Single-nucleus multi-omics of Parkinson's disease reveals a glutamatergic neuronal subtype susceptible to gene dysregulation via alteration of transcriptional networks.

The genetic architecture of Parkinson's disease (PD) is complex and multiple brain cell subtypes are involved in the neuropathological progression of the disease. Here we aimed to advance our understanding of PD genetic complexity at a cell subtype precision level. Using parallel single-nucleus (sn)RNA-seq and snATAC-seq analyses we simultaneously profiled the transcriptomic and chromatin accessibility landscapes in temporal cortex tissues from 12 PD compared to 12 control subjects at a granular single cell resolution. An integrative bioinformatic pipeline was developed and applied for the analyses of these snMulti-omics datasets. The results identified a subpopulation of cortical glutamatergic excitatory neurons with remarkably altered gene expression in PD, including differentially-expressed genes within PD risk loci identified in genome-wide association studies (GWAS). This was the only neuronal subtype showing significant and robust overexpression of SNCA. Further characterization of this neuronal-subpopulation showed upregulation of specific pathways related to axon guidance, neurite outgrowth and post-synaptic structure, and downregulated pathways involved in presynaptic organization and calcium response. Additionally, we characterized the roles of three molecular mechanisms in governing PD-associated cell subtype-specific dysregulation of gene expression: (1) changes in cis-regulatory element accessibility to transcriptional machinery; (2) changes in the abundance of master transcriptional regulators, including YY1, SP3, and KLF16; (3) candidate regulatory variants in high linkage disequilibrium with PD-GWAS genomic variants impacting transcription factor binding affinities. To our knowledge, this study is the first and the most comprehensive interrogation of the multi-omics landscape of PD at a cell-subtype resolution. Our findings provide new insights into a precise glutamatergic neuronal cell subtype, causal genes, and non-coding regulatory variants underlying the neuropathological progression of PD, paving the way for the development of cell- and gene-targeted therapeutics to halt disease progression as well as genetic biomarkers for early preclinical diagnosis.

Integrative single-nucleus multi-omics analysis prioritizes candidate cis and trans regulatory networks and their target genes in Alzheimer's disease brains.

BACKGROUND: The genetic underpinnings of late-onset Alzheimer's disease (LOAD) are yet to be fully elucidated. Although numerous LOAD-associated loci have been discovered, the causal variants and their target genes remain largely unknown. Since the brain is composed of heterogenous cell subtypes, it is imperative to study the brain on a cell subtype specific level to explore the biological processes underlying LOAD. METHODS: Here, we present the largest parallel single-nucleus (sn) multi-omics study to simultaneously profile gene expression (snRNA-seq) and chromatin accessibility (snATAC-seq) to date, using nuclei from 12 normal and 12 LOAD brains. We identified cell subtype clusters based on gene expression and chromatin accessibility profiles and characterized cell subtype-specific LOAD-associated differentially expressed genes (DEGs), differentially accessible peaks (DAPs) and cis co-accessibility networks (CCANs). RESULTS: Integrative analysis defined disease-relevant CCANs in multiple cell subtypes and discovered LOAD-associated cell subtype-specific candidate cis regulatory elements (cCREs), their candidate target genes, and trans-interacting transcription factors (TFs), some of which, including ELK1, JUN, and SMAD4 in excitatory neurons, were also LOAD-DEGs. Finally, we focused on a subset of cell subtype-specific CCANs that overlap known LOAD-GWAS regions and catalogued putative functional SNPs changing the affinities of TF motifs within LOAD-cCREs linked to LOAD-DEGs, including APOE and MYO1E in a specific subtype of microglia and BIN1 in a subpopulation of oligodendrocytes. CONCLUSIONS: To our knowledge, this study represents the most comprehensive systematic interrogation to date of regulatory networks and the impact of genetic variants on gene dysregulation in LOAD at a cell subtype resolution. Our findings reveal crosstalk between epigenetic, genomic, and transcriptomic determinants of LOAD pathogenesis and define catalogues of candidate genes, cCREs, and variants involved in LOAD genetic etiology and the cell subtypes in which they act to exert their pathogenic effects. Overall, these results suggest that cell subtype-specific cis-trans interactions between regulatory elements and TFs, and the genes dysregulated by these networks contribute to the development of LOAD.

Differential Gene Expression and DNA Methylation in the Risk of Depression in LOAD Patients.

Depression is common among late-onset Alzheimer's Disease (LOAD) patients. Only a few studies investigated the genetic variability underlying the comorbidity of depression in LOAD. Moreover, the epigenetic and transcriptomic factors that may contribute to comorbid depression in LOAD have yet to be studied. Using transcriptomic and DNA-methylomic datasets from the ROSMAP cohorts, we investigated differential gene expression and DNA-methylation in LOAD patients with and without comorbid depression. Differential expression analysis did not reveal significant association between differences in gene expression and the risk of depression in LOAD. Upon sex-stratification, we identified 25 differential expressed genes (DEG) in males, of which CHI3L2 showed the strongest upregulation, and only 3 DEGs in females. Additionally, testing differences in DNA-methylation found significant hypomethylation of CpG (cg20442550) on chromosome 17 (log2FC = -0.500, p = 0.004). Sex-stratified differential DNA-methylation analysis did not identify any significant CpG probes. Integrating the transcriptomic and DNA-methylomic datasets did not discover relationships underlying the comorbidity of depression and LOAD. Overall, our study is the first multi-omics genome-wide exploration of the role of gene expression and epigenome alterations in the risk of comorbid depression in LOAD patients. Furthermore, we discovered sex-specific differences in gene expression underlying the risk of depression symptoms in LOAD.

Environmental Consequences of Potential Strategies for China to Prepare for Natural Gas Import Disruptions.

Worldwide efforts to switch away from coal have increased the reliance on natural gas imports for countries with inadequate domestic production. In preparing for potential gas import disruptions, there have been limited attempts to quantify the environmental and human health impacts of different options and incorporate them into decision-making. Here, we analyze the air pollution, human health, carbon emissions, and water consumption impacts under a set of planning strategies to prepare for potentially fully disrupted natural gas imports in China. We find that, with China's current natural gas storage capacity, compensating for natural gas import disruptions using domestic fossil fuels (with the current average combustion technology) could lead up to 23,300 (95% CI: 22,100-24,500) excess premature deaths from air pollution, along with increased carbon emissions and aggravated water stress. Improving energy efficiency, more progressive electrification and decarbonization, cleaner fossil combustion, and expanding natural gas storage capacity can significantly reduce the number of excess premature deaths and may offer opportunities to reduce negative carbon and water impacts simultaneously. Our results highlight the importance for China to increase the domestic storage capacity in the short term, and more importantly, to promote a clean energy transition to avoid potentially substantial environmental consequences under intensifying geopolitical uncertainties in China. Therefore, mitigating potential negative environmental impacts related to insecure natural gas supply provides additional incentives for China to facilitate a clean and efficient energy system transition.

Heavy metals in agricultural soil in China: A systematic review and meta-analysis.

Research about farmland pollution by heavy metals/metalloids in China has drawn growing attention. However, there was rare information on spatiotemporal evolution and pollution levels of heavy metals in the major grain-producing areas. We extracted and examined data from 276 publications between 2010 and 2021 covering five major grain-producing regions in China from 2010 to 2021. Spatiotemporal evolution characteristics of main heavy metals/metalloids was obtained by meta-analysis. In addition, subgroup analyses were carried out to study preliminary correlations related to accumulation of the pollutants. Cadmium (Cd) was found to be the most prevailing pollutant in the regions in terms of both spatial distribution and temporal accumulation. The Huang-Huai-Hai Plain was the most severely polluted. Accumulation of Cd, mercury (Hg) and copper (Cu) increased from 2010 to 2015 when compared with the 1990 background data. Further, the levels of five key heavy metals (Cd, Cu, Hg, lead [Pb] and zinc [Zn]) showed increasing trends from 2016 to 2021 in all five regions. Soil pH and mean annual precipitation had variable influences on heavy metal accumulation. Alkaline soil and areas with less rainfall faced higher pollution levels. Farmlands cropped with mixed species showed smaller effect sizes of heavy metals than those with single upland crop, suggesting that mixed farmland use patterns could alleviate the levels of heavy metals in soil. Of various soil remediation efforts, farmland projects only held a small market share. The findings are important to support the research of risk assessment, regulatory development, pollution prevention, fund allocation and remediation actions.

Flue Gas Desulfurization Wastewater Composition and Implications for Regulatory and Treatment Train Design.

The U.S. Environmental Protection Agency is currently revising its regulations on trace element discharges from flue gas desulfurization (FGD) wastewater. In this work, we expand a predictive model of trace element behavior at coal-fired power plants (CFPPs) to estimate the trace element concentration of FGD wastewater at the plant level. We demonstrate that variation in trace element concentrations in FGD wastewater can span several orders of magnitude and is a function of both coal rank and installed air pollution control devices. This conclusion suggests that the benefits and costs of FGD wastewater treatment for the median plant will poorly describe the actual benefits and costs over the full range of existing CFPPs. Our model can be used to identify different "classes" of CFPPs for future regulatory and technology development efforts and to evaluate the robustness of proposed treatment technologies in light of large intraplant variability. The model can also elucidate new compliance pathways that exploit empirical and mechanistic relationships between coal concentration, trace element partitioning, and FGD wastewater composition.

Trace Element Mass Flow Rates from U.S. Coal Fired Power Plants.

Trace elements (TEs) exit coal-fired power plants (CFPPs) via solid, liquid, and gaseous waste streams. Estimating the TE concentrations of these waste streams is essential to selecting pollution controls and estimating emission reduction benefits. This work introduces a generalizable mass balance model for estimating TE mass flow rates in CFPP waste streams and evaluates model accuracy for the U.S. coal fleet given current data constraints. We stochastically estimate, using a bootstrapping approach, the 2015 plant-level mass flow rates of Hg, Se, As, and Cl to solid, liquid, and gas phase waste streams by combining publicly available data for combusted coal TE concentrations with estimates of TE partitioning within installed air pollution control processes. When compared with measured and reported data on TE mass flow rates, this model generally overestimates masses by 30-50%, with larger errors for Hg. The partitioning estimates are consistent for Se, As, and Cl removal from flue gas, but tend to underestimate Hg removal. While our model is suitable for first-order estimates of TE mass flows, future work to improve model performance should focus on collecting and using new data on TE concentrations in the coal blend, where data quality is the weakest.

Air Emission Reduction Benefits of Biogas Electricity Generation at Municipal Wastewater Treatment Plants.

Conventional processes for municipal wastewater treatment facilities are energy and materially intensive. This work quantifies the air emission implications of energy consumption, chemical use, and direct pollutant release at municipal wastewater treatment facilities across the U.S. and assesses the potential to avoid these damages by generating electricity and heat from the combustion of biogas produced during anaerobic sludge digestion. We find that embedded and on-site air emissions from municipal wastewater treatment imposed human health, environmental, and climate (HEC) damages on the order of $1.63 billion USD in 2012, with 85% of these damages attributed to the estimated consumption of 19 500 GWh of electricity by treatment processes annually, or 0.53% of the US electricity demand. An additional 11.8 million tons of biogenic CO2 are directly emitted by wastewater treatment and sludge digestion processes currently installed at plants. Retrofitting existing wastewater treatment facilities with anaerobic sludge digestion for biogas production and biogas-fueled heat and electricity generation has the potential to reduce HEC damages by up to 24.9% relative to baseline emissions. Retrofitting only large plants (>5 MGD), where biogas generation is more likely to be economically viable, would generate HEC benefits of $254 annually. These findings reinforce the importance of accounting for use-phase embedded air emissions and spatially resolved marginal damage estimates when designing sustainable infrastructure systems.

Air Emissions Damages from Municipal Drinking Water Treatment Under Current and Proposed Regulatory Standards.

Water treatment processes present intersectoral and cross-media risk trade-offs that are not presently considered in Safe Drinking Water Act regulatory analyses. This paper develops a method for assessing the air emission implications of common municipal water treatment processes used to comply with recently promulgated and proposed regulatory standards, including concentration limits for, lead and copper, disinfection byproducts, chromium(VI), strontium, and PFOA/PFOS. Life-cycle models of electricity and chemical consumption for individual drinking water unit processes are used to estimate embedded NOx, SO2, PM2.5, and CO2 emissions on a cubic meter basis. We estimate air emission damages from currently installed treatment processes at U.S. drinking water facilities to be on the order of $500 million USD annually. Fully complying with six promulgated and proposed rules would increase baseline air emission damages by approximately 50%, with three-quarters of these damages originating from chemical manufacturing. Despite the magnitude of these air emission damages, the net benefit of currently implemented rules remains positive. For some proposed rules, however, the promise of net benefits remains contingent on technology choice.

Spatially resolved air-water emissions tradeoffs improve regulatory impact analyses for electricity generation.

Coal-fired power plants (CFPPs) generate air, water, and solids emissions that impose substantial human health, environmental, and climate change (HEC) damages. This work demonstrates the importance of accounting for cross-media emissions tradeoffs, plant and regional emissions factors, and spatially variation in the marginal damages of air emissions when performing regulatory impact analyses for electric power generation. As a case study, we assess the benefits and costs of treating wet flue gas desulfurization (FGD) wastewater at US CFPPs using the two best available treatment technology options specified in the 2015 Effluent Limitation Guidelines (ELGs). We perform a life-cycle inventory of electricity and chemical inputs to FGD wastewater treatment processes and quantify the marginal HEC damages of associated air emissions. We combine these spatially resolved damage estimates with Environmental Protection Agency estimates of water quality benefits, fuel-switching benefits, and regulatory compliance costs. We estimate that the ELGs will impose average net costs of $3.01 per cubic meter for chemical precipitation and biological wastewater treatment and $11.26 per cubic meter for zero-liquid discharge wastewater treatment (expected cost-benefit ratios of 1.8 and 1.7, respectively), with damages concentrated in regions containing a high fraction of coal generation or a large chemical manufacturing industry. Findings of net cost for FGD wastewater treatment are robust to uncertainty in auxiliary power source, location of chemical manufacturing, and binding air emissions limits in noncompliant regions, among other variables. Future regulatory design will minimize compliance costs and HEC tradeoffs by regulating air, water, and solids emissions simultaneously and performing regulatory assessments that account for spatial variation in emissions impacts.

Quantity, Quality, and Availability of Waste Heat from United States Thermal Power Generation.

Secondary application of unconverted heat produced during electric power generation has the potential to improve the life-cycle fuel efficiency of the electric power industry and the sectors it serves. This work quantifies the residual heat (also known as waste heat) generated by U.S. thermal power plants and assesses the intermittency and transport issues that must be considered when planning to utilize this heat. Combining Energy Information Administration plant-level data with literature-reported process efficiency data, we develop estimates of the unconverted heat flux from individual U.S. thermal power plants in 2012. Together these power plants discharged an estimated 18.9 billion GJ(th) of residual heat in 2012, 4% of which was discharged at temperatures greater than 90 °C. We also characterize the temperature, spatial distribution, and temporal availability of this residual heat at the plant level and model the implications for the technical and economic feasibility of its end use. Increased implementation of flue gas desulfurization technologies at coal-fired facilities and the higher quality heat generated in the exhaust of natural gas fuel cycles are expected to increase the availability of residual heat generated by 10.6% in 2040.

Salivary gland derived peptides as a new class of anti-inflammatory agents: review of preclinical pharmacology of C-terminal peptides of SMR1 protein.

The limitations of steroidal and non steroidal anti-inflammatory drugs have prompted investigation into other biologically based therapeutics, and identification of immune selective anti-inflammatory agents of salivary origin. The traditional view of salivary glands as accessory digestive structures is changing as their importance as sources of systemically active immunoregulatory and anti-inflammatory factors is recognized. Salivary gland involvement in maintenance of whole body homeostasis is regulated by the nervous system and thus constitutes a "neuroendocrine axis". The potent anti-inflammatory activities, both in vivo and in vitro, of the tripeptide Phe-Glu-Gly (FEG) are reviewed. FEG is a carboxyl terminal peptide of the prohormone SMR1 identified in the rat submandibular salivary gland, The D-isomeric form (feG) mimics the activity of its L-isomer FEG. Macropharmacologically, feG attenuates the cardiovascular and inflammatory effects of endotoxemia and anaphylaxis, by inhibition of hypotension, leukocyte migration, vascular leak, and disruption of pulmonary function and intestinal motility. Mechanistically, feG affects activated inflammatory cells, especially neutrophils, by regulating integrins and inhibiting intracellular production of reactive oxygen species. Pharmacodynamically, feG is active at low doses (100 µg/kg) and has a long (9-12 hour) biological half life. As a therapeutic agent, feG shows promise in diseases characterized by over exuberant inflammatory responses such as systemic inflammatory response syndrome and other acute inflammatory diseases. Arthritis, sepsis, acute pancreatitis, asthma, acute respiratory inflammation, inflammatory bowel disease, and equine laminitis are potential targets for this promising therapeutic peptide. The term "Immune Selective Anti-Inflammatory Derivatives" (ImSAIDs) is proposed for salivary-derived peptides to distinguish this class of agents from corticosteroids and nonsteroidal anti-inflammatory drugs.

Effect of intraarticular injection of autologous adipose-derived mesenchymal stem and regenerative cells on clinical signs of chronic osteoarthritis of the elbow joint in dogs.

Autologous adipose-derived mesenchymal stem cell (AD-MSC) therapy involves harvesting fat from the patient, isolating the stem and regenerative cells, and administering the cells back to the patient. Autologous AD-MSC therapy in veterinary regenerative medicine has been commercially available since 2003. Previously reported results from a blinded, controlled trial in dogs with chronic osteoarthritis of the coxofemoral (hip) joint demonstrated efficacy of a single intraarticular injection of autologous AD-MSC therapy. The primary objective of the current study was to evaluate the effectiveness of this therapy in dogs with chronic osteoarthritis of the humeroradial (elbow) joints and to determine the duration of effect. Fourteen dogs were recruited. Veterinarians assessed each dog for lameness, pain on manipulation, range of motion, and functional disability using a numeric rating scale at baseline and specified intervals up to 180 days after treatment. Statistically significant improvement in outcome measures was demonstrated.

Effect of adipose-derived mesenchymal stem and regenerative cells on lameness in dogs with chronic osteoarthritis of the coxofemoral joints: a randomized, double-blinded, multicenter, controlled trial.

Autologous stem cell therapy in the field of regenerative veterinary medicine involves harvesting tissue, such as fat, from the patient, isolating the stem and regenerative cells, and administering the cells back to the patient. Autologous adipose-derived stem cell therapy has been commercially available since 2003, and the current study evaluated such therapy in dogs with chronic osteoarthritis of the hip. Dogs treated with adipose-derived stem cell therapy had significantly improved scores for lameness and the compiled scores for lameness, pain, and range of motion compared with control dogs. This is the first randomized, blinded, placebo-controlled clinical trial reporting on the effectiveness of stem cell therapy in dogs.

Use of client-specific outcome measures to assess treatment effects in geriatric, arthritic dogs: controlled clinical evaluation of a nutraceutical.

A questionnaire method was designed for dog owners to monitor the orthopedic disabilities of their pets for evaluation of a nutraceutical with joint health claims. Fifty large-breed dogs, 7 to 12 years of age, presenting with signs of osteoarthritis, were randomly allocated to placebo and active treatment groups. Degree of disability was assessed by physical examination, a standard questionnaire on daily activities, and a case-specific questionnaire that monitored specific impairments of each dog. The test product was a special milk protein concentrate (SMPC) from hyperimmunized cows, previously shown to express antiinflammatory and antiarthritic activity in humans. After a 1-week run-in period of dosing with placebo, each dog was randomly assigned to a treatment and given gelatin capsules containing either SMPC or a placebo twice daily for 8 weeks. Overall improvement was noted in 68% and 35% of the SMPC and placebo groups, respectively. Significant (P <.05) improvement in mean standardized and patient- specific questionnaire scores and in owner global assessments was detected in the SMPC group but not in the placebo group. Compared with the placebo group, the treatment response was significantly better in the SMPC group with regard to case-specific scores (P <.001) and owner global assessments (P =.004). The product was well tolerated and serum chemistry findings remained within normal limits.

Use of client-specific outcome measures to assess treatment effects in geriatric, arthritic dogs: controlled clinical evaluation of a nutraceutical.

A questionnaire method was designed for dog owners to monitor the orthopedic disabilities of their pets for evaluation of a nutraceutical with joint health claims. Fifty large-breed dogs, 7 to 12 years of age, presenting with signs of osteoarthritis, were randomly allocated to placebo and active treatment groups. Degree of disability was assessed by physical examination, a standard questionnaire on daily activities, and a case-specific questionnaire that monitored specific impairments of each dog. The test product was a special milk protein concentrate (SMPC) from hyperimmunized cows, previously shown to express antiinflammatory and antiarthritic activity in humans. After a 1-week run-in period of dosing with placebo, each dog was randomly assigned to a treatment and given gelatin capsules containing either SMPC or a placebo twice daily for 8 weeks. Overall improvement was noted in 68% and 35% of the SMPC and placebo groups, respectively. Significant (P <.05) improvement in mean standardized and patient-specific questionnaire scores and in owner global assessments was detected in the SMPC group but not in the placebo group. Compared with the placebo group, the treatment response was significantly better in the SMPC group with regard to case-specific scores (P lt;.001) and owner global assessments (P =.004). The product was well tolerated and serum chemistry findings remained within normal limits.

Effects of a milk-based bioactive micronutrient beverage on pain symptoms and activity of adults with osteoarthritis: a double-blind, placebo-controlled clinical evaluation.

OBJECTIVES: A 6 wk, double-blind, placebo-controlled study investigated the effects of a nutritional supplement beverage containing milk-based micronutrients and fortified with vitamins and minerals on pain symptoms and activity in adults with osteoarthritis. METHODS: Thirty-one subjects with osteoarthritis of both knees were randomized into two groups and given 12 oz daily of the micronutrient-containing beverage or a placebo for 6 wk. Subjects were instructed not to change their normal activities and diets. Body weights, vital signs, blood chemistries, and adverse events were monitored to assess safety. The principal outcome measurement for efficacy was the Western Ontario MacMaster Universities Osteoarthritis Index (WOMAC) derived from the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire administered weekly. RESULTS: Safety indicators remained unchanged in the test and placebo groups. All KOOS scores improved significantly (P < 0.03) over time in the micronutrient group, whereas scores only for sport function and knee-related quality of life improved in the placebo group. The overall treatment effect (based on changes in the WOMAC composite score) was significant (P = 0.016). The effect size was moderate at 0.555. CONCLUSIONS: Thus, daily consumption of the nutritional beverage containing milk-based micronutrients, vitamins, and minerals was beneficial in alleviating symptoms and dysfunction in subjects with osteoarthritis.