Loss of TMEM106B exacerbates Tau pathology and neurodegeneration in PS19 mice.

TMEM106B, a gene encoding a lysosome membrane protein, is tightly associated with brain aging, hypomyelinating leukodystrophy, and multiple neurodegenerative diseases, including frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Recently, TMEM106B polymorphisms have been associated with tauopathy in chronic traumatic encephalopathy (CTE) and FTLD-TDP patients. However, how TMEM106B influences Tau pathology and its associated neurodegeneration, is unclear. Here we show that loss of TMEM106B enhances the accumulation of pathological Tau, especially in the neuronal soma in the hippocampus, resulting in severe neuronal loss in the PS19 Tau transgenic mice. Moreover, Tmem106b-/- PS19 mice develop significantly increased abnormalities in the neuronal cytoskeleton, autophagy-lysosome activities, as well as glial activation, compared with PS19 and Tmem106b-/- mice. Together, our findings demonstrate that loss of TMEM106B drastically exacerbates Tau pathology and its associated disease phenotypes, and provide new insights into the roles of TMEM106B in neurodegenerative diseases.

Untargeted Pixel-by-Pixel Imaging of Metabolite Ratio Pairs as a Novel Tool for Biomedical Discovery in Mass Spectrometry Imaging.

Mass spectrometry imaging (MSI) is a powerful technology used to define the spatial distribution and relative abundance of structurally identified and yet-undefined metabolites across tissue cryosections. While numerous software packages enable pixel-by-pixel imaging of individual metabolites, the research community lacks a discovery tool that images all metabolite abundance ratio pairs. Importantly, recognition of correlated metabolite pairs informs discovery of unanticipated molecules contributing to shared metabolic pathways, uncovers hidden metabolic heterogeneity across cells and tissue subregions, and indicates single-timepoint flux through pathways of interest. Here, we describe the development and implementation of an untargeted R package workflow for pixel-by-pixel ratio imaging of all metabolites detected in an MSI experiment. Considering untargeted MSI studies of murine brain and embryogenesis, we demonstrate that ratio imaging minimizes systematic data variation introduced by sample handling and instrument drift, markedly enhances spatial image resolution, and reveals previously unrecognized metabotype-distinct tissue regions. Furthermore, ratio imaging facilitates identification of novel regional biomarkers and provides anatomical information regarding spatial distribution of metabolite-linked biochemical pathways. The algorithm described herein is applicable to any MSI dataset containing spatial information for metabolites, peptides or proteins, offering a potent tool to enhance knowledge obtained from current spatial metabolite profiling technologies.

IκB kinase thwarts aggregation: Phosphorylating TDP-43 for degradation.

TDP-43 aggregation is a hallmark of neurodegeneration. In this issue, Iguchi et al. (https://doi.org/10.1083/jcb.202302048) report that IκB kinase (IKK), an important mediator of inflammation, phosphorylates cytoplasmic TDP-43 to promote proteasomal degradation, revealing an unexpected link between inflammation and TDP-43 homeostasis.

Progranulin inhibits phospholipase sPLA2-IIA to control neuroinflammation.

Mutations in the granulin (GRN) gene, resulting in haploinsufficiency of the progranulin (PGRN) protein, are a leading cause of frontotemporal lobar degeneration (FTLD) and PGRN polymorphisms are associated with Alzheimer's disease (AD) and Parkinson's disease (PD). PGRN is a key regulator of microglia-mediated inflammation but the mechanism is still unknown. Here we report that PGRN interacts with sPLA2-IIA, a secreted phospholipase involved in inflammatory responses, to downregulate sPLA2-IIA activities and levels. sPLA2-IIA expression modifies PGRN deficiency phenotypes in mice and sPLA2-IIA inhibition rescues inflammation and lysosomal abnormalities in PGRN deficient mice. Furthermore, FTLD patients with GRN mutations show increased levels of sPLA2-IIA in astrocytes. Our data support sPLA2-IIA as a critical target for PGRN and a novel therapeutic target for FTLD-GRN.

eIF4A3 Promotes RNA Viruses' Replication by Inhibiting Innate Immune Responses.

Viral infection activates the type I interferons (IFNs) and cellular antiviral responses. Eukaryotic initiation factor 4A-III (eIF4A3) has been shown to promote influenza A virus (IAV) replication by promoting viral mRNA splicing and spliced mRNA nuclear export. Here, we identified eIF4A3 as a negative regulator of virus-triggered type I IFN induction. Our study found that eIF4A3 promoted multiple RNA viruses' replication by binding to IFN regulatory factor 3 (IRF3) and impaired the interaction between tank-binding kinase 1 (TBK1) and IRF3, leading to attenuation of the phosphorylation of IRF3 by TBK1, the formation of IRF3 dimer, and the nuclear translocation of IRF3. This impaired its biological functions in the nucleus, which blocked IRF3 binding to interferon-stimulated response element (ISRE) and the interaction of IRF3 and CBP/p300, resulting in inhibiting the transcription of IFN-ß and downstream IFN-stimulated genes (ISGs), thereby impairing innate antiviral immune responses against RNA viruses. These findings reveal a previously unknown function of eIF4A3 in host innate immunity and establish a mechanistic link between eIF4A3 and IRF3 activation that expands potential therapeutic strategies for viral infectious diseases. IMPORTANCE Production of type I IFN is pivotal for the cellular antiviral immunity. Virus infection leads to the activation of transcription factor IRF3 and subsequent production of type I IFN to eliminate viral infection. Thus, the regulation of IRF3 activity is an important way to affect type I IFN production. IRF3 activation requires phosphorylation, dimerization, and nuclear translocation. Here, we first reported that eIF4A3, a member of DEAD box family, served as a negative regulator of antiviral innate immune responses by inhibiting IRF3 activation. Mechanistically, eIF4A3 binds to IRF3 to impair the recruitment of IRF3 by TBK1, which is independent of eIF4A3 ATP binding, ATPase, and RNA helicase activities. Our study delineates a common mechanism of eIF4A3 promoting replication of different RNA viruses and provides important insights into the negative regulation of host antiviral innate immune responses against virus infections.

Eukaryotic Translation Elongation Factor 1 Delta Inhibits the Nuclear Import of the Nucleoprotein and PA-PB1 Heterodimer of Influenza A Virus.

The viral ribonucleoprotein (vRNP) of the influenza A virus (IAV) is responsible for the viral RNA transcription and replication in the nucleus, and its functions rely on host factors. Previous studies have indicated that eukaryotic translation elongation factor 1 delta (eEF1D) may associate with RNP subunits, but its roles in IAV replication are unclear. Herein, we showed that eEF1D was an inhibitor of IAV replication because knockout of eEF1D resulted in a significant increase in virus yield. eEF1D interacted with RNP subunits polymerase acidic protein (PA), polymerase basic 1 (PB1), polymerase basic 2 (PB2), and also with nucleoprotein (NP) in an RNA-dependent manner. Further studies revealed that eEF1D impeded the nuclear import of NP and PA-PB1 heterodimer of IAV, thereby suppressing the vRNP assembly, viral polymerase activity, and viral RNA synthesis. Together, our studies demonstrate eEF1D negatively regulating the IAV replication by inhibition of the nuclear import of RNP subunits, which not only uncovers a novel role of eEF1D in IAV replication but also provides new insights into the mechanisms of nuclear import of vRNP proteins.IMPORTANCE Influenza A virus is the major cause of influenza, a respiratory disease in humans and animals. Different from most other RNA viruses, the transcription and replication of IAV occur in the cell nucleus. Therefore, the vRNPs must be imported into the nucleus for viral transcription and replication, which requires participation of host proteins. However, the mechanisms of the IAV-host interactions involved in nuclear import remain poorly understood. Here, we identified eEF1D as a novel inhibitor for the influenza virus life cycle. Importantly, eEF1D impaired the interaction between NP and importin α5 and the interaction between PB1 and RanBP5, which impeded the nuclear import of vRNP. Our studies not only reveal the molecular mechanisms of the nuclear import of IAV vRNP but also provide potential anti-influenza targets for antiviral development.

A mathematical model for the novel coronavirus epidemic in Wuhan, China.

We propose a mathematical model to investigate the current outbreak of the coronavirus disease 2019 (COVID-19) in Wuhan, China. Our model describes the multiple transmission pathways in the infection dynamics, and emphasizes the role of the environmental reservoir in the transmission and spread of this disease. Our model also employs non-constant transmission rates which change with the epidemiological status and environmental conditions and which reflect the impact of the on-going disease control measures. We conduct a detailed analysis of this model, and demonstrate its application using publicly reported data. Among other findings, our analytical and numerical results indicate that the coronavirus infection would remain endemic, which necessitates long-term disease prevention and intervention programs.

A cholera transmission model incorporating the impact of medical resources.

We propose a mathematical model for the transmission dynamics of cholera under the impact of available medical resources. The model describes the interaction between the human hosts and the pathogenic bacteria and incorporates both the environment-to-human and human-to-human transmission routes. We conduct a rigorous equilibrium analysis to the model and establish the global asymptotic stability of the disease-free equilibrium when R0 ≤ 1 and that of the endemic equilibrium when R0 > 1. As a realistic case study, we apply our model to the Yemen cholera outbreak during 2017-2018. By fitting our simulation results to the epidemic data published by the World Health Organization, we find that different levels of disease prevalence and severity are linked to different geographical regions in this country and that cholera prevention and intervention efforts should be implemented strategically with respect to these regions in Yemen.

LYAR Suppresses Beta Interferon Induction by Targeting Phosphorylated Interferon Regulatory Factor 3.

The innate immune response is vital for host defense and must be tightly controlled, but the mechanisms responsible for its negative regulation are not fully understood. The cell growth-regulating nucleolar protein LYAR was found to promote replication of multiple viruses in our previous study. Here, we report that LYAR acts as a negative regulator of innate immune responses. We found that LYAR expression is induced by beta interferon (IFN-ß) during virus infection. Further studies showed that LYAR interacts with phosphorylated IFN regulatory factor 3 (IRF3) to impede the DNA binding capacity of IRF3, thereby suppressing the transcription of IFN-ß and downstream IFN-stimulated genes (ISGs). In addition, LYAR inhibits nuclear factor-κB (NF-κB)-mediated expression of proinflammatory cytokines. In summary, our study reveals the mechanism of LYAR in modulating IFN-ß-mediated innate immune responses by targeting phosphorylated IRF3, which not only helps us to better understand the mechanisms of LYAR-regulated virus replication but also uncovers a novel role of LYAR in host innate immunity.IMPORTANCE Type I interferon (IFN-I) plays a critical role in the antiviral innate immune responses that protect the host against virus infection. The negative regulators of IFN-I are important not only for fine-tuning the antiviral responses to pathogens but also for preventing excessive inflammation. Identification of negative regulators and study of their modulation in innate immune responses will lead to new strategies for the control of both viral and inflammatory diseases. Here, we report for the first time that the cell growth-regulating nucleolar protein LYAR behaves as a repressor of host innate immune responses. We demonstrate that LYAR negatively regulates IFN-ß-mediated immune responses by inhibiting the DNA binding ability of IFN regulatory factor 3 (IRF3). Our study reveals a common mechanism of LYAR in promoting different virus replication events and improves our knowledge of host negative regulation of innate immune responses.

Evidence for a novel mechanism of influenza A virus host adaptation modulated by PB2-627.

Influenza virus cross-species transmission is restricted by the host, but viruses overcome this restriction by accumulating mutations which allow them to adapt to a new host. Among the many factors which facilitate virus host adaptation, polymerase basic protein 2 (PB2) 627 plays an important role, although the underlying molecular mechanism has not been fully understood. In a previous study, we found that histone H1.2 (encoded by HIST1H1C) regulates human or avian influenza virus replication in different ways, indicating that it might be involved in virus host adaptation. Herein, we found that HIST1H1C expression, phosphorylation and methylation levels are decreased when infected with H1N1 influenza virus and increased when infected with H5N1 influenza virus. Overexpressing the eight gene segments of the influenza virus, we found that only PB2 significantly affects HIST1H1C expression and modifications. Since the 627 site is different between the H5N1 and H1N1 influenza viruses we constructed PB2-627E (avian variant) and PB2-627K (human variant) mutant viruses, and observed that the effects of the wild-type and the mutant viruses on HIST1H1C expression and modifications are the opposite of one another. Further analysis showed that influenza virus PB2-627 regulates HIST1H1C expression via Sp1, and specifically that PB2-627K down-regulates Sp1 and HIST1H1C while PB2-627E up-regulates Sp1 and HIST1H1C. In addition, HIST1H1C can feedback regulate DNA-dependent protein kinase and euchromatic histone-lysine N-methyltransferase 1/2, leading to altered HIST1H1C phosphorylation and methylation levels, and affecting influenza virus replication accordingly. In summary, this study illustrates the mechanism of PB2-627E/K-mediated regulation of influenza virus host adaptation.

The Nucleolar Protein LYAR Facilitates Ribonucleoprotein Assembly of Influenza A Virus.

Influenza A viral ribonucleoprotein (vRNP) is responsible for transcription and replication of the viral genome in infected cells and depends on host factors for its functions. Identification of the host factors interacting with vRNP not only improves understanding of virus-host interactions but also provides insights into novel mechanisms of viral pathogenicity and the development of new antiviral strategies. Here, we have identified 80 host factors that copurified with vRNP using affinity purification followed by mass spectrometry. LYAR, a cell growth-regulating nucleolar protein, has been shown to be important for influenza A virus replication. During influenza A virus infection, LYAR expression is increased and partly translocates from the nucleolus to the nucleoplasm and cytoplasm. Furthermore, LYAR interacts with RNP subunits, resulting in enhancing viral RNP assembly, thereby facilitating viral RNA synthesis. Taken together, our studies identify a novel vRNP binding host partner important for influenza A virus replication and further reveal the mechanism of LYAR regulating influenza A viral RNA synthesis by facilitating viral RNP assembly.IMPORTANCE Influenza A virus (IAV) must utilize the host cell machinery to replicate, but many of the mechanisms of IAV-host interaction remain poorly understood. Improved understanding of interactions between host factors and vRNP not only increases our basic knowledge of the molecular mechanisms of virus replication and pathogenicity but also provides insights into possible novel antiviral targets that are necessary due to the widespread emergence of drug-resistant IAV strains. Here, we have identified LYAR, a cell growth-regulating nucleolar protein, which interacts with viral RNP components and is important for efficient replication of IAVs and whose role in the IAV life cycle has never been reported. In addition, we further reveal the role of LYAR in viral RNA synthesis. Our results extend and improve current knowledge on the mechanisms of IAV transcription and replication.

HIST1H1C Regulates Interferon-ß and Inhibits Influenza Virus Replication by Interacting with IRF3.

Influenza virus NS2 is well known for its role in viral ribonucleoprotein nuclear export; however, its function has not been fully understood. A recent study showed that NS2 might interact with HIST1H1C (H1C, H1.2). Histones have been found to affect influenza virus replication, such as the H2A, H2B, H3, and H4, but H1 has not been detected. Here, we found that H1C interacts with NS2 via its C-terminal in the nucleus and that H1C affects influenza virus replication. The H1N1 influenza virus replicates better in H1C knockout A549 cells compared to wild-type A549 cells, primarily because of the regulation of H1C on interferon-ß (IFN-ß). Further studies showed that the H1C phosphorylation mutant (T146A) decreases IFN-ß, while H1C methylation mutants (K34A, K187A) increases IFN-ß by releasing the nucleosome and promoting IRF3 binding to the IFN-ß promoter. Interestingly, NS2 interacts with H1C, which reduces H1C-IRF3 interaction and results in the inhibition of IFN-ß enhanced by H1C. In summary, our study reveals a novel function of H1C to regulate IFN-ß and uncovers an underlying mechanism, which suggests H1C plays a role in epigenetic regulation. Moreover, our results suggest a novel mechanism for the influenza virus to antagonize the innate immune response by NS2.

A Waterborne Outbreak and Detection of Cryptosporidium Oocysts in Drinking Water of an Older High-Rise Apartment Complex in Seoul

From May to June 2012, a waterborne outbreak of 124 cases of cryptosporidiosis occurred in the plumbing systems of an older high-rise apartment complex in Seoul, Republic of Korea. The residents of this apartment complex had symptoms of watery diarrhea and vomiting. Tap water samples in the apartment complex and its adjacent buildings were collected and tested for 57 parameters under the Korean Drinking Water Standards and for additional 11 microbiological parameters. The microbiological parameters included total colony counts, Clostridium perfringens, Enterococcus, fecal streptococcus, Salmonella, Shigella, Pseudomonas aeruginosa, Cryptosporidium oocysts, Giardia cysts, total culturable viruses, and Norovirus. While the tap water samples of the adjacent buildings complied with the Korean Drinking Water Standards for all parameters, fecal bacteria and Cryptosporidium oocysts were detected in the tap water samples of the outbreak apartment complex. It turned out that the agent of the disease was Cryptosporidium parvum. The drinking water was polluted with sewage from a septic tank in the apartment complex. To remove C. parvum oocysts, we conducted physical processes of cleaning the water storage tanks, flushing the indoor pipes, and replacing old pipes with new ones. Finally we restored the clean drinking water to the apartment complex after identification of no oocysts.

Retinoids, carotenoids, and tocopherols in breast adipose tissue and serum of benign breast disease and breast cancer patients.

Various retinoic acid (RA) isomers (all-trans, 13-cis, 11-cis, and 9-cis) as well as retinol, carotenoids, and tocopherol concentrations were determined in both serum and breast adipose tissue of 22 benign breast disease patients and 52 breast cancer patients categorized into 4 stages by malignancy. Serum RA isomers were analyzed by a newly developed sensitive method combining a high-performance liquid chromatography and a gas chromatography-mass spectrometry, and retinol, carotenoid, and tocopherol concentrations using a high-performance liquid chromatography system. The breast cancer patients showed significantly lower serum retinol, whereas significantly higher breast adipose tissue retinol concentration than those of benign breast disease patients. Although breast cancer patients showed significantly higher serum all-trans and 13-cis RA concentrations, 11-cis RA in breast adipose tissue was significantly lower in the breast cancer patients than those of benign breast disease patients and it was associated with the stage of malignancy. The current study indicates that the retinol and RA isomers in the target tissue of breast tumor patients are not reflecting their concentrations in circulation. The mechanisms of tissue specific uptake of RA isomers and their functions warrant further studies.

Longitudinal study on trace mineral compositions (selenium, zinc, copper, manganese) in Korean human preterm milk.

We measured selenium, zinc, copper and manganese concentrations in the human milk of Korean mothers who gave birth to preterm infants, and compared these measurements with the recommended daily intakes. The samples of human milk were collected postpartum at week-1, -2, -4, -6, -8, and -12, from 67 mothers who gave birth to preterm infants (< 34 weeks, or birth weight < 1.8 kg). All samples were analyzed using atomic absorption spectrophotometry. The concentrations of selenium were 11.8 ± 0.5, 11.4 ± 0.8, 12.7 ± 0.9, 11.4 ± 0.8, 10.8 ± 0.9, and 10.5 ± 1.3 µg/L, zinc were 7.8 ± 0.5, 9.1 ± 0.8, 7.2 ± 0.9, 8.0 ± 0.8, 7.4 ± 0.9, and 6.6 ± 1.2 mg/L, copper were 506 ± 23.6, 489 ± 29.4, 384 ± 33.6, 356 ± 32.9, 303 ± 35.0, and 301 ± 48.0 µg/L and manganese were 133 ± 4.0, 127 ± 6.0, 125 ± 6.0, 123 ± 6.0, 127 ± 6.0, and 108 ± 9.0 µg/L at week-1, -2, -4, -6, -8, and -12, respectively. The concentrations of selenium and zinc meet the daily requirements but that of copper is low and of manganese exceeds daily requirements recommended by the American Academy of Pediatrics, Committee on Nutrition.

Carotenoids and total phenolic contents in plant foods commonly consumed in Korea.

Phytochemicals are reported to provide various biological functions leading to the promotion of health as well as the reduced risk of chronic diseases. Fat-soluble plant pigments, carotenoids, are extensively studied micronutrient phytochemicals for their potential health benefits. It is noteworthy that specific carotenoids may be responsible for different protective effects against certain diseases. In addition, each carotenoid can be obtained from different types of plant foods. Considering the fact that the phytochemical content in foods can vary according to, but not limited to, the varieties and culture conditions, it is important to establish a database of phytochemicals in locally produced plant foods. Currently, information on individual carotenoid content in plant foods commonly consumed in Korea is lacking. As the first step to support the production and consumption of sustainable local plant foods, carotenoids and total phenolic contents of plant foods commonly consumed in Korea are presented and their potential biological functions are discussed in this review.

Carotenoids and total phenolic contents in plant foods commonly consumed in Korea

Phytochemicals are reported to provide various biological functions leading to the promotion of health as well as the reduced risk of chronic diseases. Fat-soluble plant pigments, carotenoids, are extensively studied micronutrient phytochemicals for their potential health benefits. It is noteworthy that specific carotenoids may be responsible for different protective effects against certain diseases. In addition, each carotenoid can be obtained from different types of plant foods. Considering the fact that the phytochemical content in foods can vary according to, but not limited to, the varieties and culture conditions, it is important to establish a database of phytochemicals in locally produced plant foods. Currently, information on individual carotenoid content in plant foods commonly consumed in Korea is lacking. As the first step to support the production and consumption of sustainable local plant foods, carotenoids and total phenolic contents of plant foods commonly consumed in Korea are presented and their potential biological functions are discussed in this review.

Longitudinal Study on Trace Mineral Compositions (Selenium, Zinc, Copper, Manganese) in Korean Human Preterm Milk

We measured selenium, zinc, copper and manganese concentrations in the human milk of Korean mothers who gave birth to preterm infants, and compared these measurements with the recommended daily intakes. The samples of human milk were collected postpartum at week-1, -2, -4, -6, -8, and -12, from 67 mothers who gave birth to preterm infants (< 34 weeks, or birth weight < 1.8 kg). All samples were analyzed using atomic absorption spectrophotometry. The concentrations of selenium were 11.8 +/- 0.5, 11.4 +/- 0.8, 12.7 +/- 0.9, 11.4 +/- 0.8, 10.8 +/- 0.9, and 10.5 +/- 1.3 microg/L, zinc were 7.8 +/- 0.5, 9.1 +/- 0.8, 7.2 +/- 0.9, 8.0 +/- 0.8, 7.4 +/- 0.9, and 6.6 +/- 1.2 mg/L, copper were 506 +/- 23.6, 489 +/- 29.4, 384 +/- 33.6, 356 +/- 32.9, 303 +/- 35.0, and 301 +/- 48.0 microg/L and manganese were 133 +/- 4.0, 127 +/- 6.0, 125 +/- 6.0, 123 +/- 6.0, 127 +/- 6.0, and 108 +/- 9.0 microg/L at week-1, -2, -4, -6, -8, and -12, respectively. The concentrations of selenium and zinc meet the daily requirements but that of copper is low and of manganese exceeds daily requirements recommended by the American Academy of Pediatrics, Committee on Nutrition.

Serial changes of fatty acids in preterm breast milk of Korean women.

Samples of breast milk were collected at postpartum weeks 1, 2, 4, 6, 8, and 12 from 104 Korean mothers who had delivered infants at less than 34 weeks or weighing less than 1.8 kg to investigate changes in fatty acid (FAs). Full-term breast milk (FBM) collected at the end of first week postpartum from 26 Korean women delivering healthy, term infants was used for comparison. Stability in relative FA composition was maintained during the first 3 months of lactation in preterm breast milk (PBM), and the relative composition of polyunsaturated FAs (PUFA), monounsaturated FAs, and saturated FAs remained constant in PBM. However, the ω6/ω3 ratio was significantly higher as lactation progressed owing to lower ω3 PUFA in PBM. The proportions of docosahexaenoic acid (DHA) and arachidonic acid (AA) in PBM gradually decreased over time, but the DHA/AA ratio was kept constant at 1.13, higher than that of Western countries. At the end of the first week, relative proportions of FAs were similar in PBM and FBM, but absolute concentrations of FA were higher in PBM.