Microglia Rescue Vulnerable Dopamine Neurons in Parkinson’s

 With your risk of Parkinsons' poststroke. How is your competent? doctor ensuring these microglia are working in your case?

Parkinson’s Disease May Have Link to Stroke March 2017 

The latest here: 

Microglia Rescue Vulnerable Dopamine Neurons in Parkinson’s

Summary:

Researchers at the University of Oxford have discovered that human microglia can selectively prune away toxic alpha-synuclein aggregates from dopamine-producing neurons without destroying the host nerve cells. Utilizing co-cultures of human induced pluripotent stem cell (iPSC)-derived neurons and microglia, the team demonstrated that microglia employ “trogocytosis”, a precise cellular nibbling mechanism, regulated by GPNMB, P2RY12, and CD22 signaling pathways, along with an IL-10 molecular brake. The findings identify a distinct, neuroprotective microglial subtype that shields neurons in Parkinson’s disease.

Key Facts:

• Selective Pruning via Trogocytosis: Human microglia selectively extract and dispose of aggregated alpha-synuclein clumps by “nibbling” specific segments of living dopamine neurons while preserving overall neuronal viability and connectivity.
• GPNMB Identified as Functional Driver: Glycoprotein non-metastatic melanoma protein B (GPNMB), a protein previously linked to Parkinson’s risk via genome-wide association studies (GWAS), binds directly to alpha-synuclein and is required for microglia to effectively clear aggregates.
• Fine-Tuned Immune Brakes: The protective clearance mechanism is controlled by sensing receptors (P2RY12), inhibitory checkpoints (CD22), and an interleukin-10 (IL-10) autocrine brake that prevents runaway neurotoxic inflammation.

Source: University of Oxford

Beyond the Double-Edged Sword: A Precision Immune Defense

In neurodegenerative diseases, microglia, the central nervous system’s resident immune sentinels, are typically framed through a conflicted narrative. Under physiological conditions, they survey brain tissue, prune synapses, and clear cellular debris; during chronic neurodegeneration, their persistent activation drives inflammatory signaling cascades that accelerate neuronal death.

Nowhere has this paradox been more evident than in Parkinson’s disease, a condition affecting more than 10 million individuals globally. The disease is defined by the selective death of dopamine-producing neurons within the substantia nigra, driven largely by the misfolding and aggregation of alpha-synuclein into toxic intracellular clumps.

Whether human microglia can intervene constructively to rescue dopamine neurons from this proteinaceous burden, without destroying the neurons in the process, has remained an open question.

Now, a team of neuroscientists at the University of Oxford has revealed an unexpected, highly targeted defense mechanism.

The researchers established that a specialized population of human microglia actively extracts and destroys harmful alpha-synuclein aggregates directly from living dopamine neurons via trogocytosis (from the Greek trogo, meaning “to gnaw” or “to nibble”).

“What is striking is the precision of this response,” said first author Hung-Ju Chueh, Ph.D., of the University of Oxford. “The microglia were not simply engulfing damaged neurons but instead removing parts of the neuron containing aggregated alpha-synuclein, suggesting that, at certain stages of disease, microglia help neurons dispose of potentially harmful material.”

Engineering Human iPSC Co-Cultures to Model Live Interactions

To investigate interactions between human brain cells in real time, the Oxford investigators generated human induced pluripotent stem cell (iPSC) lines, co-culturing authentic human dopamine neurons alongside human microglia.

The team modeled alpha-synuclein pathology through two complementary methods: by introducing genetic alpha-synuclein gene dosage elevations (triplication), and by seeding the cultures with exogenous preformed alpha-synuclein fibrils that template the misfolding of native neuronal protein.

High-resolution cellular imaging revealed that rather than engulfing entire dying neurons via standard phagocytosis, the microglia selectively nibbled off membrane pockets enclosing the aggregated protein. This process of trogocytosis eliminated the toxic pathology while leaving the broader axonal network and cell body intact.

Single-cell RNA sequencing showed that this clearance was driven by a distinct, transcriptionally defined subpopulation of activated microglia. This subset was kept from over-activating through a balanced signaling network:

• Surveillance and Guidance: Governed by P2RY12 purinergic receptor sensing.
• Cellular Checkpoints: Regulated by CD22 inhibitory surface interactions between neurons and microglia.
• Inflammatory Suppression: Maintained by an autocrine interleukin-10 (IL-10) brake that halted secondary, collateral inflammatory tissue injury.

Solving the GPNMB Genetic Mystery in Parkinson’s

The investigation also cracked a longstanding genetic puzzle. Multiple large-scale genome-wide association studies (GWAS) had previously flagged variants in the GPNMB (glycoprotein non-metastatic melanoma protein B) gene locus as significant risk factors for Parkinson’s disease, but its mechanistic function in the brain remained unknown.

The Oxford team discovered that GPNMB is directly upregulated in human microglia when exposed to aggregate-bearing neurons, where it physically interacts with pathological alpha-synuclein within the microglial machinery.

Furthermore, post-mortem analysis of human brain tissue from patients with incidental Lewy body disease and confirmed Parkinson’s disease revealed elevated GPNMB levels within substantia nigra microglia.

To confirm causality, the team used CRISPR interference (CRISPRi) to knock down GPNMB expression in human microglia. Deprived of GPNMB, the microglia lost their ability to clear alpha-synuclein aggregates from the neighboring dopamine neurons, establishing GPNMB as an essential driver of the neuroprotective response.

“Our findings highlight that the immune response in Parkinson’s disease is more nuanced than simply being beneficial or harmful,” noted senior author George Tofaris, M.D., Ph.D., Professor of Neurology and Translational Neuroscience at the University of Oxford. “We have identified a population of human microglia that can actively remove pathological alpha-synuclein from neurons. Understanding how to enhance and monitor such beneficial microglial functions, without triggering damaging inflammation, could open up new avenues for developing disease-modifying treatments.”

Editorial Notes:

• This article was edited by a Neuroscience News editor.
• Journal paper reviewed in full.
• Additional context added by our staff.

About this Neurology Research:

• Media Contact: Christopher McIntyre
• Source: University of Oxford
• Image Credit: Image credited to Neuroscience News
• Original Research is Open Access: Science Translational Medicine (Oct 7, 2026). “Human microglia clear intraneuronal alpha- synuclein aggregates by GPNMB-mediated trogocytosis.” Authors: Hung-Ju Chueh, Antigoni Katsikoudi, Ana Aragón-González, Chor Lai Lam, Liezel Tamon, Ashwin Jainarayanan, Devika Agarwal, Sally A. Cowley, David Sims, and George K. Tofaris.
• DOI: 10.1126/scitranslmed.adz9258

Clot buster may stop promising stroke medicine from working properly

 

Your doctor is completely familiar with this and gets update from the research analyst, right? Oh no, no research analyst and your doctor doesn't keep track of stroke research!

Anakinra (2 posts to July 2012)

Clot buster may stop promising stroke medicine from working properly

A clotbusting drug commonly used to treat ischemic stroke interacts negatively with a promising anti-inflammatory treatment (anakinra), underscoring the need to test new stroke therapies alongside existing standard care.

According to The University of Manchester led study on mice, the timing of anakinra must be adjusted to avoid reducing the benefits of the clot‑busting therapy known as tissue plasminogen activator(tPA).

Stroke is the second leading cause of death and disability worldwide; experts estimate the number of people affected could rise by more than 80 per cent over the next 25 years.But despite decades of research and thousands of experimental drugs, the only approved medicines for treating the most common type of stroke are clot‑busting drugs known as plasminogen activators, like tPA.

Though tPA can be lifesaving for acute ischemic stroke, about 2–6 per cent of treated patients develop potentially fatal brain bleeding, according to the ECASS III trial of the early 2000s.

Though it must be given within 4.5 hours of symptom onset, many patients arrive too late or don’t know when symptoms started.

Scientists now know that inflammation plays a major role in worsening brain injury after a stroke, mostly driven by a molecule called interleukin‑1 (IL‑1).

Anakinra  – an interleukin‑1 receptor antagonist (IL‑1Ra) –  blocks IL‑1 and has shown promise in reducing inflammation in both laboratory and early clinical studies of stroke.

However, a  phase II clinical trial known as SCIL‑STROKE based at The Northern care Alliance NHS foundation Trust found that IL‑1Ra did not improve patient recovery overall.

“The findings of SCIL‑STROKE raise questions about whether the drug might interact negatively with standard clot‑busting treatment, “ said lead author Dr Ioana-Emilia Mosneag, based at the University of Manchester.

Because nearly three‑quarters of patients in the SCIL‑STROKE trial received the clot‑busting drug tPA before IL‑1Ra, the researchers set out to investigate whether the two treatments might negatively interact  with each other.

They re‑examined data from the SCIL-STROKE trial and discovered that patients who received tPA before IL‑1Ra had significantly lower levels of IL‑1Ra in their blood, suggesting the drug was being broken down.

Laboratory research confirmed that IL‑1Ra can be cut apart by plasmin, an enzyme produced during tPA treatment, meaning the anti‑inflammatory drug may be degraded before it can work.

Researchers then tested the interaction in a mouse model of stroke, using dosing schedules that matched those used in the clinical trial.

When IL‑1Ra was given after tPA, no harmful interaction was seen, and the protective effects of tPA were preserved.

However, when IL‑1Ra was given at the same time as tPA — during the clot‑busting process — the benefits of tPA were dramatically reduced, with brain damage shrinking by only 15 per cent compared to 68 per cent with tPA alone.

The mice receiving both drugs together also showed poorer blood flow in the brain, more inflammatory immune cells entering damaged tissue, and higher levels of harmful structures called neutrophil extracellular traps.

This indicates that the drug interaction is also detrimental to the anti-inflammatory effect of IL-1Ra.

Dr Mosneag added: “Our findings suggest that IL‑1Ra can interfere with tPA’s ability to dissolve clots when the two drugs are present in the bloodstream at the same time.

“The results also help explain why IL‑1Ra levels were lower in patients who received tPA first, as plasmin generated during clot‑busting appears to break down IL‑1Ra.

”However, the  effect of tPA on IL-RA –  the opposite order –  isn’t necessarily a problem  as IL-1RA was still active in reducing IL-6 in the SCIL-STROKE study, but this needs further evaluation.”

Co-author Professor Stuart Allan from The University of Manchester said: “This study  shows that timing is very likely to be a critical factor in the efficacy of  IL‑1Ra, which  will be beneficial if given after tPA rather than alongside it.

“We also need to test whether similar interactions occur with other clot‑busting drugs such as tenecteplase, which may be less likely to break down IL‑1Ra due to its greater specificity.”

Co-author Professor Craig Smith from the University of Manchester said: “This study has important implications for further development of IL-1Ra as a treatment for ischaemic stroke, where there remains a focus on maximising delivery of thrombolysis drugs to eligible patients as quickly as possible in clinical care.

“Future studies will need to investigate the timing and effectiveness of IL-1Ra treatment after receiving tPA.”

Timing-Dependent Cleavage of Interleukin-1 Receptor Antagonist by Alteplase Impairs Neuroprotection in Ischemic Stroke

 Will your competent? doctor and hospital do anything with this? Or is head in the sand their response? I'd start asking now so enough time is available to get some competency in your hospital!

Timing-Dependent Cleavage of Interleukin-1 Receptor Antagonist by Alteplase Impairs Neuroprotection in Ischemic Stroke

Ioana-Emilia Mosneag, PhD https://orcid.org/0000-0003-0993-8583 ioana-emilia.mosneag@manchester.ac.uk, 

Marina Rubio, PhD https://orcid.org/0000-0002-6120-4053, 

Eloïse Lemarchand, PhD, 

Yolanda Ohene, PhD https://orcid.org/0000-0002-0213-6302, 

Ben R. Dickie, PhD https://orcid.org/0000-0001-5018-2111, 

Rachel Jones, PhD https://orcid.org/0009-0001-2935-7586, 

Graham Coutts, PhD https://orcid.org/0000-0002-5865-9495, 

Eleanor Ritchie, BSc https://orcid.org/0009-0004-1594-5282, 

Daniela Martins Borges, BSc, 

Denis Vivien, PhD https://orcid.org/0000-0002-7636-2185, 

Craig J. Smith, MD https://orcid.org/0000-0002-9078-9919, and 

Stuart M. Allan, PhD https://orcid.org/0000-0001-9646-4456Author Info & Affiliations

Stroke

New online

https://doi.org/10.1161/STROKEAHA.125.054941

Abstract

BACKGROUND:

Inflammation contributes significantly to neuronal damage in ischemic stroke, with IL (interleukin)-1 being a key mediator. IL-1Ra (IL-1 receptor antagonist) inhibits IL-1 signaling, successfully reducing inflammation in preclinical and clinical stroke studies. However, in the latest phase II trial of IL-1Ra in ischemic stroke (SCIL-STROKE [Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke]), a secondary mediation analysis uncovered an alternative pathway leading to no overall functional benefit. This was the first IL-1Ra trial where participants (73%) received preceding tPA (tissue-type plasminogen activator), raising the possibility that IL-1Ra and tPA interact negatively in ischemic stroke. We aim to explore this postulated negative interaction.

METHODS:

A retrospective analysis of SCIL-STROKE trial data was performed. Next, we used a thromboembolic model of stroke in male wild-type mice (25–35 g; n=10–13), treated with tPA (10 mg/kg, 20–60 minutes poststroke), followed by IL-1Ra (100 mg/kg) either 6 doses, twice daily (after tPA), or 2 doses at 30 minutes (during tPA) and 3 hours poststroke. The primary outcome was lesion volume at 72 hours, measured by T2-magnetic resonance imaging.

RESULTS:

Reanalysis of SCIL-STROKE data revealed a 35.8% reduction in plasma IL-1Ra in patients cotreated with preceding tPA, suggesting IL-1Ra degradation. Biochemical assays confirmed IL-1Ra cleavage by plasmin. While replicating the SCIL-STROKE dosing regimen preclinically, no negative interactions were noted. However, when IL-1Ra was administered during thrombolysis, it impaired the beneficial effect of tPA, reducing lesion volume by only 15%, compared with 68% with tPA alone. Acute cotreatment of IL-1Ra and tPA also led to reduced tissue perfusion and increased leukocyte infiltration and neutrophil extracellular traps.

CONCLUSIONS:

We show that IL-1Ra is cleaved by plasmin, and its administration during thrombolysis worsens outcomes poststroke. These studies confirm a negative interaction between the 2 drugs, which can be prevented by tPA preceding IL-1Ra treatment. The findings raise broader concerns about how tPA may interfere with other neuroprotective treatments.

Graphical Abstract

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Protein changes could predict post-stroke cognitive decline

 So what? WHAT EXACTLY WILL PREVENT COGNITIVE DECLINE? You have no fucking idea on research needs in stroke! The only goal in stroke is 100% recovery! Do the research that gets there or you're fired!  Your mentors and senior researchers are obviously incompetent!

Protein changes could predict post-stroke cognitive decline

Protein changes after stroke could help identify people at risk of later memory and thinking problems, new research study suggests.

The study also suggests smoking may increase the risk of memory and thinking problems alongside ongoing inflammation after a stroke.

The research, published in Alzheimer’s & Dementia, is part of the Stroke IMPaCT study, a network of European and North American researchers working to discover how inflammation and immune responses contribute to post-stroke cognitive decline.

Lead author Natasha Carmichael, an MBPhD researcher at The University of Manchester, said: “Inflammation after stroke doesn’t just happen once and disappear. By tracking this protein over time, we may be able to identify patients at greater risk of cognitive problems and eventually tailor support or treatments to them.”

The team followed patients treated for an ischaemic stroke at Salford Royal Hospital, part of Northern Care Alliance NHS Foundation Trust.

They measured levels of interleukin-6, or IL-6, in the days after stroke and again at both six to nine and 18 to 21 months. Participants also completed detailed tests of memory and thinking.

Interleukin-6 levels increased soon after stroke and, in most people, fell back to typical levels within six to nine months. But in some patients, levels stayed high or rose again.

These individuals were about eight times more likely to develop difficulties with thinking ability.

The researchers also saw differences between smokers and non-smokers. Smokers showed a different pattern of IL-6 change after stroke, with signs of longer-lasting inflammation.

This ongoing inflammation was more strongly linked to problems with thinking and memory.

Craig Smith, professor of stroke medicine at The University of Manchester and consultant at Salford Royal, said: “Our findings suggest it’s not just the initial spike in inflammation that matters, it’s whether it properly settles down after the stroke.

“Smoking appears to interfere with this recovery, leaving people more vulnerable to memory and thinking problems.”

Stuart Allan added: “When the immune system’s recovery after stroke doesn’t occur as expected, patients appear more likely to experience cognitive difficulties.

“If future studies confirm interleukin-6 is the cause, we might one day use medications that block it to protect brain health.”

Targeting immune cells in the aged brain reveals that engineered cytokine IL-10 enhances neurogenesis and improves cognition

 We need both, do you have ANY CONFIDENCE AT ALL that your stroke medical 'professionals' will get human testing going?

Do you prefer your doctor, hospital and board of director's incompetence NOT KNOWING? OR NOT DOING? Your choice; let them be incompetent or demand action!

Targeting immune cells in the aged brain reveals that engineered cytokine IL-10 enhances neurogenesis and improves cognition

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https://doi.org/10.1016/j.immuni.2026.01.016Get rights and content

Under a Creative Commons license

Open access

Highlights

• •
  The old brain contains exhausted T cells and unbalanced microglial inflammation
• •
  Delivery of engineered proteins into old mouse brains allows immune cell targeting
• •
  Checkpoint inhibition in old brains activates T cells and microglial inflammation
• •
  Engineered IL-10 restores microglial balance, neurogenesis, and cognition in old mice

Summary

The immune system could play an important role in the age-related decline in brain function, yet specific immune-based strategies to enhance brain resilience in older individuals are lacking. Here, we combined engineered proteins and direct brain delivery to target immune cell populations within the old brain. We detected T cells with an exhaustion signature in the old brain and targeted them with a potent engineered checkpoint inhibitor (RIPR-PD1). This led to T cell expansion and strong pro-inflammatory responses in many brain cell types, notably microglia. To rescue age-related inflammatory imbalances in microglia, we used the anti-inflammatory cytokine interleukin (IL)-10. IL-10 boosted anti-inflammatory responses in old microglia, but it also triggered pro-inflammatory signaling. An engineered IL-10 variant that uncouples pro- and anti-inflammatory responses positively impacted the transcriptome of multiple cell types, enhanced neurogenesis, and improved cognition in aged mice. Our findings pave the way for immunotherapies for the aged brain.

Graphical abstract

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Introduction

Brain function deteriorates with age. Additionally, age-related neurodegenerative diseases (e.g., Alzheimer’s disease and Parkinson’s disease) surge in the elderly population. While many pathways are remodeled in the brain during aging,1,2,3,4 a key feature of old brains is immune cell infiltration and inflammation. Aging leads to a pronounced increase in the number of T cells across several brain regions in mice and humans,5,6,7 including neural stem cell (NSC) niches8,9,10,11 and white matter tracts.12,13,14,15,16 T cells from old brains are clonally expanded,8,17 suggesting they have encountered antigens. T cell infiltration and clonal expansion are further accentuated in age-related neurodegenerative diseases.18,19,20,21,22,23,24,25,26 In parallel, pro-inflammatory pathways are strongly upregulated during aging in many cell types, and this is exacerbated in Alzheimer’s disease.8,13,27,28,29,30,31,32,33,34,35,36 A systematic understanding of age-related changes in brain immune cells may inform strategies to mitigate brain aging.

Could immune-based interventions be designed to counter brain aging? Modulating immune cells and inflammatory pathways can affect the old brain.12,13,28,30,37,38,39 But previous studies have relied on broad interventions, often performed in the periphery13 and in young or disease model mice.18,24,40,41,42,43,44,45 We lack strategies to target specific immune cell subsets and pathways within the old brain to determine their mode of action. Moreover, identifying such brain immune interventions could help develop “aging immunotherapies” and would be critical to counter aspects of brain aging and age-related brain diseases.

Here, we developed a platform that leverages engineered proteins and direct brain delivery to test immune cell-specific interventions in old mice. We identified T cells with an exhaustion signature and targeted them with a potent engineered checkpoint inhibitor, leading to T cell expansion and strong pro-inflammatory responses in many cell types, including microglia. To rescue age-related inflammatory balance in microglia, we used an engineered interleukin (IL)-10 variant that uncouples pro- and anti-inflammatory responses and found that it had beneficial effects on multiple cell types and cognition in aged mice. Our findings pave the way for novel immunotherapies for the aged brain.

Results

Characterization of immune cells in the aged brain

We systematically characterized immune cells in the aging brain, focusing on the subventricular zone (SVZ) neurogenic niche—a region that contains adult NSCs and declines during aging.46,47,48,49 Leveraging previously published single-cell RNA-sequencing (scRNA-seq) datasets,8,50 we found that SVZ neurogenic niches contained microglia (the brain-resident myeloid population), macrophages, CD8+ T cells, CD4+ T cells, and low numbers of other immune cells (Figures 1A and S1A). CD8+ T cells were not very numerous but significantly increased in number with age (Figure 1A, upper and middle panel). Microglia were the most abundant immune cell type and showed the largest age-related changes in gene expression (Figure 1A, lower panel). We thus focused on CD8+ T cells and microglia for further characterization and targeting in the old brain.

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Figure 1. Characterization of immune cells in the old brain

(A) Analysis of immune cell populations in the SVZ neurogenic niche of young (3–4 months, n = 7) and old (22–29 months, n = 6) male mice in two merged scRNA-seq published datasets.8,50 Top panel, quantification of the proportion of different immune cell types relative to the total number of cells. Data are mean ± SEM; each dot represents one mouse. Middle panel, age-dependent changes (log2[old/young]) in the abundance of each cell type. Bottom panel, age-dependent changes in gene expression per cell type. Dots represent differential expression MAST Z score for each gene. Genes significantly changed with age (Bonferroni-corrected p < 0.05) are in color.

(B) scRNA-seq analysis of CD8+ T cells freshly isolated from the brain and lung of old male mice (22–25 months, n = 11 mice, pooled). Uniform manifold approximation and projection (UMAP) clustering of all T cells colored by organ of origin, downsampled to 3,724 cells per organ. One independent experiment.

(C) UMAP as in (B) colored by cell type.

(D) Changes in the percentage of T cell subtypes in old brains vs. old lungs.

(E) Heatmap of top six marker genes for each T cell subtype in the old brain.

(F) FACS quantification of percent PD1+ and CD44+CD69+ of CD8+ T cells freshly isolated from the brains and lungs of old male mice (24 months, n = 6). One independent experiment.

(G) Heatmap of T cell marker genes in T cells from same dataset as (A).

(H) Left, representative images showing exhaustion scores for T cells in coronal brain sections of young (6 months) and old (28 months) male mice in a spatial transcriptomics (MERFISH) dataset.7 Right, quantification of exhaustion scores in T cells from young (3–6 months, n = 5) and old (26–34 months, n = 6) male mice across four brain regions, cortex (CTX), striatum and adjacent regions (STR), white matter tracts of the corpus callosum and anterior commissure (CC/ACO), and the ventricle (VEN). One coronal section per mouse. Boxplots of median and lower and upper quartile values.

(I) Left, representative immunofluorescence images of SVZ from young (4 months) and old (28 months) male mice. Red, CD8+ (T cells); green, PD1+ (checkpoint protein); blue, DAPI (nuclei). Scale bar, 10 μm. Right, number of CD8+ and CD8+ PD1+ T cells in the SVZ of young (3–4 months, n = 7) and old (28–32 months, n = 7) male mice. Each dot represents one mouse (average of two sections per mouse). One independent experiment.

(J) FACS quantification of the percentage of CD8+PD1+ and CD8+CD44+CD69+ T cells of live/CD45+ cells freshly isolated from the brain of young (6 months, n = 6) and old (24 months, n = 6) male mice. One independent experiment.

(K) Average changes in gene expression in microglia of the SVZ neurogenic niche of young and old male mice from three published scRNA-seq datasets.8,50,51 Red, upregulated; blue, downregulated genes.

(L) Heatmap of log-normalized counts for pro- and anti-inflammatory genes in microglia from the SVZ in a published dataset.8

(M) Log-normalized expression values of Socs3 (left) and combined genes in the IL-10 pathway in microglia from the SVZ in a published dataset.8 Horizontal lines, median.

(N) IL-10 signaling scores for microglia in spatial transcriptomics dataset.7

(O and P) FACS histograms and quantification of inflammation proteins in microglia (CD45+CD11b+) freshly isolated from the SVZ of young (3 months) and old (24 months) male mice (n = 6). Each dot represents one mouse (mean fluorescence intensity [MFI] values from ∼500 microglia per mouse). One independent experiment.

Data are mean ± SEM. p values, two-sided Wilcoxon rank-sum test. NS, not significant.

See also Figure S1.

More at link.