Cell's sense of starvation stress, triggers TDP-43 misfolding

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It’s unknown why misfolded aggregates appear in cells cytosol during neurodegenerative diseases. If the forming mechanism was elucidated it would enable designing new and efficient therapies. One of those protein aggregates is composed of misfolded TDP-43. Aggregates hyper-phosphorylated, ubiquitinated and cleaved form of TDP-43 are found in frontotemporal dementia, in amyotrophic lateral sclerosis and in some cases of Alzheimer and Parkinson.

My feeling is that scientists, from Academy of Scientific and Innovative Research (AcSIR) in India, achieved one of the most important milestone since 2006, when Virginia Lee provided evidence of involvement of TDP-43 in ALS.

For the proper functioning of the cells, neutral pH is required. However during normal metabolism, all foods create waste products which are acidic. Accumulated waste and toxins ages the cell, sometimes causes it to change to a sick or abnormal cell. For example the cytosol of yeast cells acidifies during aging.

Cells experience a variety of stress-like conditions, in particular, nutrient starvation stress acidifies the cytosol and increases the cytosolic proton ion concentration due to the reduced efficiency of ATP proton pump.

In chemistry, protonation describes the addition of a proton to a molecule, forming an acid. Some proteins or protein domains inside the cells can function as biosensors. It has been proposed that cells sense starvation stress at the molecular level by protonating the side chains of biosensor protein molecules.

The scientists Divya Patni  and  Santosh Kumar Jha observed in a previous study that two domains of TDP-43 (tRRM) could function as a biosensor and sense pH stress. They shown that under low-pH conditions, mimicking starvation stress, TDP-43tRRM undergoes a conformational change named "L structure". enter image description here The L form structure is held by weak interactions and eventually fully misfolds and oligomerizes to form a β-sheet rich "β form". The unstructured regions of the protein gain structure during L ⇌ β conversion.

TDP-43 consists of 4 domains:

  • An N-terminal domain
  • Two RNA recognition motifs RRM1 and RRM2 working as a tandem (tRMM)
  • An unstructured C-terminal domain.

In this paper, Patni  and  Jha showed that the monomeric N form of TDP-43tRRM forms a misfolded amyloid-like protein assembly, β form, in a pH-dependent manner.

The side chains of the ionizable amino acid residues buried inside the protein structure can protonate or deprotonate only upon partial or complete unfolding.

They are promising candidates to function as gatekeeper residues for protein aggregation as it often begins with partial unfolding of the protein.

The scientists from the Academy of Scientific and Innovative Research in Ghaziabad India, hypothesized that ionization of a protein side-chain buried in the protein structure might be coupled to the formation of the misfolded β form.

An examination of the protein structure revealed that out of all of the amino acid residues whose side chain could titrate in the acidic pH range, only D105, H166, and H256 are almost completely buried in the protein structure. They systematically mutated these residues to neutral amino acids whose side chains cannot undergo protonation-deprotonation reaction ( D105A, H166Q and H256Q).

Patni  and  Jha observed that D105A and H256Q behaved like TDP-43tRRM in their pH-dependent misfolding behavior. However, H166Q retained the N-like secondary structure under low-pH conditions and did not show pH-dependent misfolding to the β form.

These results indicate that H166 is the critical side-chain residue whose protonation triggers the misfolding of TDP-43tRRM.

These results indicate also that the protonation of H166 functions as a critical trigger switch that controls the amyloid-like misfolding of TDP-43tRRM upon pH stress sensing. It appears that the protonation of H166 results in proximal or distal conformational changes that initiate the misfolding of the protein.

It’s suspected since a long time that the RNA-Recognition motifs of TDP-43 may play a role in the aberrant self-assembly of the protein. Now a clear mechanism of action had been described, while it may not be the only one, hopefully it will enable the design of new therapies.


This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

There is growing interest in the possibility that Alzheimer's disease is triggered by infection because the Alzheimer's disease brain signature protein, β-amyloid peptide, has antimicrobial activity and therefore β-amyloid peptide could be a consequence rather than a cause of Alzheimer's disease. Alzheimer's disease Several observational cohort and case-control studies have shown reduced rates of dementia after certain types of vaccines. Twenty years ago, Verreault and his colleagues reported that vaccine exposure (diphtheria / tetanus, polio, influenza) was associated with a 25-60% reduction in the subsequent development of Alzheimer's disease.

Klinger and colleagues have demonstrated a significantly reduced risk of developing Alzheimer's disease in patients with bladder cancer exposed to repeated intravesical applications of the Bacillus Calmette-Guérin vaccine, particularly in the 75+ year-old population.

Scherrer and his colleagues showed a significantly reduced rate of dementia in people vaccinated against tetanus, diphtheria and pertussis and shingles compared to those unvaccinated.

Liu and his colleagues found a reduced rate of dementia in patients with chronic kidney disease vaccinated with the influenza vaccine.

Population-wide observational cohort studies indicate a moderate association between a diagnosis of human herpes virus infection and incident dementia, and some studies indicate a potential mediating role of antiherpetic drugs.

The varicella-zoster virus (called VZV, for varicella-zoster virus) is a herpesvirus, also called HHV-3 (human herpesvirus 3), which causes chickenpox or shingles.

Human herpes viruses, also known as varicella-zoster virus, are usually contracted in early childhood when they cause chickenpox, but the virus persists throughout life and may recur in older people as shingles, and has also been associated with postherpetic neuralgia, encephalitis and / or meningitis, and respiratory disease.

To reduce the effects of the re-emergence of human herpes viruses in the elderly, national vaccination strategies have been implemented in the UK and elsewhere.

In Wales, a national shingles vaccination has been carried out since 2013, with the aim of vaccinating people aged 70 years, and a catch-up vaccination at 79 years for unvaccinated people at 70 years.

Until 2018, the only shingles vaccine available in Wales was a live attenuated vaccine against the human herpes virus (Zostavax). Since June 2018, a small proportion of the Welsh population has received the recombinant shingles vaccine (Shingrix).

In this new pre-print publication, Christian Schnier, Janet Janbek, Richard Lathe and Jürgen Haas analyzed the association of shingles vaccination with incident dementia in people vaccinated in Wales between 2013 and 2020 in an observational cohort study using national health data collected retrospectively. In addition, they analyzed whether this association was mediated by a reduction in diagnosed shingles and whether the association had a different degree in Alzheimer's disease and vascular dementia.

People exposed to the vaccine had a 39% reduced risk of being diagnosed with dementia after vaccination. This association is close to that published by Scherrer and colleagues who found a 43% reduction in dementia in people vaccinated against shingles.

The reduction in dementia in people exposed to the vaccine was slightly more pronounced for vascular dementia than for Alzheimer's disease. If true, their results suggest an association between shingles vaccination and cerebrovascular disease, rather than an association of vaccination with the pathological accumulation of toxic proteins in the brain such as the beta-amyloid peptide and the protein tau.

However, their results should be interpreted with caution because the total duration of follow-up of those vaccinated and subsequently diagnosed with herpes zoster was low, resulting in wide confidence intervals in the estimate. People exposed to the shingles vaccine had a lower risk of death from all causes except cancer, this finding could indicate a nonspecific effect of the shingles vaccination.

One potential interpretation of their results, therefore, is that the live attenuated varicella-zoster vaccine acts as an adjuvant that plays a role in immune responses against viruses.

This interpretation is supported by: (i) documented cross-immune protection when infection with one pathogen can alleviate disease caused by a second unrelated pathogen, (ii) the fact that an immune adjuvant (alum) has been reported to delay the development of Alzheimer's disease, (iii) the fact that a potent adjuvant vaccine (Bacillus Calmette-Guérin) reduces the rates of Alzheimer's disease in patients with bladder cancer.

These theories of the negative association between varicella zoster virus vaccination and dementia, however, should be considered, alongside other potential theories. Indeed, their results could come from a selection bias. Indeed, non-specific effects of the vaccine, such as lower mortality, have already been described in observational cohort studies of vaccine efficacy by Simonsen and colleagues, who attributed the association to selection bias for fragility .

To control for the selection bias of frailty, scientists at the Universities of Edinburgh and Copenhagen adjusted frailty between 65 and 70 years of age, retirement home residency, and the multiple illnesses that make up the Charlson Co-morbidity Index.

The authors cannot exclude with certainty that unvaccinated people may have a lower healthy life expectancy. This observation would be supported by the results of vaccine efficacy studies for Zostavax, which showed no significant difference in mortality between people exposed to the vaccine and those exposed to a placebo.

In addition, although their study population was large and representative of the Welsh population, the average follow-up period was rather short, as the introduction of the vaccine into a national campaign was made in 2013, which gave maximum follow-up time. about 6 years old (up to the age of 76).

Il y a un intérêt croissant dans la possibilité que la maladie d'Alzheimer soit déclenchée par une infection car la protéine de signature du cerveau de la maladie d'Alzheimer, le peptide Aβ, a une activité antimicrobienne et donc la maladie d'Alzheimer pourrait être une conséquence plutôt qu'une cause de la maladie d'Alzheimer. enter image description here Plusieurs études observationnelles de cohorte et cas-témoins ont montré une réduction des taux de démence après certains types de vaccins. Il y a vingt ans, Verreault et ses collègues ont rapporté que l'exposition au vaccin (diphtérie/tétanos, polio, grippe) était associée à une réduction de 25 à 60 % du développement ultérieur de la maladie d'Alzheimer.

Klinger et ses collègues ont démontré un risque significativement réduit de développer la maladie d'Alzheimer chez les patients atteints d'un cancer de la vessie exposés à des applications intravésicales répétées du vaccin Bacillus Calmette-Guérin, en particulier dans la population âgée de 75 ans et plus.

Scherrer et ses collègues ont montré un taux de démence significativement réduit chez les personnes vaccinées contre le tétanos, la diphtérie et la coqueluche et le zona par rapport à celles non vaccinées.

Liu et ses collègues ont trouvé un taux de démence réduit chez les patients atteints d'insuffisance rénale chronique vaccinés avec le vaccin antigrippal.

Des études de cohorte observationnelles à l'échelle de la population indiquent une association positive modérée à inexistante entre un diagnostic d'infection par le virus de l'herpès humain et une démence incidente, et certaines études indiquent un rôle médiateur potentiel des médicaments antiherpétiques.

Le virus varicelle-zona (appelé VZV, pour varicella-zoster virus) est un herpèsvirus, également appelé HHV-3 (human herpesvirus 3), responsable de la varicelle ou du zona.

Les virus de l'herpès humain, également connus sous le nom de virus varicelle-zona, sont généralement contractés dans la petite enfance lorsqu'ils provoquent la varicelle, mais le virus persiste toute la vie et peut réapparaître chez les personnes âgées sous forme de zona, et a également été associé à la névralgie post-zostérienne, à l'encéphalite et/ ou méningite et maladie respiratoire.

Pour réduire les effets de la réémergence des virus de l'herpès humain chez les personnes âgées, des stratégies nationales de vaccination ont été mises en œuvre au Royaume-Uni et ailleurs.

Au Pays de Galles, une vaccination nationale contre le zona est menée depuis 2013, dans le but de vacciner les personnes âgées de 70 ans, et une vaccination de rattrapage à 79 ans pour les personnes non vaccinées à 70 ans.

Jusqu'en 2018, le seul vaccin contre le zona disponible au Pays de Galles était un vaccin vivant atténué contre le virus de l'herpès humain (Zostavax). Depuis juin 2018, une faible proportion de la population galloise a reçu le vaccin recombinant contre le zona (Shingrix).

Dans cette nouvelle pré-publication, Christian Schnier, Janet Janbek, Richard Lathe et Jürgen Haas ont analysé l'association de la vaccination contre le zona avec la démence incidente chez les personnes vaccinées au Pays de Galles entre 2013 et 2020 dans une étude de cohorte observationnelle utilisant des données de santé nationales collectées rétrospectivement. De plus, ils ont analysé si cette association était médiée par une réduction du zona diagnostiqué et si l'association avait un degré différent dans la cas de la maladie d'Alzheimer et de la démence vasculaire.

Les personnes exposées au vaccin présentaient un risque réduit de 39 % de diagnostic de démence après la vaccination. Cette association est proche de celui publié par Scherrer et ses collègues qui ont trouvé une réduction de 43 % de la démence chez les personnes vaccinées contre le zona.

La réduction de la démence chez les personnes exposées au vaccin était légèrement plus prononcée pour la démence vasculaire que pour la maladie d'Alzheimer. Si cela est vrai, leurs résultats suggèrent une association entre la vaccination contre le zona et les pathologies cérébrovasculaires, plutôt qu'une association de la vaccination avec l'accumulation pathologique de protéines toxiques dans le cerveau telles que le peptide bêta-amyloïde et la protéine tau.

Pourtant, leurs résultats doivent être interprétés avec prudence car la durée totale de suivi des personnes vaccinées et ayant reçu un diagnostic ultérieur de zona était faible, ce qui a entraîné de larges intervalles de confiance dans l'estimation. Les personnes exposées au vaccin contre le zona présentaient un risque plus faible de mortalité toutes causes confondues sauf du cancer, ce résultat pourrait indiquer un effet non spécifique de la vaccination contre le zona.

Une interprétation potentielle de leurs résultats est donc que le vaccin vivant atténué contre le virus varicelle-zona agit comme un adjuvant qui joue un rôle dans les réponses immunitaires contre les microbes.

Cette interprétation est appuyée par : (i) une protection immunitaire croisée documentée lorsque l'infection par un agent pathogène peut soulager la maladie causée par un deuxième agent pathogène non apparenté, (ii) le fait qu'un adjuvant immunitaire (alun) a été signalé comme retardant le développement de la maladie d'Alzheimer, (iii) le fait qu'un vaccin adjuvant puissant (Bacillus Calmette-Guérin) réduit les taux de maladie d'Alzheimer chez les patients atteints de cancer de la vessie.

Ces théories de l'association négative entre la vaccination contre le virus varicelle-zona et la démence, doivent cependant être considérées, aux côtés d'autres théories potentielles. En effet, leurs résultats pourraient provenir d'un biais de sélection. En effet, des effets non spécifiques du vaccin, tels qu'une mortalité plus faible, ont déjà été décrits dans des études de cohorte observationnelles sur l'efficacité du vaccin par Simonsen et ses collègues, qui ont attribué l'association à un « biais de sélection de fragilité ».

Pour contrôler le biais de sélection de la fragilité, les scientifiques des universités d'Édimbourg et de Copenhague ont ajusté la fragilité entre 65 et 70 ans, la résidence en maison de retraite et les multiples maladies qui composent l'indice de comorbidité de Charlson.

Les auteurs ne peuvent exclure avec certitude que les personnes non vaccinées pourraient avoir une espérance de vie en bonne santé plus faible. Cette observation serait étayée par les résultats des études d'efficacité du vaccin pour Zostavax, qui n'ont montré aucune différence significative de mortalité entre les personnes exposées au vaccin et celles exposées à un placebo.

De plus, même si leur population étudiée était importante et représentative de la population galloise, la période de suivi moyenne était plutôt courte, car l'introduction du vaccin dans une campagne nationale a été faite en 2013, qui a donné un temps de suivi maximum d'environ 6 ans (jusqu'à l'âge de 76 ans).

The Risk of Alzheimer's Disease After Acute Appendicitis

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It is well known that approximately 10% cognitively healthy patients undergoing surgery will develop symptoms of cognitive dysfunction after their procedure but will recover quickly. A few percent of them will develop a Parkinson disease. It is known that persistent degree of cognitive impairment will appear in up to 10% of elderly patients up to three months after a surgical procedure. No large studies had studied the impact of surgery and anesthesia on Alzheimer disease.

There is some relation between Parkinson disease and the digestive system. Aggregated alpha synuclein is a pathologic feature of Parkinson’s disease. It has been found in the gastrointestinal tract early in the onset of the Parkinson’s disease. There has been conflicting reports on whether appendectomies increase the risk of Parkinson’s disease. The overall Relative Risk (RR) of developing Parkinson’s disease in patients after appendectomies is usually estimated at a few percent.

The aim of the current study by Chih-Sung Liang, Mu-Hong Chen of National Yang-Ming University, Taipei, was to examine the risk of Alzheimer's disease (AD) and other types of dementia following appendicitis or appendectomy for appendicitis.

The scientists used claims data from the Taiwan National Health Insurance Research Database. Participants aged ≥45 years with acute appendicitis or who received appendectomy for appendicitis were enrolled and followed up for more than 15 years.

Patients developing appendicitis and those receiving appendectomy for appendicitis had higher incidences of Alzheimer disease than the controls during the follow-up period. A Cox regression analysis showed that those patients were more likely to develop Alzheimer disease than the controls.

These patients also had higher risks all types of dementia (but not vascular dementia which is often associated with aging) than the controls. The age at dementia diagnosis was 88.51 years in the controls; however, among people who developed dementia following appendicitis, the mean age at diagnosis was 70.18 years, and dementia occurred 5.84 years after appendicitis.

Alzheimer's disease has a multifactorial etiology. Diet, cardiovascular disease, low grade systemic inflammation have been associated with it. All of these factors have some relationship with the gastrointestinal tract.


This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

The effects of trazodone on human cognition: a systematic review

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Here is an example of systematic review about an anti-depressant which has also putative benefits in human neurodegenerative diseases.

A systematic review are designed to provide an exhaustive summary of current evidence relevant to a research question. This should not be confused with meta-analysis. A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. A key benefit of this approach is the aggregation of information leading to a higher statistical power. 

However most meta-analysis are cheap attempts at publishing without doing real research. Systematic reviews must follow strict protocols. There is no cheap or easy way to do a systematic review. enter image description here.

Although it is FDA-approved only for use in the treatment of major depression, trazodone is widely used off-label to control agitation and insomnia in Alzheimer’s disease (AD) and other diseases. Yet the list of trazodone side-effects is long and some of them are frightening.

Trazodone hydrochloride and dibenzoylmethane were identified by the National Institute of Neurological Disorders and Stroke (NINDS) small-molecule library screening performed on 1040 drugs. Both drugs reversed p-eIF2α mediated translational attenuation and were neuroprotective in two mouse models of neurodegeneration. In prion-diseased mice, both drugs restored memory deficits, abrogated development of neurological signs, prevented neurodegeneration and significantly prolonged survival.

Furthermore, in an animal model of tauopathy-FTD (frontotemporal dementia), these compounds rescued memory deficits and hippocampal atrophy. Finally, both compounds were not toxic to the pancreas.

A common factor in neurodegenerative diseases, and beyond many chronic diseases is a cellular stress response that is abnormally prolonged. The response to this cellular stress (UPR, ISR and others) involves the shutdown of functions that are essential for the proper functioning of the body.

A cell main purpose is to produce proteins. This production is done in several steps: a blueprint is assembled from RNA fragments copied from DNA (a very long molecule). This blueprint is used by ribosomes to produce linear chains of amino acids. Ribosomes are often located in the rough endoplasmic reticulum, probably the most complex organelle in the cell. The endoplasmic reticulum folds this linear chain of amino-acids, thereby giving it new properties and sends it where it is needed.

When there is a cellular stress response, the endoplasmic reticulum stops working, so the newly produced proteins stay in the cytosol where they form protein aggregates named stress granules. Normally this state is of short duration, so quickly the endoplasmic reticulum works again and the stress granules are disposed by the proteolysis mechanism. In a state of stress response, there is hardly any protein production but the protein consumption resulting from metabolism continues, so if the stress response persists a long time the cells become gradually beyond repair and are destroyed by apoptosis.

A drug able to end the anomalous cellular stress response would therefore be very interesting. Indeed it would be valuable only in early phases of the disease, before too much cells died. And canceling completely the UPR mechanism is a bad idea.

UPR acts as a cellular mechanism for the regulation of protein homeostasis when there are misfolded proteins and coordinates this process through three ER transmembrane proteins: PERK, inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6).

Trazodone acts in the PERK branch of the UPR pathway downstream of eIF2α-P, preventing it from reducing levels of the ternary complex, allowing protein translation to occur, restoring neuronal protein synthesis rates, enabling a boost of memory and preventing neurodegeneration in mice models.

In summary of the systematic review, 12 of 16 clinical studies demonstrated a neutral or even a beneficial effect of trazodone on cognitive functions. The majority of these studies demonstrated a positive effect that is possibly not due to the direct effects of trazodone on cognition, but is instead mediated through an improvement in sleep disorders and depressive symptoms.

The results also highlight the possibility of a dose-independent dual effect of trazodone on human cognition, with acute utilization associated with impaired cognitive function and longitudinally long-term use with prevention of cognitive deterioration.

None of the studies evaluated its effects on the UPR pathway, and there was no evidence that trazodone could be used as an active treatment of neurodegenerative diseases itself, although this review suggests that trazodone can be integrated into the therapeutic arsenal in these cases as a safe and well-tolerated adjuvant treatment for dementia comorbidities, with minimal adverse events.


This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

ALS does not have a single cause, on the contrary every case of ALS is probably induced by a combination of factors that will lead to cellular stress. The response to this cellular stress (UPR and others) involves the shutdown of functions that are essential for the proper functioning of the body. Indeed in a state of stress response, there is no more protein production, while the protein consumption resulting from metabolism is continuing, so muscle mass is gradually destroyed.

Scientists know how to chemically or biologically induce conditions similar to ALS in model animals. One of the possibilities is to use β-Methylamino-L-alanine, or BMAA. It is a toxin from a cyanobacterium. Cyanobacteria are well known by the nickname green algae, which can be found in all places where there is stagnant water including maritime bays like that of Morlaix in France, the tidal bore of the Petitcodiac river (where there is currently an epidemic of unknown neurological disease) or aquariums. enter image description here

But toxins are not only found in standing water, they are found everywhere in the natural environment. For example, between 1990 and 2018, 14 cases of amyotrophic lateral sclerosis (ALS) were diagnosed in residents and visitors with a second home in a mountain hamlet in the French Alps. enter image description here (Frederic Coune)

A systematic investigation was then carried out. The official report is quite disappointing. It asserts that it is not possible to hypothesize that there is a link between the cases of ALS observed and a particular risk associated with this place. The report goes on to say, and this is obviously comfortable for the French administration, that there is no specific management measure whose implementation can prevent the onset of this disease.

Recent on-site investigations by Lagrange, Spencer and other colleagues from France and the United States, however, showed that all the patients had ingested wild mushrooms, especially poisonous false morels. Half of these patients had consumed Gyromitra gigas mushrooms.

Consumption of the neurotoxic fungus containing gyromitrin Gyromitra sp. (false morel), has sometimes been implicated in the sporadic genesis of amyotrophic lateral sclerosis.

There are several fungal toxins that can cause organic damage in the human body. Tricholoma equestre may contain myotoxin and repeated ingestion may cause severe rhabdomyolysis. Ingestion of Amanita smithiana and A. proxima causes kidney damage. Gyromitrin, a toxic compound that is converted to hydrazines in the stomach, is present in some species of Gyromitra. It is primarily neurotoxic, but can also induce moderate liver damage and hemolysis.

Gyromitrin is a toxin and carcinogen found in several members of the fungal genus Gyromitra, such as G. esculenta. Poisoning causes nausea, stomach cramps, and diarrhea, while severe poisoning can lead to seizures, jaundice, and even coma or death. The gyromitrin content of false morels is said to be between 40 and 732 milligrams of gyromitrin per kilogram of mushroom (wet weight). The median lethal dose (LD50) of gyromitrin is 30 to 50 mg / kg in humans. That is, in some cases a hundred grams of the fungus would be enough to reach the lethal dose.

Scientists have even shown that high consumption of fresh or dried true morels Morchella spun causes temporary neurological syndrome (SN) with cerebellar signs. For safety, they recommend to avoid consuming real morels or button mushrooms raw or undercooked, fresh or dried.


This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

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