The neuropeptide landscape of human prefrontal cortex.

Human prefrontal cortex (hPFC) is a complex brain region involved in cognitive and emotional processes and several psychiatric disorders. Here, we present an overview of the distribution of the peptidergic systems in 17 subregions of hPFC and three reference cortices obtained by microdissection and based on RNA sequencing and RNAscope methods integrated with published single-cell transcriptomics data. We detected expression of 60 neuropeptides and 60 neuropeptide receptors in at least one of the hPFC subregions. The results reveal that the peptidergic landscape in PFC consists of closely located and functionally different subregions with unique peptide/transmitter-related profiles. Neuropeptide-rich PFC subregions were identified, encompassing regions from anterior cingulate cortex/orbitofrontal gyrus. Furthermore, marked differences in gene expression exist between different PFC regions (>5-fold; cocaine and amphetamine-regulated transcript peptide) as well as between PFC regions and reference regions, for example, for somatostatin and several receptors. We suggest that the present approach allows definition of, still hypothetical, microcircuits exemplified by glutamatergic neurons expressing a peptide cotransmitter either as an agonist (hypocretin/orexin) or antagonist (galanin). Specific neuropeptide receptors have been identified as possible targets for neuronal afferents and, interestingly, peripheral blood-borne peptide hormones (leptin, adiponectin, gastric inhibitory peptide, glucagon-like peptides, and peptide YY). Together with other recent publications, our results support the view that neuropeptide systems may play an important role in hPFC and underpin the concept that neuropeptide signaling helps stabilize circuit connectivity and fine-tune/modulate PFC functions executed during health and disease.

Characterization of reduced astrocyte creatine kinase levels in Alzheimer's disease.

The creatine-phosphocreatine cycle serves as a crucial temporary energy buffering system in the brain, regulated by brain creatine kinase (CKB), in maintaining Adenosine triphosphate (ATP) levels. Alzheimer's disease (AD) has been linked to increased CKB oxidation and loss of its regulatory function, although specific pathological processes and affected cell types remain unclear. In our study, cerebral cortex samples from individuals with AD, dementia with Lewy bodies (DLB), and age-matched controls were analyzed using antibody-based methods to quantify CKB levels and assess alterations associated with disease processes. Two independently validated antibodies exclusively labeled astrocytes in the human cerebral cortex. Combining immunofluorescence (IF) and mass spectrometry (MS), we explored CKB availability in AD and DLB cases. IF and Western blot analysis demonstrated a loss of CKB immunoreactivity correlated with increased plaque load, severity of tau pathology, and Lewy body pathology. However, transcriptomics data and targeted MS demonstrated unaltered total CKB levels, suggesting posttranslational modifications (PTMs) affecting antibody binding. This aligns with altered efficiency at proteolytic cleavage sites indicated in the targeted MS experiment. These findings highlight that the proper function of astrocytes, understudied in the brain compared with neurons, is highly affected by PTMs. Reduction in ATP levels within astrocytes can disrupt ATP-dependent processes, such as the glutamate-glutamine cycle. As CKB and the creatine-phosphocreatine cycle are important in securing constant ATP availability, PTMs in CKB, and astrocyte dysfunction may disturb homeostasis, driving excitotoxicity in the AD brain. CKB and its activity could be promising biomarkers for monitoring early-stage energy deficits in AD.

Life-long impairment of glucose homeostasis upon prenatal exposure to psychostimulants.

Maternal drug abuse during pregnancy is a rapidly escalating societal problem. Psychostimulants, including amphetamine, cocaine, and methamphetamine, are amongst the illicit drugs most commonly consumed by pregnant women. Neuropharmacology concepts posit that psychostimulants affect monoamine signaling in the nervous system by their affinities to neurotransmitter reuptake and vesicular transporters to heighten neurotransmitter availability extracellularly. Exacerbated dopamine signaling is particularly considered as a key determinant of psychostimulant action. Much less is known about possible adverse effects of these drugs on peripheral organs, and if in utero exposure induces lifelong pathologies. Here, we addressed this question by combining human RNA-seq data with cellular and mouse models of neuroendocrine development. We show that episodic maternal exposure to psychostimulants during pregnancy coincident with the intrauterine specification of pancreatic ß cells permanently impairs their ability of insulin production, leading to glucose intolerance in adult female but not male offspring. We link psychostimulant action specifically to serotonin signaling and implicate the sex-specific epigenetic reprogramming of serotonin-related gene regulatory networks upstream from the transcription factor Pet1/Fev as determinants of reduced insulin production.

Long-term Trends of Dissolved Organic Carbon Dynamics in a Subtropical Forest Responding to Environmental Changes.

Dissolved organic carbon (DOC) dynamics are critical to carbon cycling in forest ecosystems and sensitive to global change. Our study, spanning from 2001 to 2020 in a headwater catchment in subtropical China, analyzed DOC and water chemistry of throughfall, litter leachate, soil waters at various depths, and streamwater. We focused on DOC transport through hydrological pathways and assessed the long-term trends in DOC dynamics amidst environmental and climatic changes. Our results showed that the annual DOC deposition via throughfall and stream outflow was 14.2 ± 2.2 and 1.87 ± 0.83 g C m-2 year-1, respectively. Notably, there was a long-term declining trend in DOC deposition via throughfall (-0.195 mg C L-1 year-1), attributed to reduced organic carbon emissions from clean air actions. Conversely, DOC concentrations in soil waters and stream waters showed increasing trends, primarily due to mitigated acid deposition. Moreover, elevated temperature and precipitation could partly explain the long-term rise in DOC leaching. These trends in DOC dynamics have significant implications for the stability of carbon sink in terrestrial, aquatic, and even oceanic ecosystems at regional scales.

Myoclonus in patients with COVID-19: Findings of autoantibodies against brain structures in cerebrospinal fluid.

BACKGROUND AND PURPOSE: COVID-19 is associated with multiple neurological manifestations. The clinical presentation, trajectory, and treatment response for three cases of myoclonus during COVID-19 infection, with no previous neurological disease, are decsribed. METODS: Analysis of cerebrospinal fluid from the cases using indirect immunohistochemistry. RESULTS: Antibodies against rodent brain tissue, and similarities in staining patterns were observed, indicating the presence of antineuronal immunoglobulin G autoantibodies targeting astrocytes in the hippocampus. CONCLUSION: Our results demontrate cerebrospinal fluid antineuronal antibodies indicating an an autoimmune involvment in the pathogenesis in COVID-19 associated myoclonus.

Genome-wide annotation of protein-coding genes in pig.

BACKGROUND: There is a need for functional genome-wide annotation of the protein-coding genes to get a deeper understanding of mammalian biology. Here, a new annotation strategy is introduced based on dimensionality reduction and density-based clustering of whole-body co-expression patterns. This strategy has been used to explore the gene expression landscape in pig, and we present a whole-body map of all protein-coding genes in all major pig tissues and organs. RESULTS: An open-access pig expression map ( www.rnaatlas.org ) is presented based on the expression of 350 samples across 98 well-defined pig tissues divided into 44 tissue groups. A new UMAP-based classification scheme is introduced, in which all protein-coding genes are stratified into tissue expression clusters based on body-wide expression profiles. The distribution and tissue specificity of all 22,342 protein-coding pig genes are presented. CONCLUSIONS: Here, we present a new genome-wide annotation strategy based on dimensionality reduction and density-based clustering. A genome-wide resource of the transcriptome map across all major tissues and organs in pig is presented, and the data is available as an open-access resource ( www.rnaatlas.org ), including a comparison to the expression of human orthologs.

High environmental costs behind rapid economic development: Evidence from economic loss caused by atmospheric acid deposition.

The rapid growth of energy-intensive and high-emission industries has propelled China's economy but has also led to massive levels of air pollutant emissions and ecological problems, such as acid deposition. Despite recent declines, atmospheric acid deposition in China is still severe. Long-term exposure to high levels of acid depositions has a substantial negative impact on the ecosystem. Evaluating these hazards and incorporating this issue into planning and decision-making processes is critical to achieving sustainable development goals in China. However, the long-term economic loss caused by atmospheric acid deposition and its temporal and spatial variation in China is unclear. Hence, the aim of this study was to assess the environmental cost of acid deposition in the agriculture, forestry, construction, and transportation industries from 1980 to 2019, using long-term monitoring, integrated data, and the dose-response method with localization parameters. The results showed that the estimated cumulative environmental cost of acid deposition was USD 230 billion, representing 0.27% of the gross domestic product (GDP) in China. This cost, was particularly high for building materials, followed by crops, forests, and roads. Temporally, the environmental cost and the ratio of environmental cost to GDP decreased from their peaks by 43% and 91%, respectively, because of emission controls targeting acidifying pollutants and promotion of clean energy. Spatially, the largest environmental cost occurred in developing provinces, indicating that more stringent emission reduction measures should be implemented in these regions. These findings highlight the huge environmental costs behind rapid development; however, the implementation of reasonable emission reduction measures can effectively reduce these environmental costs, providing a promising paradigm for other undeveloped and developing countries.

Enhancing bauxite residue properties for plant growth: Gypsum and organic amendment effects on chemical properties of soil and leachate.

Here, we assess the effects of gypsum and local organic waste as amendments to non-weathered, filter-pressed bauxite residue (BR) to improve its properties and support plant growth. In addition, we monitored the leachate quality of the amended BR under progressive leaching that simulated precipitation conditions in Northern Brazil. Free-draining column tests consisting of BR amended with gypsum and organic waste, at 5% and 10% w/w, respectively, were leached for 8 weeks to assess the effects on the chemical composition of BR and the leachates. Adding gypsum to BR reduced the exchangeable sodium (Na) percentage (ESP) from approximately 79%-48%, whereas adding only organic waste had smaller effects on ESP (from ∼79% to âˆ¼ 70%). The mean leachate pH ranged from 8.7 to 9.4 for the gypsum, and organic waste amended BR, while this was 10.3 in the leachate of the unamended BR. The treatments had similar trends of electrical conductivity throughout the experiments and were below 2 dS/cm after 8 weeks, when ∼1.700 mm simulated precipitation had leached. Aluminium (Al), Arsenic (As), and Vanadium (V) concentrations in leachates of BR with gypsum, either alone or in combination with organic waste, were significantly lowered than in leachate of non-amended BR. By contrast, metal concentrations increased if organic waste was added to BR. We conclude that amending BR with gypsum, in combination with organic waste, significantly improves the chemical properties of the solid phase and achieved rehabilitation goals for SAR and EC of the leachates after 8 weeks of leaching. However, despite high leaching rates, rehabilitation goals for pH and ESP were not achieved with gypsum either alone or combined with organic waste.

Spatiotemporal characterization of cellular tau pathology in the human locus coeruleus-pericoerulear complex by three-dimensional imaging.

Tau pathology of the noradrenergic locus coeruleus (LC) is a hallmark of several age-related neurodegenerative disorders, including Alzheimer's disease. However, a comprehensive neuropathological examination of the LC is difficult due to its small size and rod-like shape. To investigate the LC cytoarchitecture and tau cytoskeletal pathology in relation to possible propagation patterns of disease-associated tau in an unprecedented large-scale three-dimensional view, we utilized volume immunostaining and optical clearing technology combined with light sheet fluorescence microscopy. We examined AT8+ pathological tau in the LC/pericoerulear region of 20 brains from Braak neurofibrillary tangle (NFT) stage 0-6. We demonstrate an intriguing morphological complexity and heterogeneity of AT8+ cellular structures in the LC, representing various intracellular stages of NFT maturation and their diverse transition forms. We describe novel morphologies of neuronal tau pathology such as AT8+ cells with fine filamentous somatic protrusions or with disintegrating soma. We show that gradual dendritic atrophy is the first morphological sign of the degeneration of tangle-bearing neurons, even preceding axonal lesions. Interestingly, irrespective of the Braak NFT stage, tau pathology is more advanced in the dorsal LC that preferentially projects to vulnerable forebrain regions in Alzheimer's disease, like the hippocampus or neocortical areas, compared to the ventral LC projecting to the cerebellum and medulla. Moreover, already in the precortical Braak 0 stage, 3D analysis reveals clustering tendency and dendro-dendritic close appositions of AT8+ LC neurons, AT8+ long axons of NFT-bearing cells that join the ascending dorsal noradrenergic bundle after leaving the LC, as well as AT8+ processes of NFT-bearing LC neurons that target the 4th ventricle wall. Our study suggests that the unique cytoarchitecture, comprised of a densely packed and dendritically extensively interconnected neuronal network with long projections, makes the human LC to be an ideal anatomical template for early accumulation and trans-neuronal spreading of hyperphosphorylated tau.

A TRPV1-to-secretagogin regulatory axis controls pancreatic ß-cell survival by modulating protein turnover.

Ca2+-sensor proteins are generally implicated in insulin release through SNARE interactions. Here, secretagogin, whose expression in human pancreatic islets correlates with their insulin content and the incidence of type 2 diabetes, is shown to orchestrate an unexpectedly distinct mechanism. Single-cell RNA-seq reveals retained expression of the TRP family members in ß-cells from diabetic donors. Amongst these, pharmacological probing identifies Ca2+-permeable transient receptor potential vanilloid type 1 channels (TRPV1) as potent inducers of secretagogin expression through recruitment of Sp1 transcription factors. Accordingly, agonist stimulation of TRPV1s fails to rescue insulin release from pancreatic islets of glucose intolerant secretagogin knock-out(-/-) mice. However, instead of merely impinging on the SNARE machinery, reduced insulin availability in secretagogin-/- mice is due to ß-cell loss, which is underpinned by the collapse of protein folding and deregulation of secretagogin-dependent USP9X deubiquitinase activity. Therefore, and considering the desensitization of TRPV1s in diabetic pancreata, a TRPV1-to-secretagogin regulatory axis seems critical to maintain the structural integrity and signal competence of ß-cells.

Distinct amyloid-ß and tau-associated microglia profiles in Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-ß and intraneuronal hyperphosphorylated tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-ß and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-ß plaques or both amyloid-ß plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-ß load and localized to amyloid-ß plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with overt tau pathology. This full characterization of human disease-associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies.

Increased levels of inflammatory markers in the subscapularis tendon and joint capsule in patients with subacromial impingement.

PURPOSE: To analyze biopsy samples from the subscapularis tendon and from the joint capsule from male patients with subacromial impingement syndrome and compare them with samples from male patients with post-traumatic recurrent shoulder instability, to detect increased inflammatory activity that might be present inside the humeroscapular joint. METHODS: Twenty male patients scheduled for surgery for either subacromial decompression or Bankart reconstruction were included. Four biopsies from each patient were obtained during surgery from the capsule and the subscapularis tendon. Each specimen was analyzed for TNF-α, IL-6, CD-3 and CD-72. Multiplex fluorescence immunohistochemistry was performed on histological samples from the capsule and tendon to demonstrate the level of inflammatory markers. Fluorescence microscope images were acquired using an automated scanning system. On each slide, the number of pixels was registered and used in the analyses. RESULTS: The subacromial impingement syndrome group comprised eight patients, median age 53 (45-74) years, while the instability group 12, median age 27 (22-48) years (p < 0.00001). The amount of IL-6 and TNF-α was significantly higher in the subscapularis tendon of the patients with subacromial impingement syndrome compared with instability patients (p = 0.0015 and p = 0.0008 respectively). In the capsular samples, significantly higher amount of TNF-α and CD-72 was found in patients with subacromial impingement syndrome compared with instability patients (p < 0.0001 for both). On the other hand, the amount of CD-3 was significantly higher in the instability group (p = 0.0013). CONCLUSIONS: This study provides evidence that an extended inflammatory process is present, not only in the subacromial bursa but also in the glenohumeral joint in patients with subacromial impingement syndrome. LEVEL OF EVIDENCE: Level III. CLINICAL RELEVANCE: To develop a treatment targeted towards intra-articular inflammatory cytokines appears appealing.

Soil and water conservation management on hill slopes in southwest Ethiopia. II. Modeling effects of soil bunds on surface runoff and maize yield using AquaCrop.

On the cultivated slopes of the highlands of southwest Ethiopia, soil degradation due to water erosion is a challenge for crop production. To limit surface runoff and soil erosion, soil bunds often in combination with trenches, constructed along contour lines, are common. In addition to the interception of surface runoff, soil bunds may affect crop yield. Here, we evaluate effect of soil bunds on surface runoff and maize yield, using FAO's AquaCrop model, calibrated based on field experiments in the Bokole-Karetha watershed, in SW Ethiopia. Experiments were conducted in 2018 and 2019 on three neighboring fields, each comprising plots in triplicate without and with soil bunds. Experimental data from 2018 to 2019, which were average and above average with respect to rainfall, indicate that water availability was sufficient or even in excess for maize production. Soil bunds significantly (p < 0.05) reduced surface runoff, but maize yield did not differ significantly. In plots without soil bunds, the AquaCrop model described surface runoff satisfactorily after slight adjustment of the curve number (related to infiltration capacity) in one of the three fields. Maize yields were reproduced adequately after calibrating soil fertility and adjusting water productivity. After calibration and validation, the AquaCrop model was used to hindcast surface runoff and grain yield from 1999 to 2017, given available climatic data for the region. Hindcasts show that maize yield in the Bokole-Karetha watershed, with its relatively high rainfall, is not significantly affected by rainfall in two of the three fields. In the third field maize yield decreases slightly, but significantly (p < 0.05) with rainfall. In the short run, yield differences between plots with and without soil bunds are not significant. However, eventually high surface runoff from plots without soil bunds are expected to result in unsustainable crop production, due to significant erosion and degradation of the often nutrient-poor soils. Implementation of soil and water management techniques, combined with fertilization, are important to prevent soil degradation and nutrient stress on sloping land.

Nitrification is the primary source for NO in N-saturated subtropical forest soils: Results from in situ 15 N labeling.

RATIONALE: Acidic subtropical forest soils that receive high atmospheric nitrogen (N) deposition have been identified as important sources of nitric oxide (NO). The relative importance of major processes producing NO is unclear. METHODS: To partition NO sources, we conducted an in situ tracing experiment with 15 NH4 NO3 and NH4 15 NO3 in well-drained acid soils of an N-saturated subtropical forest in Chongqing, southwest China. RESULTS: In the 15 NH4 NO3 treatment, the 15 N signature of NO emitted from the foot of the hillslope (Lower site) was similar to that of the NH4 + pool, indicating predominant autotrophic nitrification for NO formation. In the NH4 15 NO3 treatment, the 15 N enrichment of NO was smaller than that of the NO3 - pool, suggesting minor contribution of denitrification to NO production (~15%). CONCLUSIONS: Nitrification is the main process responsible for NO emissions, even in monsoonal summers when soil water-filled pore space values are relatively high.

Dishevelled enables casein kinase 1-mediated phosphorylation of Frizzled 6 required for cell membrane localization.

Frizzleds (FZDs) are receptors for secreted lipoglycoproteins of the Wingless/Int-1 (WNT) family, initiating an important signal transduction network in multicellular organisms. FZDs are G protein-coupled receptors (GPCRs), which are well known to be regulated by phosphorylation, leading to specific downstream signaling or receptor desensitization. The role and underlying mechanisms of FZD phosphorylation remain largely unexplored. Here, we investigated the phosphorylation of human FZD6 Using MS analysis and a phospho-state- and -site-specific antibody, we found that Ser-648, located in the FZD6 C terminus, is efficiently phosphorylated by casein kinase 1 ϵ (CK1ϵ) and that this phosphorylation requires the scaffolding protein Dishevelled (DVL). In an overexpression system, DVL1, -2, and -3 promoted CK1ϵ-mediated FZD6 phosphorylation on Ser-648. This DVL activity required an intact DEP domain and FZD-mediated recruitment of this domain to the cell membrane. Substitution of the CK1ϵ-targeted phosphomotif reduced FZD6 surface expression, suggesting that Ser-648 phosphorylation controls membrane trafficking of FZD6 Phospho-Ser-648 FZD6 immunoreactivity in human fallopian tube epithelium was predominantly apical, associated with cilia in a subset of epithelial cells, compared with the total FZD6 protein expression, suggesting that FZD6 phosphorylation contributes to asymmetric localization of receptor function within the cell and to epithelial polarity. Given the key role of FZD6 in planar cell polarity, our results raise the possibility that asymmetric phosphorylation of FZD6 rather than asymmetric protein distribution accounts for polarized receptor signaling.

A secretagogin locus of the mammalian hypothalamus controls stress hormone release.

A hierarchical hormonal cascade along the hypothalamic-pituitary-adrenal axis orchestrates bodily responses to stress. Although corticotropin-releasing hormone (CRH), produced by parvocellular neurons of the hypothalamic paraventricular nucleus (PVN) and released into the portal circulation at the median eminence, is known to prime downstream hormone release, the molecular mechanism regulating phasic CRH release remains poorly understood. Here, we find a cohort of parvocellular cells interspersed with magnocellular PVN neurons expressing secretagogin. Single-cell transcriptome analysis combined with protein interactome profiling identifies secretagogin neurons as a distinct CRH-releasing neuron population reliant on secretagogin's Ca(2+) sensor properties and protein interactions with the vesicular traffic and exocytosis release machineries to liberate this key hypothalamic releasing hormone. Pharmacological tools combined with RNA interference demonstrate that secretagogin's loss of function occludes adrenocorticotropic hormone release from the pituitary and lowers peripheral corticosterone levels in response to acute stress. Cumulatively, these data define a novel secretagogin neuronal locus and molecular axis underpinning stress responsiveness.

Denitrification as a major regional nitrogen sink in subtropical forest catchments: Evidence from multi-site dual nitrate isotopes.

Increasing nitrogen (N) deposition in subtropical forests in south China causes N saturation, associated with significant nitrate (NO3- ) leaching. Strong N attenuation may occur in groundwater discharge zones hydrologically connected to well-drained hillslopes, as has been shown for the subtropical headwater catchment "TieShanPing", where dual NO3- isotopes indicated that groundwater discharge zones act as an important N sink and hotspot for denitrification. Here, we present a regional study reporting inorganic N fluxes over two years together with dual NO3- isotope signatures obtained in two summer campaigns from seven forested catchments in China, representing a gradient in climate and atmospheric N input. In all catchments, fluxes of dissolved inorganic N indicated efficient conversion of NH4+ to NO3- on well-drained hillslopes, and subsequent interflow of NO3- over the argic B-horizons to groundwater discharge zones. Depletion of 15 N- and 18 O-NO3- on hillslopes suggested nitrification as the main source of NO3- . In all catchments, except one of the northern sites, which had low N deposition rates, NO3- attenuation by denitrification occurred in groundwater discharge zones, as indicated by simultaneous 15 N and 18 O enrichment in residual NO3- . By contrast to the southern sites, the northern catchments lack continuous and well-developed groundwater discharge zones, explaining less efficient N removal. Using a model based on 15 NO3- signatures, we estimated denitrification fluxes from 2.4 to 21.7 kg N ha-1 year-1 for the southern sites, accounting for more than half of the observed N removal. Across the southern catchments, estimated denitrification scaled proportionally with N deposition. Together, this indicates that N removal by denitrification is an important component of the N budget of southern Chinese forests and that natural NO3- attenuation may increase with increasing N input, thus partly counteracting further aggravation of N contamination of surface waters in the region.

Neuronal Expression of Opioid Gene is Controlled by Dual Epigenetic and Transcriptional Mechanism in Human Brain.

Molecular mechanisms that define patterns of neuropeptide expression are essential for the formation and rewiring of neural circuits. The prodynorphin gene (PDYN) gives rise to dynorphin opioid peptides mediating depression and substance dependence. We here demonstrated that PDYN is expressed in neurons in human dorsolateral prefrontal cortex (dlPFC), and identified neuronal differentially methylated region in PDYN locus framed by CCCTC-binding factor binding sites. A short, nucleosome size human-specific promoter CpG island (CGI), a core of this region may serve as a regulatory module, which is hypomethylated in neurons, enriched in 5-hydroxymethylcytosine, and targeted by USF2, a methylation-sensitive E-box transcription factor (TF). USF2 activates PDYN transcription in model systems, and binds to nonmethylated CGI in dlPFC. USF2 and PDYN expression is correlated, and USF2 and PDYN proteins are co-localized in dlPFC. Segregation of activatory TF and repressive CGI methylation may ensure contrasting PDYN expression in neurons and glia in human brain.

Anoctamin 2 identified as an autoimmune target in multiple sclerosis.

Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system and also is regarded as an autoimmune condition. However, the antigenic targets of the autoimmune response in MS have not yet been deciphered. In an effort to mine the autoantibody repertoire within MS, we profiled 2,169 plasma samples from MS cases and population-based controls using bead arrays built with 384 human protein fragments selected from an initial screening with 11,520 antigens. Our data revealed prominently increased autoantibody reactivity against the chloride-channel protein anoctamin 2 (ANO2) in MS cases compared with controls. This finding was corroborated in independent assays with alternative protein constructs and by epitope mapping with peptides covering the identified region of ANO2. Additionally, we found a strong interaction between the presence of ANO2 autoantibodies and the HLA complex MS-associated DRB1*15 allele, reinforcing a potential role for ANO2 autoreactivity in MS etiopathogenesis. Furthermore, immunofluorescence analysis in human MS brain tissue showed ANO2 expression as small cellular aggregates near and inside MS lesions. Thus this study represents one of the largest efforts to characterize the autoantibody repertoire within MS. The findings presented here demonstrate that an ANO2 autoimmune subphenotype may exist in MS and lay the groundwork for further studies focusing on the pathogenic role of ANO2 autoantibodies in MS.

Soil pH as the chief modifier for regional nitrous oxide emissions: New evidence and implications for global estimates and mitigation.

Nitrous oxide (N2 O) is a greenhouse gas that also plays the primary role in stratospheric ozone depletion. The use of nitrogen fertilizers is known as the major reason for atmospheric N2 O increase. Empirical bottom-up models therefore estimate agricultural N2 O inventories using N loading as the sole predictor, disregarding the regional heterogeneities in soil inherent response to external N loading. Several environmental factors have been found to influence the response in soil N2 O emission to N fertilization, but their interdependence and relative importance have not been addressed properly. Here, we show that soil pH is the chief factor explaining regional disparities in N2 O emission, using a global meta-analysis of 1,104 field measurements. The emission factor (EF) of N2 O increases significantly (p < .001) with soil pH decrease. The default EF value of 1.0%, according to IPCC (Intergovernmental Panel on Climate Change) for agricultural soils, occurs at soil pH 6.76. Moreover, changes in EF with N fertilization (i.e. ΔEF) is also negatively correlated (p < .001) with soil pH. This indicates that N2 O emission in acidic soils is more sensitive to changing N fertilization than that in alkaline soils. Incorporating our findings into bottom-up models has significant consequences for regional and global N2 O emission inventories and reconciling them with those from top-down models. Moreover, our results allow region-specific development of tailor-made N2 O mitigation measures in agriculture.