Browsing by Subject "Manganese"
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Item Assigning the EPR Fine Structure Parameters of the Mn(II) Centers in Bacillus subtilis Oxalate Decarboxylase by Site-Directed Mutagenesis and DFT/MM Calculations(American Chemical Society, 2014-02-12) Campomanes, Pablo; Kellett, Whitney F.; Easthon, Lindsey M.; Ozarowski, Andrew; Allen, Karen N.; Angerhofer, Alexander; Rothlisberger, Ursula; Richards, Nigel G. J.; Department of Chemistry & Chemical Biology, School of ScienceOxalate decarboxylase (OxDC) catalyzes the Mn-dependent conversion of the oxalate monoanion into CO2 and formate. EPR-based strategies for investigating the catalytic mechanism of decarboxylation are complicated by the difficulty of assigning the signals associated with the two Mn(II) centers located in the N- and C-terminal cupin domains of the enzyme. We now report a mutational strategy that has established the assignment of EPR fine structure parameters to each of these Mn(II) centers at pH 8.5. These experimental findings are also used to assess the performance of a multistep strategy for calculating the zero-field splitting parameters of protein-bound Mn(II) ions. Despite the known sensitivity of calculated D and E values to the computational approach, we demonstrate that good estimates of these parameters can be obtained using cluster models taken from carefully optimized DFT/MM structures. Overall, our results provide new insights into the strengths and limitations of theoretical methods for understanding electronic properties of protein-bound Mn(II) ions, thereby setting the stage for future EPR studies on the electronic properties of the Mn(II) centers in OxDC and site-specific variants.Item The association of bone, fingernail and blood manganese with cognitive and olfactory function in Chinese workers(Elsevier, 2019-05-20) Rolle-McFarland, Danelle; Liu, Yingzi; Mostafaei, Farshad; Zauber, S. Elizabeth; Zhou, Yuanzhong; Li, Yan; Fan, Quiyan; Zheng, Wei; Nie, Linda H.; Wells, Ellen M.; Neurology, School of MedicineOccupational manganese (Mn) exposure has been associated with cognitive and olfactory dysfunction; however, few studies have incorporated cumulative biomarkers of Mn exposure such as bone Mn (BnMn). Our goal was to assess the cross-sectional association between BnMn, blood Mn (BMn), and fingernail Mn (FMn) with cognitive and olfactory function among Mn-exposed workers. A transportable in vivo neutron activation analysis (IVNAA) system was designed and utilized to assess BnMn among 60 Chinese workers. BMn and FMn were measured using inductively coupled plasma mass spectrometry. Cognitive and olfactory function was assessed using Animal and Fruit Naming tests, World Health Organization/University of California-Los Angeles Auditory Verbal Learning Test (AVLT) and the University of Pennsylvania Smell Identification Test (UPSIT). Additional data were obtained via questionnaire. Regression models adjusted for age, education, factory of employment, and smoking status (UPSIT only), were used to assess the relationship between Mn biomarkers and test scores. In adjusted models, increasing BnMn was significantly associated with decreased performance on average AVLT scores [β (95% confidence interval (CI)) = -0.65 (-1.21, -0.09)] and Animal Naming scores [β (95% CI) = -1.54 (-3.00, -0.07)]. Increasing FMn was significantly associated with reduced performance measured by the average AVLT [β (95% CI) = -0.35 (-0.70, -0.006)] and the difference in AVLT scores [β (95% CI) = -0.40 (-0.77, -0.03)]. BMn was not significantly associated with any test scores; no significant associations were observed with Fruit Naming or UPSIT tests. BnMn and FMn, but not BMn, are associated with cognitive function in Mn-exposed workers. None of theItem Heavy metals and neurodevelopment of children in low and middle-income countries: A systematic review(PLOS, 2022-03-31) Heng, Yi Yan; Asad, Iqra; Coleman, Bailey; Menard, Laura; Benki-Nugent, Sarah; Were, Faridah Hussein; Karr, Catherine J.; McHenry, Megan S.; Pediatrics, School of MedicineBackground: The presence of harmful environmental exposures, which disproportionately affects low-and-middle income countries (LMICs), contributes to >25% of deaths and diseases worldwide and detrimentally affects child neurodevelopment. Few resources succinctly summarize the existing literature on this topic. Our objective is to systematically review and characterize the evidence regarding the relationship between heavy metals and neurodevelopment of children in LMICs. Methods: We conducted a medical librarian-curated search on multiple online databases to identify articles that included individuals <18 years living in a LMIC, quantitatively measured exposure to a heavy metal (either prenatal or postnatal), and used a standardized measurement of neurodevelopment (i.e. cognitive, language, motor, and behavior). Reviews, editorials, or case studies were excluded. Results were analyzed qualitatively, and quality was assessed. Results: Of the 18,043 screened articles, 298 full-text articles were reviewed, and 100 articles met inclusion criteria. The included studies represented data from 19 LMICs, only one of which was classified as a low-income country. Ninety-four percent of postnatal lead and all postnatal manganese studies showed a negative association with metal exposure and neurodevelopment, which were the strongest relationships among the metals studied. Postnatal exposure of mercury was associated with poor neurodevelopment in only half of studies. Limited data on postnatal arsenic and cadmium suggests an association with worse neurodevelopment. Findings were mixed for prenatal arsenic and lead, although some evidence supports that the neurotoxicity of lead was amplified in the presence of manganese. Conclusions and potential impact: We found that lead and manganese appear to consistently have a detrimental effect on the neurodevelopment of children, and more evidence is needed for mercury, arsenic, and cadmium. Better characterization of these effects can motivate and inform prioritization of much needed international policies and programs to reduce heavy metal exposures for young children within LMICs.Item High-Resolution Crystal Structures Reveal Plasticity in the Metal Binding Site of Apurinic/Apyrimidinic Endonuclease I(American Chemical Society, 2014-10-21) He, Hongzhen; Chen, Qiujia; Georgiadis, Millie M.; Department of Biochemistry & Molecular Biology, IU School of MedicineApurinic/apyrimidinic endonuclease I (APE1) is an essential base excision repair enzyme that catalyzes a Mg2+-dependent reaction in which the phosphodiester backbone is cleaved 5′ of an abasic site in duplex DNA. This reaction has been proposed to involve either one or two metal ions bound to the active site. In the present study, we report crystal structures of Mg2+, Mn2+, and apo-APE1 determined at 1.4, 2.2, and 1.65 Å, respectively, representing two of the highest resolution structures yet reported for APE1. In our structures, a single well-ordered Mn2+ ion was observed coordinated by D70 and E96; the Mg2+ site exhibited disorder modeled as two closely positioned sites coordinated by D70 and E96 or E96 alone. Direct metal binding analysis of wild-type, D70A, and E96A APE1, as assessed by differential scanning fluorimetry, indicated a role for D70 and E96 in binding of Mg2+ or Mn2+ to APE1. Consistent with the disorder exhibited by Mg2+ bound to the active site, two different conformations of E96 were observed coordinated to Mg2+. A third conformation for E96 in the apo structure is similar to that observed in the APE1–DNA–Mg2+ complex structure. Thus, binding of Mg2+ in three different positions within the active site of APE1 in these crystal structures corresponds directly with three different conformations of E96. Taken together, our results are consistent with the initial capture of metal by D70 and E96 and repositioning of Mg2+ facilitated by the structural plasticity of E96 in the active site.Item Manganese causes neurotoxic iron accumulation via translational repression of Amyloid Precursor Protein (APP) and H-Ferritin(Wiley, 2018-12-27) Venkataramani, Vivek; Doeppner, Thorsten R.; Willkommen, Desiree; Cahill, Catherine M.; Xin, Yongjuan; Ye, Guilin; Liu, Yanyan; Southon, Adam; Aron, Allegra; Au‐Yeung, Ho Yu; Huang, Xudong; Lahiri, Debomoy K.; Wang, Fudi; Bush, Ashley I.; Wulf, Gerald G.; Ströbel, Philipp; Michalke, Bernhard; Rogers, Jack T.; Psychiatry, School of MedicineFor more than 150 years, it is known that occupational overexposure of manganese (Mn) causes movement disorders resembling Parkinson's disease (PD) and PD‐like syndromes. However, the mechanisms of Mn toxicity are still poorly understood. Here, we demonstrate that Mn dose‐ and time‐dependently blocks the protein translation of amyloid precursor protein (APP) and heavy‐chain Ferritin (H‐Ferritin), both iron homeostatic proteins with neuroprotective features. APP and H‐Ferritin are post‐transcriptionally regulated by iron responsive proteins, which bind to homologous iron responsive elements (IREs) located in the 5′‐untranslated regions (5′‐UTRs) within their mRNA transcripts. Using reporter assays, we demonstrate that Mn exposure repressed the 5′‐UTR‐activity of APP and H‐Ferritin, presumably via increased iron responsive proteins‐iron responsive elements binding, ultimately blocking their protein translation. Using two specific Fe2+‐specific probes (RhoNox‐1 and IP‐1) and ion chromatography inductively coupled plasma mass spectrometry (IC‐ICP‐MS), we show that loss of the protective axis of APP and H‐Ferritin resulted in unchecked accumulation of redox‐active ferrous iron (Fe2+) fueling neurotoxic oxidative stress. Enforced APP expression partially attenuated Mn‐induced generation of cellular and lipid reactive oxygen species and neurotoxicity. Lastly, we could validate the Mn‐mediated suppression of APP and H‐Ferritin in two rodent in vivo models (C57BL6/N mice and RjHan:SD rats) mimicking acute and chronic Mn exposure. Together, these results suggest that Mn‐induced neurotoxicity is partly attributable to the translational inhibition of APP and H‐Ferritin resulting in impaired iron metabolism and exacerbated neurotoxic oxidative stress.Item Subchronic Manganese Exposure Impairs Neurogenesis in the Adult Rat Hippocampus(Oxford University Press, 2018-06-01) Adamson, Sherleen Xue-Fu; Shen, Xubo; Jiang, Wendy; Lai, Vivien; Wang, Xiaoting; Cannon, Jason R.; Chen, Jinhui; Zheng, Wei; Shannahan, Jonathan H.; Neurological Surgery, School of MedicineAdult neurogenesis takes place in the brain subventricular zone (SVZ) in the lateral walls of lateral ventricles and subgranular zone (SGZ) in the hippocampal dentate gyrus (HDG), and functions to supply newborn neurons for normal brain functionality. Subchronic Mn exposure is known to disrupt adult neurogenesis in the SVZ. This study was designed to determine whether Mn exposure disturbed neurogenesis within the adult HDG. Adult rats (10 weeks old) received a single dose of bromodeoxyuridine (BrdU) at the end of 4-week Mn exposure to label the proliferating cells. Immunostaining and cell counting data showed that BrdU(+) cells in Mn-exposed HDG were about 37% lower than that in the control (p < .05). The majority of BrdU(+) cells were identified as Sox2(+) cells. Another set of adult rats received BrdU injections for 3 consecutive days followed by 2- or 4-week Mn exposure to trace the fate of BrdU-labeled cells in the HDG. The time course studies indicated that Mn exposure significantly reduced the survival rate (54% at 2 weeks and 33% at 4 weeks), as compared with that in the control (80% at 2 weeks and 51% at 4 weeks) (p < .01). A significant time-dependent migration of newborn cells from the SGZ toward the granule cell layer was also observed in both control and Mn-exposed HDG. Triple-stained neuroblasts and mature neurons further revealed that Mn exposure significantly inhibited the differentiation of immature neuroblasts into mature neurons in the HDG. Taken together, these observations suggest that subchronic Mn exposure results in a reduced cell proliferation, diminished survival of adult-born neurons, and inhibited overall neurogenesis in the adult HDG. Impaired adult neurogenesis is likely one of the mechanisms contribute to Mn-induced Parkinsonian disorder.Item Subject-Specific Mapping of Excess Manganese Accumulation in the Brain of Welders Using Magnetic Resonance Imaging Relaxometry(MDPI, 2025-02-25) Monsivais, Humberto; Dydak, Ulrike; Radiology and Imaging Sciences, School of MedicineChronic overexposure to manganese (Mn) can occur in occupational settings, such as welding, leading to increased Mn levels in the brain. Excess brain Mn accumulation may result in neurotoxicity, which is characterized by Parkinsonian-like symptoms including motor and cognitive dysfunctions. In this work, we demonstrate a novel methodology for personalized diagnosis and spatial characterization of abnormal Magnetic Resonance Imaging R1 (R1 = 1/T1) relaxation rates arising from excessive Mn accumulation in welders' brains. Utilizing voxel-wise population-derived norms based on a frequency age-matched non-exposed group (n = 25), we demonstrate the ability to conduct subject-specific assessments and mapping of Mn exposure using MRI relaxometry. Our results show elevated R1 in multiple brain regions in individual welders, but also extreme between-subject variability in Mn accumulation, debasing the concept that high exposures correlate with uniformly high Mn deposition in the brain. Consequently, the presented personalized methodology serves as a counterpart to group-based comparison, which allows for understanding the level of individual exposure and the toxicokinetics of Mn accumulation. This work lays a foundation for improved occupational health assessments and preventive measures against neurotoxic metal exposure.Item Synthesis of lithium manganese phosphate by controlled sol-gel method and design of all solid state lithium ion batteries(2015) Penumaka, Rani Vijaya; Zhu, LikunDue to the drastic increase in the cost of fossil fuels and other environmental issues, the demand for energy and its storage has risen globally. Rather than being dependent on intermittent energy sources like wind and solar energy, focus has been on alternative energy sources. To eliminate the need for fossil fuels, advances are being made to provide energy for hybrid electric vehicles (HEV), plug-in hybrid vehicles (PHEV) and pure electric vehicles (EV) thus providing scope for much greener environment. Hence, focus has been on development in lithium ion batteries to provide with materials that have high energy density and voltage. Ortho olivine lithium transitional metals are known to be abundant and inexpensive; these compounds are less noxious than other cathode materials. Advancement in research is being done in finding iron and manganese compounds as cathode materials for advanced technologies. However, Lithium manganese phosphates are known to suffer with poor electrochemical performances due the manganese dissolution in the organic liquid electrolyte due to Jahn-Teller Lattice distortion. This problem was tried to endorse in this thesis. In the second chapter by synthesizing nano sized cathode particles with good electronic conductivity, good performance was achieved. In the third chapter additive olivine cathode was synthesized my modified sol gel process. A wt. % of TMSP was added as an additive in the organic liquid electrolyte. By comparing the properties between the two kinds of electrolytes it was observed that by the addition of the additive in the organic electrolyte good electrochemical properties could be achieved hindering the Mn dissolution in the electrolyte. In the final chapter, a composite solid electrolyte was fabricated by using NASICON-type glass ceramic of Lithium aluminum titanium phosphate (LATP) with organic binder of Polyethylene oxide. The flexible solid electrolyte exhibited good ionic conductivity. An all solid state cell was fabricated using the composite solid electrolyte using LiMn2O4 as the symmetric electrodes. At different pressures, the performance of the solid state cell was studied.Item Thalamic GABA Predicts Fine Motor Performance in Manganese-Exposed Smelter Workers(Public Library of Science, 2014-02-04) Long, Zaiyang; Li, Xiang-Rong; Xu, Jun; Edden, Richard A. E.; Qin, Wei-Ping; Long, Li-Ling; Murdoch, James B.; Zheng, Wei; Jiang, Yue-Ming; Dydak, Ulrike; Radiology and Imaging Sciences, School of MedicineOverexposure to manganese (Mn) may lead to parkinsonian symptoms including motor deficits. The main inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is known to play a pivotal role in the regulation and performance of movement. Therefore this study was aimed at testing the hypothesis that an alteration of GABA following Mn exposure may be associated with fine motor performance in occupationally exposed workers and may underlie the mechanism of Mn-induced motor deficits. A cohort of nine Mn-exposed male smelter workers from an Mn-iron alloy factory and 23 gender- and age-matched controls were recruited and underwent neurological exams, magnetic resonance spectroscopy (MRS) measurements, and Purdue pegboard motor testing. Short-echo-time MRS was used to measure N-Acetyl-aspartate (NAA) and myo-inositol (mI). GABA was detected with a MEGA-PRESS J-editing MRS sequence. The mean thalamic GABA level was significantly increased in smelter workers compared to controls (p = 0.009). Multiple linear regression analysis reveals (1) a significant association between the increase in GABA level and the duration of exposure (R(2) = 0.660, p = 0.039), and (2) significant inverse associations between GABA levels and all Purdue pegboard test scores (for summation of all scores R(2) = 0.902, p = 0.001) in the smelter workers. In addition, levels of mI were reduced significantly in the thalamus and PCC of smelter workers compared to controls (p = 0.030 and p = 0.009, respectively). In conclusion, our results show clear associations between thalamic GABA levels and fine motor performance. Thus in Mn-exposed subjects, increased thalamic GABA levels may serve as a biomarker for subtle deficits in motor control and may become valuable for early diagnosis of Mn poisoning.Item The association of bone and blood manganese with motor function in Chinese workers(Elsevier, 2022) Rolle-McFarland, Danelle; Liu, Yingzi; Mostafaei, Farshad; Zauber, S. Elizabeth; Zhou, Yuanzhong; Li, Yan; Fan, Quiyan; Zheng, Wei; Nie, Linda H.; Wells, Ellen M.; Neurology, School of MedicineManganese (Mn) is an essential element. However, Mn overexposure is associated with motor dysfunction. This cross-sectional study assessed the association between bone Mn (BnMn) and whole blood Mn (BMn) with motor function in 59 Chinese workers. BnMn and BMn were measured using a transportable in vivo neutron activation analysis system and inductively coupled plasma mass spectrometry, respectively. Motor function (manual coordination, postural sway, postural hand tremor, and fine motor function) was assessed using the Coordination Ability Test System (CATSYS) and the Purdue Pegboard. Relationships between Mn biomarkers and motor test scores were analyzed with linear regression models adjusted for age, education, current employment, and current alcohol consumption. BMn was significantly inversely associated with hand tremor intensity (dominant hand (β=-0.04, 95 % confidence interval (CI):-0.07, -0.01; non-dominant hand β=-0.05, 95 % CI:-0.08, -0.01) hand tremor center frequency (non-dominant hand β=-1.61, 95 % CI:-3.03, -0.19) and positively associated with the Purdue Pegboard Assembly Score (β = 4.58, 95 % CI:1.08, 8.07). BnMn was significantly inversely associated with finger-tapping performance (non-dominant hand β=-0.02, 95 % CI:-0.04,-0.004), mean sway (eyes closed and foam β=-0.68, 95 % CI:-1.31,-0.04), and positively associated with hand tremor center frequency (dominant hand, β = 0.40, 95 % CI:0.002, 0.80). These results suggest BMn is related to better postural hand tremor and fine motor control and BnMn is related to worse motor coordination and postural hand tremor but better (i.e., less) postural sway. The unexpected positive results might be explained by choice of biomarker or confounding by work-related motor activities. Larger, longitudinal studies in this area are recommended.