Association of ambient air pollution with hemoglobin levels and anemia in the general population of Korean adults.

BACKGROUND: Emerging evidence has suggested significant associations between ambient air pollution and changes in hemoglobin levels or anemia in specific vulnerable groups, but few studies have assessed this relationship in the general population. This study aimed to evaluate the association between long-term exposure to air pollution and hemoglobin concentrations or anemia in general adults in South Korea. METHODS: A total of 69,830 Korean adults from a large-scale nationwide survey were selected for our final analysis. Air pollutants included particulate matter with an aerodynamic diameter less than or equal to 10 micrometers (PM10), particulate matter with an aerodynamic diameter less than or equal to 2.5 micrometers, nitrogen dioxide, sulfur dioxide (SO2), and carbon monoxide (CO). We measured the serum hemoglobin concentration to assess anemia for each participant. RESULTS: In the fully adjusted model, exposure levels to PM10, SO2, and CO for one and two years were significantly associated with decreased hemoglobin concentrations (all p < 0.05), with effects ranging from 0.15 to 0.62% per increase in interquartile range (IQR) for each air pollutant. We also showed a significant association of annual exposure to PM10 with anemia (p = 0.0426); the odds ratio (OR) [95% confidence interval (CI)] for anemia per each increase in IQR in PM10 was estimated to be 1.039 (1.001-1.079). This association was also found in the 2-year duration of exposure (OR = 1.046; 95% CI = 1.009-1.083; adjusted Model 2). In addition, CO exposure during two years was closely related to anemia (OR = 1.046; 95% CI = 1.004-1.091; adjusted Model 2). CONCLUSIONS: This study provides the first evidence that long-term exposure to air pollution, especially PM10, is significantly associated with reduced hemoglobin levels and anemia in the general adult population.

Assembly of FAP93 at the proximal axoneme in Chlamydomonas cilia.

To identify proteins specific to the proximal ciliary axoneme, we used iTRAQ to compare short (~2 µm) and full-length (~11 µm) axonemes of Chlamydomonas. Known compoents of the proximal axoneme such as minor dynein heavy chains and LF5 kinase as well as the ciliary tip proteins FAP256 (CEP104) and EB1 were enriched in short axonemes whereas proteins present along the length of the axoneme were of similar abundance in both samples. The iTRAQ analysis revealed that FAP93, a protein of unknown function, and protein phosphatase 2A (PP2A) are enriched in the short axonemes. Consistently, immunoblots show enrichment of FAP93 and PP2A in short axonemes and immunofluorescence confirms the localization of FAP93 and enrichment of PP2A at the proximal axoneme. Ciliary regeneration reveals that FAP93 assembles continuously but more slowly than other axonemal structures and terminates at 1.03 µm in steady-state axonemes. The length of FAP93 assembly correlates with ciliary length, demonstrating ciliary length-dependent assembly of FAP93. Dikaryon rescue experiments show that FAP93 can assemble independently of IFT transport. In addition, FRAP analysis of GFP-tagged FAP93 demonstrates that FAP93 is stably anchored in axoneme. FAP93 may function as a scaffold for assembly of other specific proteins at the proximal axoneme.

Effects of vitamin D on associations between air pollution and mental health outcomes in Korean adults: Results from the Korea National Health and Nutrition Examination Survey (KNHANES).

BACKGROUND: Evidence suggests that low individual vitamin D levels enhance adverse effects associated with air pollution on mental health conditions. The aim of this study was to identify associations between ambient air pollution exposure, mental health, and serum vitamin D status in the general population of South Korea. METHODS: We included national representative data for 29,373 adults in the final analysis. We measured serum 25-hydroxyvitamin D concentrations to assess vitamin D status for each participant. We assessed mental health factors (i.e., perceived stress, depressive symptoms, and suicidal ideation), and analyzed associations between these factors and individuals' annual average exposures to air pollutants, including particulate matter with an aerodynamic diameter ≤ 10 µm (PM10), nitrogen dioxide (NO2), sulfur dioxide, and carbon monoxide (CO). RESULTS: Using an adjusted model, we found PM10 affected mental health outcomes, such as perceived stress (odds ratio [OR] = 1.04; 95 % confidence interval [CI] = 1.00-1.09), depression symptoms (OR = 1.12; 95 % CI = 1.06-1.18), and suicidal ideation (OR = 1.11; 95 % CI = 1.05-1.17). Effects of the pollutants NO2 and CO were significant only in the group with perceived stress and depressive symptoms. PM10 and NO2 exposures were significantly associated with increased odds of adverse mental health in participants with vitamin D deficiency. LIMITATIONS: Since the cross-sectional design of KNHANES data, it is not possible to evaluate the causal relationship between air pollution exposure, vitamin D status and mental health. CONCLUSIONS: This study results suggest that associations between ambient air pollution and mental health outcomes were stronger in participants with vitamin D deficiency.

Associations between ambient air pollution, obesity, and serum vitamin D status in the general population of Korean adults.

BACKGROUND: Although a growing body of evidence suggests air pollution is associated with low serum vitamin D status, few studies have reported whether obesity status affects this relationship. The aim of this study was to identify associations between ambient air pollution exposure, obesity, and serum vitamin D status in the general population of South Korea. METHODS: This study was conducted in a cross-sectional design. A total of 30,242 Korean adults from a nationwide general population survey were included for our final analysis. Air pollutants included particulate matter with an aerodynamic diameter ≤ 10 µm (PM10), nitrogen dioxide (NO2), and carbon monoxide (CO). We measured serum 25-hydroxyvitamin D concentration to assess vitamin D status for each participant. Multiple linear and logistic regression analyses were performed to identify associations between ambient air pollution and vitamin D status in each subgroup according to body mass index level. RESULTS: The annual average concentrations of PM10, NO2, and CO were significantly associated with a lower serum vitamin D concentration and higher risk of vitamin D deficiency. The results show a significant association between serum vitamin D status and PM10 exposure in obese subgroup. Based on the gender, females with obesity showed more strong association (negative) between different air pollutants and low serum vitamin D concentration and a higher risk of vitamin D deficiency. However, this pattern was not observed in men. CONCLUSIONS: This study provides the first evidence that women with obesity may be more vulnerable to vitamin D deficiency in the context of persistent exposure to air pollution.

Composition and function of ciliary inner-dynein-arm subunits studied in Chlamydomonas reinhardtii.

Motile cilia (also interchangeably called "flagella") are conserved organelles extending from the surface of many animal cells and play essential functions in eukaryotes, including cell motility and environmental sensing. Large motor complexes, the ciliary dyneins, are present on ciliary outer-doublet microtubules and drive movement of cilia. Ciliary dyneins are classified into two general types: the outer dynein arms (ODAs) and the inner dynein arms (IDAs). While ODAs are important for generation of force and regulation of ciliary beat frequency, IDAs are essential for control of the size and shape of the bend, features collectively referred to as waveform. Also, recent studies have revealed unexpected links between IDA components and human diseases. In spite of their importance, studies on IDAs have been difficult since they are very complex and composed for several types of IDA motors, each unique in composition and location in the axoneme. Thanks in part to genetic, biochemical, and structural analysis of Chlamydomonas reinhardtii, we are beginning to understand the organization and function of the ciliary IDAs. In this review, we summarize the composition of Chlamydomonas IDAs particularly focusing on each subunit, and discuss the assembly, conservation, and functional role(s) of these IDA subunits. Furthermore, we raise several additional questions/challenges regarding IDAs, and discuss future perspectives of IDA studies.

The IDA3 adapter, required for intraflagellar transport of I1 dynein, is regulated by ciliary length.

We determined how the ciliary motor I1 dynein is transported. A specialized adapter, IDA3, facilitates I1 dynein attachment to the ciliary transporter called intraflagellar transport (IFT). Loading of IDA3 and I1 dynein on IFT is regulated by ciliary length.

Chlamydomonas DYX1C1/PF23 is essential for axonemal assembly and proper morphology of inner dynein arms.

Cytoplasmic assembly of ciliary dyneins, a process known as preassembly, requires numerous non-dynein proteins, but the identities and functions of these proteins are not fully elucidated. Here, we show that the classical Chlamydomonas motility mutant pf23 is defective in the Chlamydomonas homolog of DYX1C1. The pf23 mutant has a 494 bp deletion in the DYX1C1 gene and expresses a shorter DYX1C1 protein in the cytoplasm. Structural analyses, using cryo-ET, reveal that pf23 axonemes lack most of the inner dynein arms. Spectral counting confirms that DYX1C1 is essential for the assembly of the majority of ciliary inner dynein arms (IDA) as well as a fraction of the outer dynein arms (ODA). A C-terminal truncation of DYX1C1 shows a reduction in a subset of these ciliary IDAs. Sucrose gradients of cytoplasmic extracts show that preassembled ciliary dyneins are reduced compared to wild-type, which suggests an important role in dynein complex stability. The role of PF23/DYX1C1 remains unknown, but we suggest that DYX1C1 could provide a scaffold for macromolecular assembly.

Leucine Carboxyl Methyltransferase 1 (LCMT-1) Methylates Protein Phosphatase 4 (PP4) and Protein Phosphatase 6 (PP6) and Differentially Regulates the Stable Formation of Different PP4 Holoenzymes.

The protein phosphatase 2A (PP2A) subfamily of phosphatases, PP2A, PP4, and PP6, are multifunctional serine/threonine protein phosphatases involved in many cellular processes. Carboxyl methylation of the PP2A catalytic subunit (PP2Ac) C-terminal leucine is regulated by the opposing activities of leucine carboxyl methyltransferase 1 (LCMT-1) and protein phosphatase methylesterase 1 (PME-1) and regulates PP2A holoenzyme formation. The site of methylation on PP2Ac is conserved in the catalytic subunits of PP4 and PP6, and PP4 is also methylated on that site, but the identities of the methyltransferase enzyme for PP4 are not known. Whether PP6 is methylated is also not known. Here we use antibodies specific for the unmethylated phosphatases to show that PP6 is carboxyl-methylated and that LCMT-1 is the major methyltransferase for PP2A, PP4, and PP6 in mouse embryonic fibroblasts (MEFs). Analysis of PP2A and PP4 complexes by blue native polyacrylamide gel electrophoresis (BN-PAGE) indicates that PP4 holoenzyme complexes, like those of PP2A, are differentially regulated by LCMT-1, with the PP4 regulatory subunit 1 (PP4R1)-containing PP4 complex being the most dramatically affected by the LCMT-1 loss. MEFs derived from LCMT-1 knock-out mouse embryos have reduced levels of PP2A B regulatory subunit and PP4R1 relative to control MEFs, indicating that LCMT-1 is important for maintaining normal levels of these subunits. Finally, LCMT-1 homozygous knock-out MEFs exhibited hyperphosphorylation of HDAC3, a reported target of the methylation-dependent PP4R1-PP4c complex. Collectively, our data suggest that LCMT-1 coordinately regulates the carboxyl methylation of PP2A-related phosphatases and, consequently, their holoenzyme assembly and function.

STRIPAK complexes: structure, biological function, and involvement in human diseases.

The mammalian striatin family consists of three proteins, striatin, S/G2 nuclear autoantigen, and zinedin. Striatin family members have no intrinsic catalytic activity, but rather function as scaffolding proteins. Remarkably, they organize multiple diverse, large signaling complexes that participate in a variety of cellular processes. Moreover, they appear to be regulatory/targeting subunits for the major eukaryotic serine/threonine protein phosphatase 2A. In addition, striatin family members associate with germinal center kinase III kinases as well as other novel components, earning these assemblies the name striatin-interacting phosphatase and kinase (STRIPAK) complexes. Recently, there has been a great increase in functional and mechanistic studies aimed at identifying and understanding the roles of STRIPAK and STRIPAK-like complexes in cellular processes of multiple organisms. These studies have identified novel STRIPAK and STRIPAK-like complexes and have explored their roles in specific signaling pathways. Together, the results of these studies have sparked increased interest in striatin family complexes because they have revealed roles in signaling, cell cycle control, apoptosis, vesicular trafficking, Golgi assembly, cell polarity, cell migration, neural and vascular development, and cardiac function. Moreover, STRIPAK complexes have been connected to clinical conditions, including cardiac disease, diabetes, autism, and cerebral cavernous malformation. In this review, we discuss the expression, localization, and protein domain structure of striatin family members. Then we consider the diverse complexes these proteins and their homologs form in various organisms, emphasizing what is known regarding function and regulation. Finally, we explore possible roles of striatin family complexes in disease, especially cerebral cavernous malformation.

Protein phosphatase 2a (PP2A) binds within the oligomerization domain of striatin and regulates the phosphorylation and activation of the mammalian Ste20-Like kinase Mst3.

BACKGROUND: Striatin, a putative protein phosphatase 2A (PP2A) B-type regulatory subunit, is a multi-domain scaffolding protein that has recently been linked to several diseases including cerebral cavernous malformation (CCM), which causes symptoms ranging from headaches to stroke. Striatin association with the PP2A A/C (structural subunit/catalytic subunit) heterodimer alters PP2A substrate specificity, but targets and roles of striatin-associated PP2A are not known. In addition to binding the PP2A A/C heterodimer to form a PP2A holoenzyme, striatin associates with cerebral cavernous malformation 3 (CCM3) protein, the mammalian Mps one binder (MOB) homolog, Mob3/phocein, the mammalian sterile 20-like (Mst) kinases, Mst3, Mst4 and STK25, and several other proteins to form a large signaling complex. Little is known about the molecular architecture of the striatin complex and the regulation of these sterile 20-like kinases. RESULTS: To help define the molecular organization of striatin complexes and to determine whether Mst3 might be negatively regulated by striatin-associated PP2A, a structure-function analysis of striatin was performed. Two distinct regions of striatin are capable of stably binding directly or indirectly to Mob3--one N-terminal, including the coiled-coil domain, and another more C-terminal, including the WD-repeat domain. In addition, striatin residues 191-344 contain determinants necessary for efficient association of Mst3, Mst4, and CCM3. PP2A associates with the coiled-coil domain of striatin, but unlike Mob3 and Mst3, its binding appears to require striatin oligomerization. Deletion of the caveolin-binding domain on striatin abolishes striatin family oligomerization and PP2A binding. Point mutations in striatin that disrupt PP2A association cause hyperphosphorylation and activation of striatin-associated Mst3. CONCLUSIONS: Striatin orchestrates the regulation of Mst3 by PP2A. It binds Mst3 likely as a dimer with CCM3 via residues lying between striatin's calmodulin-binding and WD-domains and recruits the PP2A A/C heterodimer to its coiled-coil/oligomerization domain. Residues outside the previously reported coiled-coil domain of striatin are necessary for its oligomerization. Striatin-associated PP2A is critical for Mst3 dephosphorylation and inactivation. Upon inhibition of PP2A, Mst3 activation appears to involve autophosphorylation of multiple activation loop phosphorylation sites. Mob3 can associate with striatin sequences C-terminal to the Mst3 binding site but also with sequences proximal to striatin-associated PP2A, consistent with a possible role for Mob 3 in the regulation of Mst3 by PP2A.