction accuracy, particularly among males aged <55 years (C-index = 0.640). We demonstrated that while the integration of wPRSsum with PCE did not significantly outperform the PCE-only model (C-index: 0.703 for combined and 0.704 for PCE-only), it provided enhanced stratification of CVD risk. The highest risk group, identified through the combination of high wPRSsum and PCE scores, exhibited an HR of 4.99 for incident CVD ( p = 1.45 × 10 -15 ). These findings highlight the potential of integrating genetic risk assessments with traditional clinical tools for effective CVD risk stratification. Although the addition of wPRSsum to the PCE provided a marginal predictive improvement, it proved valuable in identifying high-risk individuals and supporting personalized treatment strategies. This study reinforces the utility of multi-PRS in conjunction with clinical risk assessment tools, paving the way for more tailored approaches for CVD prevention and management in diverse populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Park, Jang, Park, Kim, Park and Kim.)

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes 1,2 and molecular mechanisms that are often specific to cell type 3,4 . Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10 -8 ) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores 5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care., (© 2024. The Author(s).)

Intermittent fasting (IF), an alternating pattern of dietary restriction, reduces obesity-induced insulin resistance and inflammation. However, the crosstalk between adipose tissue and the hippocampus in diabetic encephalopathy is not fully understood. Here, we investigated the protective effects of IF against neuroinflammation and cognitive impairment in high-fat diet(HFD)-fed mice. Histological analysis revealed that IF reduced crown-like structures and adipocyte apoptosis in the adipose tissue of HFD mice. In addition to circulating lipocalin-2 (LCN2) and galectin-3 (GAL3) levels, IF reduced HFD-induced increases in LCN2- and GAL3-positive macrophages in adipose tissue. IF also improved HFD-induced memory deficits by inhibiting blood-brain barrier breakdown and neuroinflammation. Furthermore, immunofluorescence showed that IF reduced HFD-induced astrocytic LCN2 and microglial GAL3 protein expression in the hippocampus of HFD mice. These findings indicate that HFD-induced adipocyte apoptosis and macrophage infiltration may play a critical role in glial activation and that IF reduces neuroinflammation and cognitive impairment by protecting against blood-brain barrier leakage.

This study aimed to evaluate the differences in the clinical significance of antinuclear antibody (ANA) according to their titers and patterns in the diagnosis of systemic autoimmune diseases (AiD) in pediatric patients. Of the 2442 children who had undergone an ANA test, 473 (19.4%) were positive for ANA, of whom 33 (7.0%) were diagnosed with significant AiD. The positive predictive value (PPV) for significant AiD was considerably high on application of an ANA titer of ≥1:640, and the PPV of a dense fine speckled (DFS) pattern was significantly lower compared with those of speckled and homogenous patterns. The diagnostic value of ANA positivity for AiD is limited, and the clinical significance of the DFS pattern is relatively lower compared with that of other patterns, such as homogenous and speckled patterns, in children. It is necessary to approach the significance of ANA in children individually depending on titers and patterns.

We have developed a new analytical peak separation analysis for superposed [Formula: see text]-ray peaks on [Formula: see text]Cu and [Formula: see text]Ga to measure the [Formula: see text]Zn(p,2p)[Formula: see text]Cu and [Formula: see text]Zn(p,2n)[Formula: see text]Ga reactions, unlike in most previous works that were employing a radiochemical separation to measure them. Based on the nuclear data such as the [Formula: see text]-ray intensity and the half-life for each nuclide, we may develop a new analytical method that enables us to estimate the respective counts arising from each nuclide, thereby obtaining the nuclear reactions. The newly developed analytical method can universally be applied to separate the superposed [Formula: see text]-ray spectra of any two nuclides, especially superior in separating the nuclides with different half-lives. In comparison with the data in the literature, the two reactions in the present work are in good agreement with those of some previous works. In addition, we compared the present [Formula: see text]Zn(p,2n)[Formula: see text]Ga reaction without the peak separation to the data in the literature without the chemical separation, and find that a good agreement is evident, enhancing the reliability of the [Formula: see text]Zn(p,x)[Formula: see text]Zn and [Formula: see text]Zn(p,3n)[Formula: see text]Ga reactions, which are further measured in the present work., (© 2023. The Author(s).)

Chemotherapy-induced cachexia causes severe metabolic abnormalities independently of cancer and reduces the therapeutic efficacy of chemotherapy. The underlying mechanism of chemotherapy-induced cachexia remains unclear. Here we investigated the cytarabine (CYT)-induced alteration in energy balance and its underlying mechanisms in mice. We compared energy balance-associated parameters among the three groups of mice: CON, CYT, and PF (pair-fed mice with the CYT group) that were intravenously administered vehicle or CYT. Weight gain, fat mass, skeletal muscle mass, grip strength, and nocturnal energy expenditure were significantly lowered in the CYT group than in the CON and PF groups. The CYT group demonstrated less energy intake than the CON group and higher respiratory quotient than the PF group, indicating that CYT induced cachexia independently from the anorexia-induced weight loss. Serum triglyceride was significantly lower in the CYT group than in the CON group, whereas the intestinal mucosal triglyceride levels and the lipid content within the small intestine enterocyte were higher after lipid loading in the CYT group than in the CON and PF groups, suggesting that CYT inhibited lipid uptake in the intestine. This was not associated with obvious intestinal damage. The CYT group showed increased zipper-like junctions of lymphatic endothelial vessel in duodenal villi compared to that in the CON and CYT groups, suggesting their imperative role in the CYT-induced inhibition of lipid uptake. CYT worsens cachexia independently of anorexia by inhibiting the intestinal lipid uptake, via the increased zipper-like junctions of lymphatic endothelial vessel., Competing Interests: Conflict of interest The authors declare no conflict of interests with this article contents., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: In obesity and type 2 diabetes mellitus, leptin promotes insulin resistance and contributes to the progression of NASH via activation of hepatic stellate cells (HSCs). However, the pathogenic mechanisms that trigger HSC activation in leptin-deficient obesity are still unknown. This study aimed to determine how HSC-targeting lipocalin-2 (LCN2) mediates the transition from simple steatosis to NASH., Approach and Results: Male wild-type (WT) and ob/ob mice were fed a high-fat diet (HFD) for 20 weeks to establish an animal model of NASH with fibrosis. Ob/ob mice were subject to caloric restriction or recombinant leptin treatment. Double knockout (DKO) mice lacking both leptin and lcn2 were also fed an HFD for 20 weeks. In addition, HFD-fed ob/ob mice were treated with gadolinium trichloride to deplete Kupffer cells. The LX-2 human HSCs and primary HSCs from ob/ob mice were used to investigate the effects of LCN2 on HSC activation. Serum and hepatic LCN2 expression levels were prominently increased in HFD-fed ob/ob mice compared with normal diet-fed ob/ob mice or HFD-fed WT mice, and these changes were closely linked to liver fibrosis and increased hepatic α-SMA/matrix metalloproteinase 9 (MMP9)/signal transducer and activator of transcription 3 (STAT3) protein levels. HFD-fed DKO mice showed a marked reduction of α-SMA protein compared with HFD-fed ob/ob mice. In particular, the colocalization of LCN2 and α-SMA was increased in HSCs from HFD-fed ob/ob mice. In primary HSCs from ob/ob mice, exogenous LCN2 treatment induced HSC activation and MMP9 secretion. By contrast, LCN2 receptor 24p3R deficiency or a STAT3 inhibitor reduced the activation and migration of primary HSCs., Conclusions: LCN2 acts as a key mediator of HSC activation in leptin-deficient obesity via α-SMA/MMP9/STAT3 signaling, thereby exacerbating NASH., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of American Association for the Study of Liver Diseases.)

Lipocalin-2 (LCN2) is an acute-phase protein that regulates inflammatory responses to bacteria or lipopolysaccharide (LPS). Although the bacteriostatic role of LCN2 is well studied, the function of LCN2 in acute lung damage remains unclear. Here, LCN2 knockout (KO) mice were used to investigate the role of LCN2 in LPS-treated mice with or without recombinant LCN2 (rLCN2). In addition, we employed patients with pneumonia. RAW264.7 cells were given LCN2 inhibition or rLCN2 with or without iron chelator deferiprone. LCN2 KO mice had a higher survival rate than wild-type (WT) mice after LPS treatment. In addition to elevated LCN2 levels in serum and bronchoalveolar lavage fluid (BALF), LPS treatment also increased LCN2 protein in alveolar macrophage lysates of BALF. LCN2 deletion attenuated neutrophil and macrophage infiltration in the lungs of LPS-treated mice as well as serum and BALF interleukin-6 (IL-6). Circulating proinflammatory cytokines and LCN2-positive macrophages were prominently increased in the BALF of pneumonia patients. In addition to increase of iron-stained macrophages in pneumonia patients, increased iron-stained macrophages and oxidative stress in LPS-treated mice were inhibited by LCN2 deletion. In contrast, rLCN2 pretreatment aggravated lung inflammation and oxidative stress in LPS-treated WT mice and then resulted in higher mortality. In RAW264.7 cells, exogenous LCN2 treatment also increased inflammation and oxidative stress, whereas LCN2 knockdown markedly diminished these effects. Furthermore, deferiprone inhibited inflammation, oxidative stress, and phagocytosis in RAW264.7 cells with high LCN2 levels, as well as LPS-induced acute lung injury in WT and LCN2 KO mice. Thus, these findings suggest that LCN2 plays a key role in inflammation and oxidative stress following acute lung injury and that LCN2 is a potential therapeutic target for pneumonia or acute lung injury., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Jawoongo (JW) is a topical herbal ointment that has been used as an alternative treatment option for atopic dermatitis. Topical ointments are known to have less bioavailability because the stratum corneum allows only lipophilic and low molecular weight drugs to pass across it. This study aimed to investigate whether applying microneedle patches (MNP) increases the therapeutic effect of 2,4-dinitrochlorobenzene (DNCB)+JW for atopic dermatitis by enhancing transdermal delivery., Methods: Atopic dermatitis was induced by DNCB in BALB/c mice. The combination treatment of JW and MNP was estimated to study the effect of MNP in improving transdermal delivery. Histological analysis, quantitative real-time PCR (qPCR), and immunofluorescence were performed to verify the effect of MNP in enhancing the therapeutic effects of DNCB+JW on atopic dermatitis in mice., Results: Both combination treatment and DNCB+JW treatment ameliorated histological alterations and reduced skin thickness and infiltration of CD4+ T cells in atopic dermatitis-like skin lesions in DNCB-exposed BALB/c mice. However, the improvement of histological alterations was better in the combination treatment, which was almost normal. Furthermore, the combination treatment exhibited a larger decrease in mRNA levels of IL-4, IL-6, IL-13, iNOS, and TNF-α, compared to DNCB+JW only. In addition, skin thickness and infiltration of CD4+ T cells in the sensitized skin were significantly lower using the combination treatment than using DNCB+JW only., Conclusion: Combination treatment with JW and MNP further decreased skin thickness and several inflammatory cytokines in atopic dermatitis like skin lesions compared to treatment using JW alone. These findings suggest that applying a dissolvable MNP after JW application could be useful for treating atopic dermatitis., (© 2022 S. Karger AG, Basel.)

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery., Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism., Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk., (© 2022. The Author(s).)

Metabolic traits are heritable phenotypes widely-used in assessing the risk of various diseases. We conduct a genome-wide association analysis (GWAS) of nine metabolic traits (including glycemic, lipid, liver enzyme levels) in 125,872 Korean subjects genotyped with the Korea Biobank Array. Following meta-analysis with GWAS from Biobank Japan identify 144 novel signals (MAF ≥ 1%), of which 57.0% are replicated in UK Biobank. Additionally, we discover 66 rare (MAF < 1%) variants, 94.4% of them co-incident to common loci, adding to allelic series. Although rare variants have limited contribution to overall trait variance, these lead, in carriers, substantial loss of predictive accuracy from polygenic predictions of disease risk from common variant alone. We capture groups with up to 16-fold variation in type 2 diabetes (T2D) prevalence by integration of genetic risk scores of fasting plasma glucose and T2D and the I349F rare protective variant. This study highlights the need to consider the joint contribution of both common and rare variants on inherited risk of metabolic traits and related diseases., (© 2022. The Author(s).)

Currently, protective clothing used in clinical field is the most representative example of efforts to reduce radiation exposure to radiation workers. However, lead is classified as a substance harmful to the human body that can cause lead poisoning. Therefore, research on the development of lead-free radiation shielding bodies is being conducted. In this study, the shielding body was manufactured by changing the size, layer, and height of the nozzle, using a 90.7% pure tungsten filament, a 3D printer material, and we compared its performance with existing protection tools. Our findings revealed that the shielding rate of the mixed tungsten filament was higher than that of the existing protective tools, confirming its potency to replace lead as the most protective material in clinical field.

In this study, the response of antibiotic resistance genes (ARGs), mobile gene elements (intI1), and human bacterial pathogens (HBPs) to addition of manure biochar (1-10 g/L) was studied in anaerobic digestion (AD) at 20-55 °C for treating dairy manure. Twelve ARGs comprising five tetracycline resistance genes, two sulfonamide resistance genes, two macrolide resistance genes, three β-lactam antibiotic resistance genes, and intI1 were analyzed by quantitative PCR. High-throughput sequencing data were matched against a database of putative 538 HBPs. Significant removal of ARGs (except for tetO and ermB) and intI1 was observed in all the samples. Manure biochar resulted in significant removal of ARGs and HBPs; however, negative effects were also observed in some conditions. This is the first study to provide to explore the fates of ARGs and HBPs by adding manure biochar to AD., (Copyright © 2022. Published by Elsevier Ltd.)

Human leukocyte antigen (HLA) gene variants in the major histocompatibility complex (MHC) region are associated with numerous complex human diseases and quantitative traits. Previous phenome-wide association studies (PheWAS) for this region demonstrated that HLA association patterns to the phenome have both population-specific and population-shared components. We performed MHC PheWAS in the Korean population by analyzing associations between phenotypes and genetic variants in the MHC region using the Korea Biobank Array project data samples from the Korean Genome and Epidemiology Study cohorts. Using this single-population dataset, we curated and analyzed 82 phenotypes for 125 673 Korean individuals after imputing HLA using CookHLA, a recently developed imputation framework. More than one-third of these phenotypes showed significant associations, confirming 56 known associations and discovering 13 novel association signals that were not reported previously. In addition, we analyzed heritability explained by the variants in the MHC region and genetic correlations among phenotypes based on the MHC variants., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

We have developed chelator-free copper-64-incorporated iron oxide (IO) nanoparticle (NPs) which have both magnetic and radioactive properties being applied to positron emission tomography (PET)-magnetic resonance imaging (MRI). We have found that the IO nanoparticles composed of radioactive isotope 64 Cu may act as a contrast agent being a diagnostic tool for PET as well as a good T 2 MRI nanoprobe due to their good r 2 / r 1 ratio. Furthermore, we demonstrate that the 64 Cu incorporation at the core of core-shell-structured IO NPs exhibits a good in vivo stability, giving us an insightful strategy for the design of a contrast agent for the PET-MRI system.

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology., Competing Interests: Declaration of interests G.C.-P. is currently an employee of 23andMe Inc. M.J.C. is the Chief Scientist for Genomics England, a UK Government company. B.M. Psaty serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. G. Thorleifsson, A.H., D.F.G., H. Holm, U.T., and K.S. are employees of deCODE/Amgen Inc. V.S. has received honoraria for consultations from Novo Nordisk and Sanofi and has an ongoing research collaboration with Bayer Ltd. M. McCarthy has served on advisory panels for Pfizer, NovoNordisk, and Zoe Global and has received honoraria from Merck, Pfizer, Novo Nordisk, and Eli Lilly and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. M. McCarthy and A. Mahajan are employees of Genentech and holders of Roche stock. M.S. receives funding from Pfizer Inc. for a project unrelated to this work. M.E.K. is employed by SYNLAB MVZ Mannheim GmbH. W.M. has received grants from Siemens Healthineers, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from AMGEN, grants from Astrazeneca, grants and personal fees from Sanofi, grants and personal fees from Alexion Pharmaceuticals, grants and personal fees from BASF, grants and personal fees from Abbott Diagnostics, grants and personal fees from Numares AG, grants and personal fees from Berlin-Chemie, grants and personal fees from Akzea Therapeutics, grants from Bayer Vital GmbH , grants from bestbion dx GmbH, grants from Boehringer Ingelheim Pharma GmbH Co KG, grants from Immundiagnostik GmbH, grants from Merck Chemicals GmbH, grants from MSD Sharp and Dohme GmbH, grants from Novartis Pharma GmbH, grants from Olink Proteomics, and other from Synlab Holding Deutschland GmbH, all outside the submitted work. A.V.K. has served as a consultant to Sanofi, Medicines Company, Maze Pharmaceuticals, Navitor Pharmaceuticals, Verve Therapeutics, Amgen, and Color Genomics; received speaking fees from Illumina and the Novartis Institute for Biomedical Research; received sponsored research agreements from the Novartis Institute for Biomedical Research and IBM Research, and reports a patent related to a genetic risk predictor (20190017119). S. Kathiresan is an employee of Verve Therapeutics and holds equity in Verve Therapeutics, Maze Therapeutics, Catabasis, and San Therapeutics. He is a member of the scientific advisory boards for Regeneron Genetics Center and Corvidia Therapeutics; he has served as a consultant for Acceleron, Eli Lilly, Novartis, Merck, Novo Nordisk, Novo Ventures, Ionis, Alnylam, Aegerion, Haug Partners, Noble Insights, Leerink Partners, Bayer Healthcare, Illumina, Color Genomics, MedGenome, Quest, and Medscape; and he reports patents related to a method of identifying and treating a person having a predisposition to or afflicted with cardiometabolic disease (20180010185) and a genetics risk predictor (20190017119). D.K. accepts consulting fees from Regeneron Pharmaceuticals. D.O.M.-K. is a part-time clinical research consultant for Metabolon, Inc. D. Saleheen has received support from the British Heart Foundation, Pfizer, Regeneron, Genentech, and Eli Lilly pharmaceuticals. P.N. reports investigator-initated grants from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis, personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Novartis, Roche / Genentech, is a co-founder of TenSixteen Bio, is a scientific advisory board member of Esperion Therapeutics, geneXwell, and TenSixteen Bio, and spousal employment at Vertex, all unrelated to the present work. The spouse of C.J.W. is employed by Regeneron., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Lipocalin-2 (LCN2) is an acute-phase protein that has been linked to insulin resistance, diabetes, and neuroinflammatory diseases. Triggering receptor expressed on myeloid cells-2 (TREM2) has been also implicated in microglia-mediated neuroinflammation. However, the potential role of LCN2 on TREM2 in diabetic mouse models is not fully understood., Methods: We investigated hepatic and hippocampal TREM2 expressions in high-fat diet (HFD) and streptozotocin (STZ)-induced diabetic LCN2 knockout (KO) mice., Results: In addition to increased serum LCN2 level, diabetic wild-type (WT) mice had insulin resistance and hepatic steatosis. However, LCN2 deletion attenuated these metabolic parameters in diabetic mice. We also found that LCN2 deletion reduced hepatic inflammation and microglial activation in diabetic mice. In particular, diabetic LCN2 KO mice had a reduction in hepatic and hippocampal TREM2 expressions compared with diabetic WT mice. Furthermore, we found that many TREM2-positive Kupffer cells and microglia in diabetic WT mice were reduced through LCN2 deletion., Conclusions: These findings indicate that LCN2 may promote hepatic inflammation and microglial activation via upregulation of TREM2 in diabetic mice.

Gut dysbiosis is closely associated with the outbreak of inflammatory bowel disease (IBD) and psychiatric disorder. The Enterobacteriaceae population was higher in the feces of patients with inflammatory bowel disease (IBD-F) than in those of healthy control volunteers (HC-F). The Enterococcaceae and Lactobacillaceae populations were higher in the feces of IBD patients with depression (IBD/D + -F) vs. the feces of IBD patients without depression (IBD/D - -F). Therefore, we examined the effects of Klebsiella oxytoca, Escherichia coli, Cronobacter sakazakii, Enterococcus faecium, and Pediococcus acidolactici overpopulated in IBD/D + -F and their byproducts LPS and exopolysaccharide (EPS) on the occurrence of depression and colitis in mice. Oral gavages of Klebsiella oxytoca, Escherichia coli, and Cronobacter sakazakii belonging to Enterobacteriaceae, singly or together, caused dose-dependently colitis and depression-like behaviors in germ-free and specific-pathogen-free mice. Although Enterococcus faecium and Pediococcus acidolactici did not significantly cause colitis and depression-like behaviors, they significantly deteriorated Klebsiella oxytoca- or Escherichia coli-induced colitis, neuroinflammation, and anxiety/depression-like behaviors and increased blood LPS, corticosterone, and IL-6 levels. The EPSs from Enterococcus faecium and Pediococcus acidolactici also worsened Klebsiella oxytoca LPS-induced colitis, neuroinflammation, and depression-like behaviors in mice and increased the translocation of fluorescein isothiocyanate-conjugated LPS into the hippocampus. However, Bifidobacterium longum, which was lower in IBD/D + -F vs. IBD/D - -F, or its EPS suppressed them. In conclusion, Enterococcus faecium and Pediococcus acidolactici, known as a probiotic strain, and their EPSs may be a risk factor for the outbreak of depression and IBD., (© 2022. The Author(s).)

Gut microbiota dysbiosis is strongly associated with psychiatric disorders and inflammatory bowel disease (IBD). Herein, we examined whether the fecal microbiota of IBD patients with depression (IBDD) and their gut microbiota culture (iGm) could cause depression and colitis in mice and anti-inflammatory probiotics could mitigate depression in iGm-transplanted or immobilization stress (IS)-exposed mice. Fecal microbiota transplantation (FMT) from IBDD patients, which exhibited Enterobacteriaceae -rich gut microbiota, and its gut microbiota culture (iGm) increased depression-like behaviors in mice. Their treatments heightened the blood lipopolysaccharide (LPS) level and colonic IL-1β and IL-6 expression. However, FMT from healthy volunteers or sulfasalazine treatment alleviated cGm-induced depressive-like behaviors and hippocampal and colonic inflammation in mice. Moreover, oral administration of Lactobacillus plantarum NK151, Bifidobacterium longum NK173, and Bifidobacterium bifidum NK175, which inhibited LPS-induced IL-6 expression in macrophages, alleviated cGm-induced depression-like behaviors, hippocampal NF-κB + Iba1 + cell numbers and IL-1β and IL-6 expression, blood LPS, IL-6, and creatinine levels, and colonic NF-κB + CD11c + number and IL-1β and IL-6 expression in mice. Treatment with NK151, NK173, or NK175 mitigated immobilization stress (IS)-induced depressive-like behaviors, neuroinflammation, and gut inflammation in mice. NK151, NK173, or NK175 also decreased IS-induced blood LPS, IL-6, and creatinine levels. The transplantation of Enterobacteriaceae -rich gut microbiota can cause depression and colitis, as IS exposure, and anti-inflammatory NK151, NK173, and NK175, may alleviate stress-induced fatigue, depression, and colitis by regulating the expression of proinflammatory and anti-inflammatory cytokines through the suppression of gut bacterial LPS.

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10 -9 ), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

This study evaluated the relationship between pyrolysis temperature (300-900 ℃), characteristics of swine manure (SM)-derived biochar (BC), and its adsorption of levofloxacin (LEV). The surface structure and chemistry of SM-derived BCs were characterized using Brunauer-Emmett-Teller analysis, scanning electron microscopy, Fourier-transform infrared spectroscopy, X-ray diffraction, Raman spectroscopy, and X-ray photoelectron spectroscopy. According to the characteristic analysis, the surface area and graphitization degree of SM-derived BC increased as temperature rose. The highest adsorption capacity was achieved by BC-900 (158 mg/g); this level was higher than that achieved in previous studies and comparable to that of commercial activated carbons. Characterization and adsorption experiments indicated that pore-filling, π-π stacking interaction, π-π electron donor-acceptor, H-bonding, and hydrophobic interactions each played a critical role in the adsorption of LEV on SM-derived BC. Collectively, this study confirms the potential utility of SM-derived BC for the removal of antibiotics., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: We studied the association between Henoch-Schönlein purpura nephritis (HSPN) and complement system activation. Methods: We retrospectively reviewed the pathologic findings and medical records of 35 children and 12 adults with HSPN and compared the differences according to C4d positivity in three groups consisting of total 47 patients, 35 pediatric and 12 adult patients, respectively. C4d staining of renal biopsy was additionally performed at the time of diagnosis or retrospectively using archival biopsy material. Results: The overall rate of C4d positivity was 53.2%: 20 (57.1%) of the 35 children and five (41.7%) of the 12 adults. Among the groups there was no significant difference in the severity of proteinuria, renal function, presence of crescents or mesangial proliferation stratified by C4d positivity, unlike IgA nephropathy. Conclusions: We suggest that the activation of complement system is not correlated with the clinical or pathological severity of HSPN.

Doxorubicin (DOX) is an effective anticancer drug with the side effect of irreparable cardiomyopathy. Lipocalin-2 (LCN2) has been identified as an important regulator of oxidative stress and inflammation in cardiovascular disease pathophysiology. Here, we demonstrate that LCN2 deletion increases autophagic flux in the DOX-treated hearts. Mice were injected intraperitoneally six times with 30 mg/kg DOX. Echocardiography showed that DOX-treated wild-type (WT) mice had markedly weaker cardiac function compared to saline-treated WT mice. In DOX-treated LCN2 knockout (KO) mice, cardiac function was partially restored. Histological analysis showed a reduction in cardiomyocyte diameter in DOX-treated WT mice that was ameliorated in DOX-treated LCN2KO mice. Cardiac levels of phosphorylated signal transducer and activator of transcription 3, LCN2, heme oxygenase-1, and NAD (P) H dehydrogenase were markedly greater in DOX-treated WT mice than in DOX-treated LCN2KO mice. Light chain 3B (LC3B)II expression was higher in DOX-treated WT mice, but lower in DOX-treated LCN2KO mice when compared to saline-treated WT mice. Less co-localization of LC3B and lysosomal-associated membrane protein 1 was observed in DOX-treated WT mice than in DOX-treated LCN2KO mice. LCN2 co-localized with LC3B-stained cells in the DOX-treated WT mouse heart, but not in the DOX-treated LCN2KO mouse heart. These findings indicate that the cardiotoxic effect of DOX is due to autophagosome accumulation mediated by LCN2 upregulation and that LCN2 may inhibit autophagic flux, leading to DOX-induced cardiomyopathy., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: There have been some cases where abnormal histopathologic findings could not be found in the kidney could even with proper specimen collection through percutaneous renal biopsy (PRB) in accordance with its indication. We analyzed the incidence and clinical outcomes of children who showed normal histopathological findings in their PRBs., Methods: The medical records of 552 pediatric subjects who underwent PRB between 2005 and 2016 were reviewed. Twenty-six subjects were excluded because allograft biopsy was performed in nine subjects, and the age at biopsy was greater than 18 years in 17 subjects. Finally, 526 subjects were enrolled in this study., Results: Of the 526 pediatric patients, 32 (6.1%) showed no histopathological abnormalities in their PRBs. The male-to-female ratio of the patients was 1.9:1, and the mean ages at the first visit and at biopsy were 10.6 ± 4.1 and 11.4 ± 3.8 years, respectively. In accordance with the biopsy indications, recurrent gross hematuria showed the highest incidence rate, but combined hematuria and proteinuria had the lowest incidence rate regarding normal renal histopathology among all the subjects. At a mean follow-up of 35.5 ± 23.6 months, urinary abnormalities had improved in more than 50% of the subjects with normal renal histopathology, and none of the patients showed progression to end-stage renal disease or required rebiopsy due to symptom worsening during the follow-up period., Conclusion: The clinical outcomes of children with normal PRB histopathologic findings are generally good. Further studies to evaluate their long-term outcomes are needed.

Genome-wide association studies (GWASs) facilitated the discovery of countless disease-associated variants. However, GWASs have mostly been conducted in European ancestry samples. Recent studies have reported that these European-based association results may reduce disease prediction accuracy when applied in non-Europeans. Therefore, previously reported variants should be validated in non-European populations to establish reliable scientific evidence for precision medicine. In this study, we validated known associations with type 2 diabetes (T2D) and related metabolic traits in 125,850 samples from a Korean population genotyped by the Korea Biobank Array (KBA). At the end of December 2020, there were 8,823 variants associated with glycemic traits, lipids, liver enzymes, and T2D in the GWAS catalog. Considering the availability of imputed datasets in the KBA genome data, publicly available East-Asian T2D summary statistics, and the linkage disequilibrium among the variants (r2 < 0.2), 2,900 independent variants were selected for further analysis. Among these, 1,837 variants (63.3%) were statistically significant (p ≤ 0.05). Most of the non-replicated variants (n = 1,063) showed insufficient statistical power and decreased minor allele frequencies compared with the replicated variants. Moreover, most of known variants showed <10% genetic heritability. These results could provide valuable scientific evidence for future study designs, the current power of GWASs, and future applications in precision medicine in the Korean population.

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use 1 . Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels 2 , heart disease remains the leading cause of death worldwide 3 . Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS 4-23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns 24 . Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine 25 , we anticipate that increased diversity of participants will lead to more accurate and equitable 26 application of polygenic scores in clinical practice., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Bacterial lipopolysaccharide (LPS) is a risk factor for the outbreak of Alzheimer's disease. Therefore, we isolated Lactobacillus plantarum NK151 and Bifidobacterium longum NK173 from a human fecal bacteria collection, which inhibited Escherichia coli LPS production, and examined their effects on the Escherichia coli K1- or LPS-induced cognitive impairment in mice. Oral gavage of NK151, NK173, or their (4 : 1) mixture (NKm) significantly alleviated Escherichia coli K1-induced cognitive impairment-like behaviors in the Y-maze and novel object recognition tasks. Their treatments decreased IL-1β, IL-6, and TNF-α expression and NF-κB + /Iba1 + and LPS + /Iba1 + cell populations in the hippocampus, while the brain-derived neurotrophic factor (BDNF) + /neuronal nuclei (NeuN) + cell population and BDNF to proBNDF expression increased. They suppressed LPS-induced cognition impairment-like behaviors and neuroinflammation marker levels in the hippocampus. Treatment with them reduced Escherichia coli K1- or LPS-induced LPS and apolipoprotein E levels in the blood and inflammatory marker levels in the colon. Furthermore, treatment with them modulated fecal Proteobacteria, Bacteroidetes, and Verrucomicrobia populations. Of these gut bacteria, Bacteroidaceae, Odoribacteraceae, Lactobacillaceae, Bifidobacteriaceae, Rikenellaceae, Helicobacteraceae, and Deferribacteraceae are correlated with cognitive function and blood and fecal LPS levels. These findings suggest that NK151 and NK173 may alleviate cognitive impairment with colitis by upregulating NF-κB-mediated BDNF expression through the suppression of fecal and blood bacterial LPS levels.

Gut lactobacilli and bifidobacteria on the immune homeostasis. Therefore, to understand the mechanism in vivo, we selected human fecal Lactobacillus rhamnosus NK210 and Bifidobacterium longum NK219, which strongly suppressed the IFN-γ to IL-10 expression (IIE) ratio in lipopolysaccharide-stimulated macrophages. Thereafter, we examined their effects on the endotoxin, antibiotics, or antitumor drug-stimulated immune imbalance in mice. Intraperitoneal injection of lipopolysaccharide and oral gavage of ampicillin increased IFN-γ and TNF-α expression in the spleen, colon, and hippocampus, while IL-10 expression decreased. However, intraperitoneal injection of cyclophosphamide suppressed IFN-γ, TNF-α, and IL-10 expression. LPS exposure induced splenic natural killer cell cytotoxicity against YAC-1 cells (sNK-C) and peritoneal macrophage phagocytosis against Candida albicans (pMA-P) activities, while cyclophosphamide and ampicillin treatments suppressed sNK-C and pMA-P activities. However, LPS, ampicillin, cyclophosphamide all increased IIE and TNF-α to IL-10 expression (TIE) ratios. Oral administration of NK210 and/or NK219 significantly reduced LPS-induced sNK-C, pMA-P, and IFN-γ expression, while cyclophosphamide- or ampicillin-suppressed sNK-C and pMA-P activities, cyclophosphamide-suppressed IFN-γ, TNF-α, and IL-10 expression, and ampicillin-suppressed IL-10 expression increased. Nevertheless, they suppressed LPS-, ampicillin-, or cyclophosphamide-induced IIE and TIE ratios, cognitive impairment, and gut dysbiosis. In particular, NK219, but not NK210, increased the IIE expression ratio in vitro and in vivo, and enhanced sNK-C and pMA-P activities in normal control mice, while cognitive function and gut microbiota composition were not significantly affected. These findings suggest that NK210, Lactobacillus sp, and NK219, Bifidobacterium additively or synergistically alleviate gut dysbiosis, inflammation, and cognitive impairment with immune imbalance by controlling IIE and TIE ratios., (© 2021. The Author(s).)

Gut dysbiosis is closely associated with the occurrence of inflammatory bowel disease (IBD) and psychiatric disorder. Here, to understand the difference of gut microbiota composition and physiological effect between IBD patients with (IBD/D + ) or without depression (IBD/D - ), we analyzed the fecal microbiota composition of patients with IBD with (/D + ) or without depression (/D - ) and healthy volunteers (HVs) and examined the effects of these fecal microbiota transplantations (FMTs) on the occurrence of systemic inflammation and anxiety/depression in mice. FMTs from patients with IBD/D + or IBD/D - caused IBD-like colitis in the transplanted mice: they increased the myeloperoxidase activity, IL-1β and IL-6 expression, and NF-κB + /CD11c + cell population in the colon. Transplantation of the IBD/D + patient feces (IBD/D + -F) caused IBD-like colitis more strongly than that of IBD/D - -F. FMTs from patients with IBD/D + also caused anxiety-/depression-like behaviors, increased the NF-κB + /Iba1 + and lipopolysaccharide (LPS) + /Iba1 + cell populations, and decreased the BDNF + /NeuN + cell population in the hippocampus. They increased LPS levels in the blood. FMTs from patients with IBD/D - caused anxiety-like, but not depression-like, behaviors. α-/β-diversities and composition of gut microbiota in IBD-F were different from those of HV feces (HV-F). The Enterobacteriaceae and Enterococcaceae populations and LPS levels were higher in the IBD-F than in the HV-F. The Enterococcaceae population was higher in IBD/D + -F vs. IBD/D - -F. However, the transplantation of HV-F into mice previously transplanted with IBD/D + -F significantly reduced depression-like behaviors, NF-κB + /Iba1 + and LPS + /Iba1 + cell populations in the hippocampus, LPS levels in the feces and blood, and IL-1β expression in the colon. These findings suggest that the outbreak of depression/anxiety may be dependent on the systemic inflammation with a leaky gut through the gut dysbiosis-attributable overproduction of bacterial LPS and suppression of tight junction protein expression in patients with IBD., (© 2021. The Author(s).)

We investigate the magnetic properties in carbonyl iron (CI) particles before and after Ni[Formula: see text] and H[Formula: see text] ion beam irradiation. Upon increasing temperatures, the saturation magnetization ([Formula: see text]) in hysteresis loops exhibits an anomalous increase at a high temperature for the unirradiated and the Ni[Formula: see text]-beam-irradiated samples, unlike in H[Formula: see text]-beam-irradiated sample. Moreover, the magnetization values at low and high temperatures are more intense after Ni[Formula: see text] beam irradiation, whereas after H[Formula: see text] beam irradiation those are remarkably suppressed. Hematite ([Formula: see text]-Fe[Formula: see text]O[Formula: see text]) phase introduced on the surface of our CI particles undergoes the Morin transition that was observed in our magnetization-temperature curves. The Morin transition causing canted antiferromagnetism above the Morin temperature was found in the unirradiated and Ni[Formula: see text]-beam-irradiated samples, but not in H[Formula: see text]-beam-irradiated sample. It is thus revealed that the CI particles undergoing the Morin transition cause the anomalous increase in [Formula: see text]. We may suggest that Ni[Formula: see text] ion beam increases uncompensated surface spins on the CI particles resulting in a more steep Morin transition and the intensified [Formula: see text]. Ion-beam irradiation may thus be a good tool for controlling the magnetic properties of CI particles, tailoring our work for future applications., (© 2021. The Author(s).)

Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor (GLP-1R) agonist that protects against brain injury. However, little is known about the effect of Ex-4 on kainic acid (KA)-induced seizures and hippocampal cell death. Therefore, this study evaluated the neuroprotective effects of Ex-4 pretreatment in a mouse model of KA-induced seizures. Three days before KA treatment, mice were intraperitoneally injected with Ex-4. We found that Ex-4 pretreatment reversed KA-induced reduction of GLP-1R expression in the hippocampus and attenuated KA-induced seizure score, hippocampal neuronal death, and neuroinflammation. Ex-4 pretreatment also dramatically reduced hippocampal lipocalin-2 protein in KA-treated mice. Furthermore, immunohistochemical studies showed that Ex-4 pretreatment significantly alleviated blood-brain barrier leakage. Finally, Ex-4 pretreatment stimulated hippocampal expression of phosphorylated cyclic adenosine monophosphate (cAMP) response element-binding protein (p-CREB), a known target of GLP-1/GLP-1R signaling. These findings indicate that Ex-4 pretreatment may protect against KA-induced neuronal damage by regulating GLP-1R/CREB-mediated signaling pathways.

The linewidth broadening caused by various physicochemical effects does limit the well-known advantage of ultrahigh color purity of metal halide perovskites (MHPs) for use in next-generation light-emitting diodes (LEDs). We have theoretically examined the quantum- and dielectric-confinement effects of a quantum dot (QD) on the degree of photoluminescence linewidth broadening. It is predicted that the linewidth (Δ λ QC ) is mainly contributed by the two opposing effects: (i) the linewidth broadening due to the repulsive kinetic energy of confined excitons (ΔλQCKE) and (ii) the overall linewidth narrowing caused by the attractive Coulomb interaction (ΔλQCCoul). It is shown that the relative contribution essentially remains at a constant value and is evaluated asΔλQCCoul/ΔλQCKE=0.42, which is independent of the QD size and the chemical nature of semiconducting emitter. We have computed Δ λ QC for various QD sizes of the prototypical MHP emitter, MAPbBr 3 , where MA denotes a methylammonium (CH 3 NH 3 ) organic cation. The calculated results show that the linewidth broadening due to the quantum confinement (Δ λ QC ) increases rapidly beginning at the QD radius approximately equal to 6.5 nm but Δ λ QC is less than 2 nm even at R = 1.5 nm. Thus, Δ λ QC is much narrower than the linewidth caused by the exciton-LO phonon Fröhlich coupling (∼23.4 nm) which is known as the predominant mechanism of linewidth broadening in hybrid MHPs. Thus, the linewidth broadening due to the quantum confinement (Δ λ QC ) is not a risk factor in the realization of MHP-based ultrahigh-quality next-generation LEDs., (© 2021 IOP Publishing Ltd.)