Thursday 26 November 2020

Calcium Folinate (Leucovorin) to Prevent as well as Treat Autism?


Belgium is famous for many things from chocolate and beer to comic books like Tintin.

  Even the Smurfs are from Belgium.


If you want to investigate autism you might need the skills of the most famous fictional Belgian, Hercule Poirot.

Today’s post is about the detective work of Dr Ramaekers from Liège.

Liège is a city in the French-speaking part of Belgium. The northern half of Belgium speak Dutch and southern half speak French. The capital Brussels is officially a bilingual city, but if you do not want to upset an unknown local, the safest language to use is actually English.

Liège used to be a major European centre for steel making.  My elder son tells me that Liège is still famous for making guns.

In 2020 Liège is the European home of Folate receptor antibodies research and more importantly, its treatment.

Outside of Brussels the touristy parts of Belgium include Bruges, Gent and Antwerp, where your French from school is less useful. If you like medieval towns, excellent food and mayonnaise on fries/chips these places are well worth a visit, on a sunny day.   I used to go there on business.

The point of today’s post goes beyond the fact that Dr Ramaekers and Dr Frye have demonstrated that a large sub-group of autism benefit from supplementation with calcium Folinate (Leucovorin).

Ramaekers is looking at Folate Receptor Autoimmunity in the parents, to understand why/how the child developed autism in the first place and then taking the very logical step to prevent future autism.

My elder son is very keen that I master the art/science of preventing future autism, so as to ensure his own children will be neurotypical.

Attempting to prevent future autism will very likely also give some protection against all those "autism-lite conditions", like selective eating, AD(H)D, dyslexia, dyspraxia etc.

At the 2020 Synchrony autism conference, Dr Ramaekers spoke about how several healthy babies have now been born to parents treated with Leucovorin for their Folate Receptor Autoimmunity.  I assume the parents already have at least one child with autism and do not want more.  I thought that was a bold move by Dr Ramaekers. Dr Ramaekers has been publishing research on Folate Receptor Autoimmunity for many years and so I suppose he has the freedom to do this.  In some countries I think you would not be able to do this, or at least talk about it.  Anyway, “dix points Dr Ramaekers”  (ten out of ten).

As with the potential use by mothers of the antioxidant NAC during pregnancy, the mode of action is epigenetic and preventing differentially expressed genes (DEGs), or just call them miss-expressed genes.

In Dr Ramaeker's case he does have a biomarker to identify parents likely to benefit from his autism prevention strategy.  He uses the FRα autoantibody test and so could you.

I have been having an interesting public discussion with Dr Ramaeker's on the online app used for the Synchrony 2020 autism conference. The key point arising is that you can avoid the side effects of using Leucovorin (Calcium Folinate) by slowing increasing the dosage over several weeks.  Here is the relevant part:-

You had one naughty remark concerning the Use of folinic acid causing agression. My response is that folinic acid will increase the production of BH4 which will suddenly increase the synaptic levels of dopamine AND serotonin AND cause temporarily overstimulation of downregulated dopamine AND serotonin receptors. After about 6 weeks will settle down as a new equilibrium will be installeer. So I begin with low dosage folinic acid AND slowly increase at interval of 4 weeks.It was a wonderfull overview about your sons history.

For anyone interested to watch my Bumetanide presentation, that Dr Ramaekers, AJ and Lisa  seem to have enjoyed, here is a link.

The paper by Dr Ramaekers below is open access and many people will find it interesting to read the entire paper.  Just skip over any parts that get too complicated.


Improving Outcome in Infantile Autism with Folate Receptor Autoimmunity and Nutritional Derangements: A Self-Controlled Trial

Background. In contrast to multiple rare monogenetic abnormalities, a common biomarker among children with infantile autism and their parents is the discovery of serum autoantibodies directed to the folate receptor alpha (FRα) localized at blood-brain and placental barriers, impairing physiologic folate transfer to the brain and fetus. Since outcome after behavioral intervention remains poor, a trial was designed to treat folate receptor alpha (FRα) autoimmunity combined with correction of deficient nutrients due to abnormal feeding habits. 

Methods. All participants with nonsyndromic infantile autism underwent a routine protocol measuring CBC, iron, vitamins, coenzyme Q10, metals, and trace elements. Serum FRα autoantibodies were assessed in patients, their parents, and healthy controls. A self-controlled therapeutic trial treated nutritional derangements with addition of high-dose folinic acid if FRα autoantibodies tested positive. The Childhood Autism Rating Scale (CARS) monitored at baseline and following 2 years of treatment was compared to the CARS of untreated autistic children serving as a reference. 

Results. In this self-controlled trial (82 children; mean age ± SD: 4.4 ± 2.3 years; male:female ratio: 4.8:1), FRα autoantibodies were found in 75.6 % of the children, 34.1 % of mothers, and 29.4 % of fathers versus 3.3 % in healthy controls. Compared to untreated patients with autism (n=84) whose CARS score remained unchanged, a 2-year treatment decreased the initial CARS score from severe (mean ± SD: 41.34 ± 6.47) to moderate or mild autism (mean ± SD: 34.35 ± 6.25; paired t-test p<0.0001), achieving complete recovery in 17/82 children (20.7 %). Prognosis became less favorable with the finding of higher FRα autoantibody titers, positive maternal FRα autoantibodies, or FRα antibodies in both parents. 

Conclusions. Correction of nutritional deficiencies combined with high-dose folinic acid improved outcome for autism, although the trend of a poor prognosis due to maternal FRα antibodies or FRα antibodies in both parents may warrant folinic acid intervention before conception and during pregnancy.



The treatment protocol for the self-controlled treatment trial based upon abnormal biochemical findings and FRα autoantibodies.

Abnormal biomarker

Daily oral supplement dosage

Zinc deficiency

0.15-0.25 mg/kg zinc-sulfate

Selenium deficiency

3-5 µg/kg sodium-selenite

Manganese deficiency

5-10 mg/kg Vitamin C, 20 IU/kg Vitamine E, with 1 coffespoon Soya oil at night.

Manganese excess


Heavy metal excess (Cu, Al, Hg, Pb)


Raised copper/zinc ratio


Bèta-carotene excess

idem; limit foods rich in bèta-carotene

Vitamin A deficiency

600-1500 µg

Vitamin D (25-hydroxy-D)

10 µg or 400 IU

Vitamin C deficiency

5-10 mg/kg Vitamine C (maximal 500mg)

Ubiquinon-10 deficiency

2 mg/kg co-enzyme Q10

Vitamin E deficiency

20 IU/kg

Gamma-Tocopherole deficiency

1 coffeespoon soya, corn or sesame oil

Bèta-carotene deficiency

Consume tomato or carot juices

Serum folate deficiency

0.5 mg/kg folinic acid

RBC folate deficiency

0.5 mg/kg folinic acid

Apolipoproteine B deficiency

Supplement vitamins A D E, and vitamine K in case of secondary coagulation disorder

FR-alpha antibodies

Start with 0.5-1 mg/kg folinic acid daily;

Increase to 2 mg/kg daily without a clinical response after six months. Maximum daily dose 50 mg.



In the study they used the CARS rating scale to measure the severity of autism.

A score 30 and above 30 means autism.  37 and above means severe autism.

The results do look good.  This was not a study with a placebo group for comparison.

Blue is before therapy and orange is after therapy.



The upper figure (a) shows the plotted CARS with age for 84 untreated patients. The middle figure (b) shows the effect of treatment among 82 treated patients (blue bars represent CARS at baseline and orange bars the CARS after two years treatment). Figure (c) represents the treatment results among different groups with FR autoantibodies in the child (K), mother (M), or father (P).



Our self-controlled treatment trial showed that the presence of maternal FRα autoantibodies or FRα antibodies in both parents tended to be associated with a higher initial baseline CARS score among affected children with autism. Thus, this may explain that the final result and change in CARS score following 2-year treatment was less pronounced as compared to all other groups, although the small number of patients within each group did not allow a profound statistical analysis. These issues will be clarified when more patients will be included into similar treatment trials. Our findings in a minority of 7 out of 68 families (10%) identified no FRα autoantibodies in the children whereas FRα antibodies could only be detected in the mother (N=5), father (N=1), or both parents (N=1). Although feeding and nutrient problems for each child have to be taken into account, this finding suggests that parental FRα antibodies may impair folate transport into oocytes and spermatozoides and also block sufficient folate transport across the placental barrier to the embryo and fetus. Because an adequate folate pool is essential for purine and pyrimidine synthesis, and for mediating epigenetic mechanisms involving DNA methylation and histone modification, the initial embryonic development and subsequent stages of neurodevelopment will rely heavily on availability of adequate folate. Therefore, the risk of autism with its poor prognosis in the offspring associated with parental FRα antibodies warrants FRα testing among future parents followed by folinic acid intervention before conception and during pregnancy.

The common feeding disturbances associated with autism may provoke oxidative stress due to altered nutritional states where elevated metals (copper, manganese) or beta-carotene act as prooxidants through induction of Fenton chemistry. Nutritional deficiencies of radical scavenging vitamins (vitamins A, C, E, and gamma-tocopherol) as well as metals and trace elements (copper, zinc, manganese, and selenium), being cofactors of antioxidative enzymes, predispose to failing antioxidant defences. Moderate apolipoprotein B deficiency has been encountered in a significant number of autistic subjects and leads to deficient liposoluble vitamins A, D, E, and K. Deficiency of a number of vitamins and coenzyme Q10 necessary for mitochondrial metabolism, will result in mitochondrial dysfunction. Thus, oxidative stress in the brain due to mitochondrial dysfunction, elevated prooxidants, or deficient antioxidants on the one hand and FRα autoimmunity on the other hand, represent two independent variables at the basis of autism where correction of each variable showed a clinical response with a decline in the CARS score. Therefore, in addition to treatment for FRα autoimmunity [9, 10, 29], specific supplements are required to correct nutritional deficiencies in order to ameliorate intermediary metabolism and to neutralize abundant reactive oxygen species (ROS) deranging brain metabolism and function. As stated above, it appears from our findings in this study that the group of patients, where FRα antibodies tested negative in the child and its parents, benefitted only through correction of nutritional derangements as their CARS score dropped significantly.

In our study we also detected deficiencies of serum and red blood cell folate in 18.3 % of all patients. In vitro studies have supported the concept of an existing link between oxidative stress and deranged folate homeostasis. In a previous study we found that the generation of superoxide anions in vitro catabolizes 5-methyl-tetrahydrofolate by 75% within one hour, which can be prevented through preincubation with the radical scavenger ascorbic acid [26]. This study also found that KB-cells in culture exposed to superoxide anions and hydrogen peroxide reduces cellular folate incorporation mediated by FRα or RFC1 transport mechanisms. Thus transmembrane folate passage mediated by these transporters at the placenta and choroid plexus is expected to be impaired in the presence of ROS and predisposes to intrauterine folate deficiency and cerebral folate deficiency.

The consequences of folate deficiency affecting brain development may be more prominent in autistic children from mothers with folate deficiency or the presence of maternal FRα autoantibodies during pregnancy. Our finding of a higher initial baseline CARS score and less favorable outcome in these children confirms this hypothesis. In summary, the treatment response will be influenced in a negative fashion by the presence of maternal FRα autoantibodies, by late-onset treatment associated with a higher initial CARS score and in the event of elevated antibody titers. Paternal FRα antibodies may also influence the outcome and need to be further investigated, because we only identified one family.


5. Conclusion

In the pathogenesis of low-functioning autism, feeding disturbances predisposing to oxidative stress and acquisition of folate receptor autoantibodies during the pre- or postnatal period appear to play an important role by affecting intermediary metabolism and potentially deranging epigenetic control mechanisms. Early detection and appropriate therapeutic intervention is postulated to reverse core features and improve outcome.




Today’s paper showed several interesting things:- 

·        Correcting the effects of very poor diet can have a dramatic benefit on autism, regardless of folate status.

·        Folate receptor problems are very common in autism.  FRα autoantibodies were found in three quarters of children with autism and a third of their mothers and fathers, versus just 3 % in healthy controls.

·        A trial of Calcium Folinate (Leucovorin) for anyone with autism looks like a “no-brainer” but, as Dr Ramaekers cautions, mega dose folate might be unwise in the 25% of autism who do not have FRα autoantibodies.  

Note that in the study, prognosis became less favorable with the finding of higher FRα autoantibody levels, maternal FRα autoantibodies, or FRα antibodies in both parents.

·        Couples/parents who want (more) children, but want to avoid autism, should consider first taking the FRα autoantibody test

if you get a positive result, you might contact our man in Liège.

·       Generic Calcium Folinate (Leucovorin) is cheap in most of the world.  As usual, the exception is the United States. 

     I will have to write a post on prenatal bumetanide to prevent autism. Dr Ben Ari did mention again at the Synchrony event the potential for this therapy.  It seems that the oxytocin released by the mother during delivery not only helps to trigger the developmental GABA switch that forces neurons to transition from immature to mature over the first couple of weeks after birth, but it also causes a one time shock reduction in chloride during delivery (this shock may indeeed be the GABA switch trigger).  It seems that the fragile brain is given protection during delivery, with GABA switching from the fetal excitatory state to one of extreme inhibition, just for birthing.  This protective sudden drop in chloride levels does not occur in autism models and likely not in human autism either. The logic would be to give the mother bumetanide for 2 weeks before her delivery date.  This would protect the baby's brain during birth and hopefully help ensure the GABA switch occurs and the child develops normally.




Saturday 14 November 2020

Averting Autism - Antenatal Antioxidants? But Male, Female or Both?


 Salem College


Today’s post is the first of two new ones about preventing/minimizing future autism.  The second post will be about Dr Ramaekers’ idea of using Calcium Folinate, which he has already put into use in human parents seeking to avoid autism in their next child. 

Before we start, I should point out that while readers of this blog, and it seems Dr Ramaekers, likely wish that autism and its symptoms did not exist, there are some people, well paid to research autism, who think autism is a good thing. I really do wonder why such people receive any public funding and wonder what kind of University would employ such people. It is like researching deafness, but not wanting to treat it - better they stay home.

Simon Baron-Cohen, PhD, Director of the Autism Research Centre at Cambridge, who co-led the study, added, "Some people may be worried that basic research into differences in the autistic and typical brain prenatally may be intended to 'prevent,' 'eradicate,' or 'cure' autism. This is not our motivation, and we are outspoken in our values in standing up against eugenics and in valuing neurodiversity. Such studies will lead to a better understanding of brain development in both autistic and typical individuals."

Even more odd is that Baron-Cohen's sister had a rare mutation of the GNAQ gene that led to intellectual disability and a reduced lifespan. Why would you not want to treat/prevent that?  Treating your sister would not have meant you did not value her, it would have been another sign that you loved her. 

A positive example is another autism researcher, Manuel Casanova, and his family, who set up a research effort for people who have a disorder related to the gene NGLY1.  Sadly, Manuel's grandson passed away, but the research goes on.   

If you can escape from intellectual disability, someone should make it happen.  That someone might be you.


I must admit I had never heard of Salem College.  It is an all-female college in Winston-Salem, North Carolina.  It is the source of another idea to avert autism, this time treating the future father with an anti-oxidant like NAC.  NAC was already on my list for future mothers.  When it comes to autism, it looks like little Salem College is going to be more useful than stuffy old Cambridge University.

I am rather surprised there still are all female colleges, but in the US, there are many.

My mother went to an all-female college at Cambridge University, back then they had no mixed colleges.  Only after 1948 could women even receive a degree at the end of their studies. Cambridge University still has three all-female colleges.

Clearly male post-conception antioxidant supplementation is not going to help.

We have already seen in the research that the future father can damage the DNA he passes on to his offspring.  This was done via epigenetic tags on his DNA caused by things like recreational drug use, or smoking tobacco.

The author of today’s paper look’s exclusively at autism risk from the father, but exactly the same therapy during pregnancy can reduce risk from the mother.  The maternal immune activation model is one of the most studied in autism. We also know that emotional stress during pregnancy increases autism risk.  Emotional stress leads to oxidative stress.

The only issue I had with this preventative approach is whether there are any negative effects from antioxidants during pregnancy.  There may well be none, since the body just adjusts production of its own antioxidants.

There was an interesting experiment I mentioned a while back about giving antioxidant or “detox” juices to healthy young people.  The anti-oxidants from the fruits just made the body reduce its own production of GSH/glutathione, so the net result of the detox juice was actually negative.  People in oxidative stress benefit from anti-oxidant therapy, everyone else is wasting their money.

There are highly conflicting reports as to whether autism tends to come from the mother’s half of the child’s DNA or from the father’s half.  In reality it does not matter, it can from either, both or neither.  What is important is to take whatever simple safe steps you can to avert future autism. 

Future parents taking NAC and Calcium Folinate, might as well join the idea of keeping pets at home during pregnancy to get exposure to the evolutionarily expected bacteria that are needed to calibrate the immune system of the fetus/baby. Humans have been living with dogs, and very importantly their bacteria, for 11,000 years.  Only very recently did humans come up with the idea of trying to kill 99.9% of bacteria in their homes. 

Dogs are humans' oldest companions, DNA shows

I really do not see anyone doing a placebo controlled clinical trial on any of this.  Nobody who agrees to participate will accept the risk of being in the placebo group.  You would have to create a control group out of people who did not want to join the trial.  The people who join the trial are self-selected and are more likely to be health conscious, or have a family history of autism or dys-something else.

Male preconception antioxidant supplementation may lower autism risk: a call for studies

Current research indicates that a sizable number of autism spectrum disorder (ASD) cases arise from de novo mutations (DNMs) occurring within the paternal germline, usually in an age-dependent manner. Andrologists have reported that somatic cells and gametes share the same pathologies that generate these DNMs—specifically, DNA hypomethylation caused by oxidative nucleoside base damage. Because many ASD researchers seek to identify genetic risk factors, teams are developing methods of assessing aberrant DNA patterns, such as parental gonadal mosaicism. Several studies propose antioxidant supplementation as a strategy to lower autism risk, and/or suggest connections between childhood neurodevelopmental disorders such as autism and paternally-derived DNMs. Actual data, however, are currently not available to determine whether male preconception antioxidant supplementation effectively lowers autism risk. The purpose of this paper is to (1) explore the mechanisms causing DNMs, specifically DNA hypomethylation; (2) explain how antioxidant supplementation may lower the risk of having a child with ASD; and, (3) advocate for the implementation of large prospective studies testing (2). These studies may very well find that male preconception supplementation with antioxidants prevents neurodevelopmental disorders in offspring, in much the same way that female prenatal consumption of folate was found to decrease the risk of birth defects. If this is indeed the case, the alarming rise in autism prevalence rates of the past few decades will slow—or even cease—upon the initiation of public awareness campaigns.


Antenatal antioxidants to avert autism?

Paternally derived de novo mutations (DNMs) caused by oxidative stress (OS) have been implicated in the development of autism spectrum disorders (ASDs). Whether preconception antioxidant supplementation can reduce the incidence of ASDs by reducing OS is an area of uncertainty and potentially important future scientific investigation.

The recently completed double blind, multicenter, randomized controlled Males, Antioxidants, and Infertility (MOXI) trial by the Reproductive Medicine Network (RMN), funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), investigated whether antioxidants improve male fertility, as measured by semen parameters and sperm DNA integrity at 3 months and pregnancy by 6 months of treatment [11]. The RMN investigators found that antioxidant treatment of the male partner does not improve semen parameters, sperm DNA integrity, or in vivo pregnancy rates in couples with male factor infertility, prompting the question whether antioxidant therapy should no longer be routinely recommended for infertile men [12]. It would be intriguing to evaluate the offspring from the participant couples of the MOXI trial for ASD. However, with only 13 live births in the antioxidant group and 21 live births in the placebo arm, the study would be vastly underpowered to demonstrate a benefit of antioxidants in the prevention of a condition with an incidence of 1 in 54 children.

The next post is about Dr Ramaeker's clinical trial of calcium folinate in children with autism and his comments about their parents and future siblings.


Thursday 5 November 2020

Lethargy and Autism


That alternative world, where you fix things when they are not working

I do sometimes forget the world that most people live in, when it comes to (not) understanding and (not) treating autism.

I decided to write this post on lethargy and autism, after being prompted by a friend who contacted me and told me that his son with autism is very lethargic (physically and mentally). I replied with the suggestion that he try a little scoop of Agmatine Sulphate.  Now his son is able to go for long walks, without constantly wanting to stop for a rest.  The Dad asked me to share his positive experience with Agmatine.

A few years ago, this boy was diagnosed by Dr Kelley with mitochondrial dysfunction.  People with mitochondrial dysfunction should indeed have poor exercise endurance, this is because they lack the enzymes needed in a process called oxidative phosphorylation (OXPHOS).  OXPHOS is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing the chemical energy in the form of ATP.  If you run low on ATP you need to sit and take a rest.

You can run low on ATP for reasons other than a lack of these mitochondrial enzyme complexes. You also need enough glucose and oxygen.

Agmatine has numerous modes of action.  It affects the following (and more): -

·         Neurotransmitter receptors and receptor ionophores. Nicotinic, imidazoline I1 and I2, α2-adrenergic, glutamate NMDAr, and serotonin 5-HT2A and 5HT-3 receptors.

·         Ion channels. Including: ATP-sensitive K+ channels, voltage-gated Ca2+ channels, and acid-sensing ion channels (ASICs).

·         Membrane transporters. Agmatine specific-selective uptake sites, organic cation transporters (mostly OCT2 subtype), extraneuronal monoamine transporters (ENT), polyamine transporters, and mitochondrial agmatine specific-selective transport system.

·         Nitric oxide (NO) synthesis modulation. Both differential inhibition and activation of NO synthase (NOS) isoforms is reported.[9][10]

·         Polyamine metabolism. Agmatine is a precursor for polyamine synthesis, competitive inhibitor of polyamine transport, inducer of spermidine/spermine acetyltransferase (SSAT), and inducer of antizyme.

·         Protein ADP-ribosylation. Inhibition of protein arginine ADP-ribosylation.

·         Matrix metalloproteases (MMPs). Indirect down-regulation of the enzymes MMP 2 and 9.

·         Advanced glycation end product (AGE) formation. Direct blockade of AGEs formation.

·         NADPH oxidase. Activation of the enzyme leading to H2O2 production.[11]


I did make the chart below a couple of years ago to figure out why Agmatine would give such an energy boost, and see how all these substances fit in with each other.  My conclusion was that an increase in endothelial nitric oxide was a plausible explanation, since the effect is fast.

Agmatine increases the enzyme eNOS which the leads to nitic oxide (NO) being produced in endothelial cells, this triggers a series of steps that results in vascular relaxation, which means more blood flow.

More blood flow means more glucose and oxygen to fuel mitochondria to make ATP.


When I did a quick Google search for “Lethargy and Autism”, I was surprised to find an entirely different explanation from the “old world”, where autism is still untreatable, at the UK’s National Autistic Society.


Autistic fatigue - a guide for parents and carers

Exhaustion (fatigue) and then burnout can happen to anybody. Being autistic can make fatigue and burnout more likely, due to the pressures of social situations and sensory overload. If your child or the person you care for is experiencing fatigue or burnout, helping them to manage their energy levels is essential, as this guide explains. 

There are various things that can cause autistic fatigue. Autistic adults suggest several causes, including: 

·        sensory overload 

·        dealing with social situations 

·        masking or camouflaging their autistic traits

·        suppressing stimming 

·        a sense of not meeting other people’s/society’s expectations of them.

Changes in your routines or day-to-day life, such as a change of school or job, can increase anxiety and can be additional causes for autistic fatigue and burnout.


What can I do if the person I care for is experiencing autistic fatigue and burnout?

Use energy accounting

Energy accounting is a system used to set manageable limits on your energy levels so you do not deplete yourself to the point of burnout. 

Help your child or the person you care for to set a limit on how much energy they have in a day or week and estimate how much certain activities drain them. Also work out how much certain activities energise them. 

You can then try to plan and balance their activities and energy over a day or week to try and manage stress limits. Make sure you build in time for relaxation and recovery. 


Time off and rest/relaxation

Whether you use energy accounting or not, time off from work or school and other high-stress activities is key to managing stress levels. Ensuring time for activities/interests that re-energise and promote relaxation is key. This could be connecting with family and friends or enjoying hobbies or interests. 


Time without having to mask

Autistic people often feel the need to hide or mask their autistic traits in public, for example by suppressing the urge to stim. It can be important to factor times into your child’s day for things like stimming, somewhere they feel comfortable and able to do so.



Lethargy with autism in this blog is a biologically treatable condition.

Taking time off to rest is not a cure for lethargy, it is just a coping strategy.

Why just cope, when you can live to your full potential?

The bunny managed to figure this out. (fit alkaline batteries)


You would think that hyperactivity would be more often a problem than lethargy in those with autism, but that is another story.