A Suite of Transgenic Driver and Reporter Mouse Lines with Enhanced Brain-Cell-Type Targeting and Functionality.

Modern genetic approaches are powerful in providing access to diverse cell types in the brain and facilitating the study of their function. Here, we report a large set of driver and reporter transgenic mouse lines, including 23 new driver lines targeting a variety of cortical and subcortical cell populations and 26 new reporter lines expressing an array of molecular tools. In particular, we describe the TIGRE2.0 transgenic platform and introduce Cre-dependent reporter lines that enable optical physiology, optogenetics, and sparse labeling of genetically defined cell populations. TIGRE2.0 reporters broke the barrier in transgene expression level of single-copy targeted-insertion transgenesis in a wide range of neuronal types, along with additional advantage of a simplified breeding strategy compared to our first-generation TIGRE lines. These novel transgenic lines greatly expand the repertoire of high-precision genetic tools available to effectively identify, monitor, and manipulate distinct cell types in the mouse brain.

Effect of Community Water Service on Lead in Drinking Water in an Environmental Justice Community.

Multiple recent studies have found elevated lead (Pb) concentrations in tap water in U.S. homes relying on unregulated private wells. The main Pb source is dissolution from household plumbing, fixtures, and well components. Here, we leverage a natural experiment and citizen science approach to evaluate how extending community water service to an environmental justice community relying on private wells affects Pb in household water. We analyzed Pb in 260 first-draw kitchen tap water samples collected by individual homeowners over a 5-month period in residences that did and did not connect to the community system. Before the community water system was extended, 25% of homes had Pb > 15 µg/L (the U.S. regulatory action level for community water systems) in first-draw water samples. Pb was significantly correlated with nickel (ρ = 0.61), zinc (ρ = 0.50), and copper (ρ = 0.40), suggesting that corrosion of brass fittings and fixtures is the main Pb source. Among homes that connected to the community system, Pb decreased rapidly and was sustained at levels well below 15 µg/L over the study period. Overall, connecting to the municipal water supply was associated with a 92.5% decrease in first-draw tap water Pb.

Urinary Cadmium and Incident Heart Failure: A Case-Cohort Analysis Among Never-Smokers in Denmark.

BACKGROUND: Epidemiologic studies suggest cadmium exposure is associated with cardiovascular disease risk, including heart failure. However, prior findings may be influenced by tobacco smoking, a dominant source of cadmium exposure and risk factor for heart failure. The present study leverages up to 20 years of follow-up in the Danish Diet, Cancer and Health cohort to examine the relationship between urinary cadmium and incident heart failure among people who never smoked. METHODS: Between 1993 and 1997, 19,394 never-smoking participants (ages 50-64 years) enrolled and provided a urine sample. From this sample, we randomly selected a subcohort of 600 men and 600 women and identified 958 incident heart failure cases occurring between baseline and 2015. Using a case-cohort approach, we estimated adjusted hazard ratios (aHR) for heart failure in Cox proportional hazards models with age as the time scale. RESULTS: Participants had relatively low concentrations of urinary cadmium, as expected for never smokers (median = 0.20; 25th, 75th = 0.13, 0.32 µg cadmium/g creatinine). In adjusted models, we found that higher urinary cadmium was associated with a higher rate of incident heart failure overall (aHR = 1.1 per interquartile range difference [95% CI = 1.0, 1.2). In sex-stratified analyses, the association seemed restricted to men (aHR = 1.5 [95% CI = 1.2, 1.9]). CONCLUSIONS: In this cohort of people who never smoked tobacco, environmental cadmium was positively associated with incident heart failure, especially among men.

Salicylate coordination in metal-protochelin complexes.

Molybdenum (Mo) is an essential trace element for bacteria that is utilized in myriad metalloenzymes that directly couple to the biogeochemical cycling of nitrogen, sulfur, and carbon. In particular, Mo is found in the most common nitrogenase enzyme, and the scarcity and low bioavailability of Mo in soil may be a critical factor that contributes to the limitation of nitrogen fixation in forests and agroenvironments. To overcome this scarcity, microbes produce exudates that specifically chelate scarce metals, promoting their solubilization and uptake. Here, we have determined the structure and stability constants of Mo bound by protochelin, a siderophore produced by bacteria under Mo-depleted conditions. Spectrophotometric titration spectra indicated a coordination shift from a catecholate to salicylate binding mode for MoVI-protochelin (Mo-Proto) complexes at pH < 5. pKa values obtained from analysis of titrations were 4.8 ± 0.3 for MoVIO2H3Proto- and 3.3 ± 0.1 for MoVIO2H4Proto. The occurrence of negatively charged Mo-Proto complexes at pH 6 was also confirmed by mass spectrometry. K-edge Extended X-ray absorption fine structure spectroscopy confirmed the change in Mo coordination at low pH, and structural fitting provides insights into the physical architecture of complexes at neutral and acidic pH. These findings suggest that Mo can be chelated by protochelin across a wide environmental pH range, with a coordination shift occurring at pH < 5. This chelation and associated coordination shift may impact biological availability and mineral surface retention of Mo under acidic conditions.

Internal dose of vanadium in rats following repeated exposure to vanadyl sulfate and sodium orthovanadate via drinking water.

Vanadium is a ubiquitous environmental contaminant that exists in multiple oxidation states. Humans are exposed to vanadyl (V4+) and vanadate (V5+) from dietary supplements, food, and drinking water and hence there is a concern for adverse human health. The current investigation is aimed at identifying vanadium oxidation states in vitro and in vivo and internal concentrations following exposure of rats to vanadyl sulfate (V4+) or sodium metavanadate (V5+) via drinking water for 14 d. Investigations in simulated gastric and intestinal fluids showed that V4+ was stable in gastric fluid while V5+ was stable in intestinal fluid. Analysis of rodent plasma showed that the only vanadium present was V4+, regardless of the exposed compound suggesting conversion of V5+ to V4+ in vivo and/or instability of V5+ species in biological matrices. Plasma, blood, and liver concentrations of total vanadium, after normalizing for vanadium dose consumed, were higher in male and female rats following exposure to V5+ than to V4+. Following exposure to either V4+ or V5+, the total vanadium concentration in plasma was 2- to 3-fold higher than in blood suggesting plasma as a better matrix than blood for measuring vanadium in future work. Liver to blood ratios were 4-7 demonstrating significant tissue retention following exposure to both compounds. In conclusion, these data point to potential differences in absorption and disposition properties of V4+ and V5+ salts and may explain the higher sensitivity in rats following drinking water exposure to V5+ than V4+ and highlights the importance of internal dose determination in toxicology studies.

Constraints on the Coupling between Axionlike Dark Matter and Photons Using an Antiproton Superconducting Tuned Detection Circuit in a Cryogenic Penning Trap.

We constrain the coupling between axionlike particles (ALPs) and photons, measured with the superconducting resonant detection circuit of a cryogenic Penning trap. By searching the noise spectrum of our fixed-frequency resonant circuit for peaks caused by dark matter ALPs converting into photons in the strong magnetic field of the Penning-trap magnet, we are able to constrain the coupling of ALPs with masses around 2.7906-2.7914 neV/c^{2} to g_{aγ}<1×10^{-11} GeV^{-1}. This is more than one order of magnitude lower than the best laboratory haloscope and approximately 5 times lower than the CERN axion solar telescope (CAST), setting limits in a mass and coupling range which is not constrained by astrophysical observations. Our approach can be extended to many other Penning-trap experiments and has the potential to provide broad limits in the low ALP mass range.

A comparative review: Chronic Kidney Disease of unknown etiology (CKDu) research conducted in Latin America versus Asia.

INTRODUCTION: The incidence of chronic kidney disease of unknown or uncertain etiology (CKDu) is recognized as a global non-communicable health crisis. The goal of this work is to compare the types of research studies in Latin America and Asia, two regions with increasing CKDu incidence. METHODS: A comparative literature review was conducted to evaluate the CKDu research design for peer-reviewed articles published from 2015 to 2019. Full texts were reviewed to identify study location, study type, study design, risk factors evaluated, and if applicable, sample type and number. RESULTS: In Asia and Latin America, 82 and 65 articles were identified in total, respectively, with 55 field studies in Asia versus 34 in Latin America. In Asia, research was focused on drinking water (34), heavy metals (20), and agrochemical product usage (19) as potential risk factors. In Latin America, research focused mostly on heat stress/dehydration (36) and agrochemical product usage (18) as potential CKDu risk factors. Biological samples were collected more frequently than environmental samples, especially in Latin America. DISCUSSION: Research to pinpoint the risk factors associated with CKDu to date is not standardized and typically limited in geographical scope. The emphasis of CKDu research varies by geographic region, with a greater priority placed on water quality and chemical exposure in Asia, versus dehydration and heat stress in Latin America. Using a harmonized approach to CKDu research would yield improved understanding of the risk factors associated with CKDu and how they compare across affected regions.

Urinary cadmium and stroke - a case-cohort study in Danish never-smokers.

BACKGROUND: and Purpose: Cadmium has been associated with risk of cardiovascular events, including stroke. Human cadmium exposure occurs primarily through diet and tobacco smoke. Recent cohort studies have found an association with stroke, but residual confounding from smoking, could not be ruled out. We therefore conducted a case-cohort study to evaluate whether cadmium is associated with stroke in never-smokers. METHODS: The Danish Diet Cancer and Health cohort consists of Danes 50-64 years old, recruited in 1993-1997. From never-smoking cohort members without previous cancer or stroke we sampled a sub-cohort of 1200 persons. We also identified all (n = 534) cases in the cohort with a validated stroke diagnosis between baseline and 2009. We quantified cadmium and creatinine concentrations from baseline urine samples and used cadmium per creatinine as our main exposure metric. We used Cox proportional hazards models to estimate hazard ratios (HRs) with age as time scale and adjusting for BMI, education and urinary cotinine with and without stratification by sex. RESULTS: The median urinary cadmium concentration was 0.21 µg cadmium/g creatinine in cases and 0.19 µg/g in the sub-cohort. The majority (83%) of stroke cases were diagnosed with ischemic stroke. The HR for stroke in the highest quartile of exposure (median 0.44 µg/g creatinine) was 1.11 (95% CI: 0.79-1.54) compared with the lowest quartile (median 0.10 µg/g creatinine). The HR per inter quartile range (IQR, 0.19 µg/g creatinine) was 1.02 (95% CI: 0.92-1.12). Among men, the HR per IQR higher levels of cadmium (0.16 µg/g creatinine) was 1.18 (95% CI: 0.92-1.52), and 1.00 (95% CI: 0.89-1.12) among women. Adjusting for creatinine or using osmolality instead of creatinine standardization generally attenuated observed relationships. CONCLUSIONS: Our results do not support that low levels of cadmium exposure among never-smokers are strongly associated with risk of stroke, although results varied somewhat by sex and method of accounting for urinary dilution.

Low levels of lead and glutathione markers of redox status in human blood.

Exposure to lead (Pb) is implicated in a plethora of health threats in both adults and children. Increased exposure levels are associated with oxidative stress in the blood of workers exposed at occupational levels. However, it is not known whether lower Pb exposure levels are related to a shift toward a more oxidized state. To assess the association between blood lead level (BLL) and glutathione (GSH) redox biomarkers in a population of healthy adults, BLL and four GSH markers (GSH, GSSG, GSH/GSSG ratio and redox potential E h ) were measured in the blood of a cross-sectional cohort of 282 avid seafood-eating healthy adults living on Long Island (NY). Additionally, blood levels of two other metals known to affect GSH redox status, selenium (Se) and mercury (Hg), and omega-3 index were tested for effect modification. Regression models were further adjusted for demographic and smoking status. Increasing exposure to Pb, measured in blood, was not associated with GSSG, but was associated with lower levels of GSH/GSSG ratio and more positive GSH redox potential E h , driven by its association with GSH. No effect modification was observed in analyses stratified by Hg, Se, omega-3 index, sex, age, or smoking. Blood Pb is associated with lower levels of GSH and the GSH/GSSG ratio in this cross-sectional study of healthy adults.

Mercury exposure, serum antinuclear antibodies, and serum cytokine levels in the Long Island Study of Seafood Consumption: A cross-sectional study in NY, USA.

Mercury (Hg) is a well-known neurotoxin, and has been more recently studied specifically as an immunotoxin. In experimental and a few epidemiologic studies, Hg has been associated with distinct cytokine profiles and antinuclear antibody (ANA) positivity, though patterns at lower levels of exposure, typical of seafood consumers with a western diet, are not well characterized. Seafood consumers (n=287) recruited on Long Island, NY completed food frequency and health questionnaires and provided blood for analysis of Hg, poly-unsaturated fatty acids (omega-3 and omega-6 fatty acids), selenium (Se), ANA, and several cytokines (IL-1ß, IL-4, IL-10, TNF-α, IL-17, IFN-γ, and IL-1ra). Logistic and linear regression analyses were conducted to evaluate associations between serum Hg and cytokines and ANA. Adjusted models accounted for gender, age, ethnicity, income, education, smoking, BMI, selenium, omega-3 fatty acids, omega-6 fatty acids, omega-6/omega-3 ratio, and fish intake. Sex-stratified models were also generated with the expectation that immune profiles would differ between women and men. Median blood Hg was 4.58µg/L with 90th %ile =19.8µg/L. Nine individuals displayed ANA positivity at serum titers above 1:80; many of the cytokines were below detection limits, and the ability to detect was used in the logistic regression analyses. In linear and logistic regression analyses, Hg was not significantly associated with any of the seven investigated cytokines or with ANA-positivity. Therefore, Hg was not associated with altered immune profiles in this population of seafood consumers.

Optimizing alignment and growth of low-loss YAG single crystal fibers using laser heated pedestal growth technique.

The effect of misalignments of different optical components in the laser heated pedestal growth apparatus have been modeled using Zemax optical design software. By isolating the misalignments causing the non-uniformity in the melt zone, the alignment of the components was fine-tuned. Using this optimized alignment, low-loss YAG single crystal fibers of 120 µm diameter were grown, with total attenuation loss as low as 0.5 dB/m at 1064 nm.

Disposition of intravenously or orally administered silver nanoparticles in pregnant rats and the effect on the biochemical profile in urine.

Few investigations have been conducted on the disposition and fate of silver nanoparticles (AgNP) in pregnancy. The distribution of a single dose of polyvinylpyrrolidone (PVP)-stabilized AgNP was investigated in pregnant rats. Two sizes of AgNP, 20 and 110 nm, and silver acetate (AgAc) were used to investigate the role of AgNP diameter and particle dissolution in tissue distribution, internal dose and persistence. Dams were administered AgNP or AgAc intravenously (i.v.) (1 mg kg-1 ) or by gavage (p.o.) (10 mg kg-1 ), or vehicle alone, on gestation day 18 and euthanized at 24 or 48 h post-exposure. The silver concentration in tissues was measured using inductively-coupled plasma mass spectrometry. The distribution of silver in dams was influenced by route of administration and AgNP size. The highest concentration of silver (µg Ag g-1 tissue) at 48 h was found in the spleen for i.v. administered AgNP, and in the lungs for AgAc. At 48 h after p.o. administration of AgNP, the highest concentration was measured in the cecum and large intestine, and for AgAc in the placenta. Silver was detected in placenta and fetuses for all groups. Markers of cardiovascular injury, oxidative stress marker, cytokines and chemokines were not significantly elevated in exposed dams compared to vehicle-dosed control. NMR metabolomics analysis of urine indicated that AgNP and AgAc exposure impact the carbohydrate, and amino acid metabolism. This study demonstrates that silver crosses the placenta and is transferred to the fetus regardless of the form of silver. Copyright © 2016 John Wiley & Sons, Ltd.

Growth of single-crystal YAG fiber optics.

Single-crystal YAG (Y3Al5O12) fibers have been grown by the laser heated pedestal growth technique with losses as low as 0.3 dB/m at 1.06 µm. These YAG fibers are as long as about 60 cm with diameters around 330 µm. The early fibers were grown from unoriented YAG seed fibers and these fibers exhibited facet steps or ridges on the surface of the fiber. However, recently we have grown fibers using an oriented seed to grow step-free fibers. Scattering losses made on the fibers indicate that the scattering losses are equal to about 30% of the total loss.

Lasing characteristics of Ho:YAG single crystal fiber.

Lasing was demonstrated for the first time at 2.09 µm in 0.5% Holmium (Ho) doped YAG single crystal fiber (SCF) fabricated using the Laser Heated Pedestal Growth (LHPG) method. Output power of 23.5 W with 67.5% optical-to-optical slope efficiency is, to the best of our knowledge, the highest output power achieved at 2 µm from a SCF fabricated using LHPG. With continued improvement in the quality of the SCF and better thermal management, output power of few 100s W and higher, especially in the 2 µm spectral region, is realizable in the very near future.

Quest to identify geochemical risk factors associated with chronic kidney disease of unknown etiology (CKDu) in an endemic region of Sri Lanka-a multimedia laboratory analysis of biological, food, and environmental samples.

The emergence of a new form of chronic kidney disease of unknown etiology (CKDu) in Sri Lanka's North Central Province (NCP) has become a catastrophic health crisis. CKDu is characterized as slowly progressing, irreversible, and asymptomatic until late stages and, importantly, not attributed to diabetes, hypertension, or other known risk factors. It is postulated that the etiology of CKDu is multifactorial, involving genetic predisposition, nutritional and dehydration status, exposure to one or more environmental nephrotoxins, and lifestyle factors. The objective of this limited geochemical laboratory analysis was to determine the concentration of a suite of heavy metals and trace element nutrients in biological samples (human whole blood and hair) and environmental samples (drinking water, rice, soil, and freshwater fish) collected from two towns within the endemic NCP region in 2012 and 2013. This broad panel, metallomics/mineralomics approach was used to shed light on potential geochemical risk factors associated with CKDu. Based on prior literature documentation of potential nephrotoxins that may play a role in the genesis and progression of CKDu, heavy metals and fluoride were selected for analysis. The geochemical concentrations in biological and environmental media areas were quantified. Basic statistical measurements were subsequently used to compare media against applicable benchmark values, such as US soil screening levels. Cadmium, lead, and mercury were detected at concentrations exceeding US reference values in many of the biological samples, suggesting that study participants are subjected to chronic, low-level exposure to these elements. Within the limited number of environmental media samples, arsenic was determined to exceed initial risk screening and background concentration values in soil, while data collected from drinking water samples reflected the unique hydrogeochemistry of the region, including the prevalence of hard or very hard water, and fluoride, iron, manganese, sodium, and lead exceeding applicable drinking water standards in some instances. Current literature suggests that the etiology of CKDu is likely multifactorial, with no single biological or hydrogeochemical parameter directly related to disease genesis and progression. This preliminary screening identified that specific constituents may be present above levels of concern, but does not compare results against specific kidney toxicity values or cumulative risk related to a multifactorial disease process. The data collected from this limited investigation are intended to be used in the subsequent study design of a comprehensive and multifactorial etiological study of CKDu risk factors that includes sample collection, individual surveys, and laboratory analyses to more fully evaluate the potential environmental, behavioral, genetic, and lifestyle risk factors associated with CKDu.

The fate of siderophores: antagonistic environmental interactions in exudate-mediated micronutrient uptake.

Organisms acquire metals from the environment by releasing small molecules that solubilize and promote their specific uptake. The best known example of this nutrient uptake strategy is the exudation of siderophores, which are a structurally-diverse class of molecules that are traditionally viewed as being integral to iron uptake. Siderophores have been proposed to act through a variety of processes, but their effectiveness can be mitigated by a variety of chemical and physical processes of both biotic and abiotic origin. Processes that occur at the surface of minerals can degrade or sequester siderophores, preventing them from fulfilling their function of returning metals to the organism. In addition, biotic processes including enzymatic degradation of the siderophore and piracy of the metal or of the siderophore complex also disrupt iron uptake. Some organisms have adapted their nutrient acquisition strategies to address these potential pitfalls, producing multiple siderophores and other exudates that take advantage of varying kinetic and thermodynamic factors to allow the continued uptake of metals. A complete understanding of the factors that contribute to metal uptake in nature will require a concerted effort to study processes identified in laboratory systems in the context of more complicated environmental systems.

Silver/cyclic olefin copolymer hollow glass waveguides for infrared laser delivery.

Metal/dielectric-coated hollow glass waveguides (HGWs) have been studied extensively for the efficient transmission of radiation over a broad spectral range. In this study, a low-absorption optical polymer, cyclic olefin copolymer (COC), is investigated as a dielectric material for HGWs designed for the delivery of various IR lasers. Using established silver (Ag) plating techniques and a newly optimized polymer-coating procedure, Ag/COC HGWs with low attenuation coefficients are fabricated for operation at the following three wavelengths: 808 nm, 1.064 µm, and 2.94 µm. The spectral responses of the HGW designs are used to develop a film thickness dependency of the COC layer formation based on the concentration of the solution used in the polymer deposition procedure. Further, the attenuation coefficients of the HGWs are measured using the cutback method at the three wavelengths as a function of the curvature of the waveguide. In order of increasing operation, the attenuation coefficients are measured to be 0.549, 0.095, and 0.298 dB/m for the HGWs in the straight configuration. These experimental values for the straight attenuation coefficients are compared to theoretical values calculated using a ray transfer matrix approach and are found to be in good agreement.

Ho:YAG single crystal fiber: fabrication and optical characterization.

0.5% Holmium (Ho) doped YAG single crystal fiber (SCF) was fabricated using Laser Heated Pedestal Growth (LHPG) method and characterized for its optical absorption and emission properties involving transitions between the 5I8 and 5I7 energy levels. The results verified the absorption peaks suitable for in-band direct pumping at 1908 nm and 1932 nm with the emission occurring between 2050 and 2150 nm. Small signal gain measurements were also performed for demonstrating the fiber like characteristics of the SCF.

Theory and practical considerations of multilayer dielectric thin-film stacks in Ag-coated hollow waveguides.

This analysis explores the theory and design of dielectric multilayer reflection-enhancing thin film stacks based on high and low refractive index alternating layers of cadmium sulfide (CdS) and lead sulfide (PbS) on silver (Ag)-coated hollow glass waveguides (HGWs) for low loss transmission at midinfrared wavelengths. The fundamentals for determining propagation losses in such multilayer thin-film-coated Ag hollow waveguides is thoroughly discussed, and forms the basis for further theoretical analysis presented in this study. The effects on propagation loss resulting from several key parameters of these multilayer thin film stacks is further explored in order to bridge the gap between results predicted through calculation under ideal conditions and deviations from such ideal models that often arise in practice. In particular, the effects on loss due to the number of dielectric thin film layers deposited, deviation from ideal individual layer thicknesses, and surface roughness related scattering losses are presented and thoroughly investigated. Through such extensive theoretical analysis the level of understanding of the underlying loss mechanisms of multilayer thin-film Ag-coated HGWs is greatly advanced, considerably increasing the potential practical development of next-generation ultralow-loss mid-IR Ag/multilayer dielectric-coated HGWs.