Hyperlysinemia is an autosomal recessive inborn error of L-lysine degradation. To date only one causal mutation in the AASS gene encoding α-aminoadipic semialdehyde synthase has been reported. We aimed to better define the genetic basis of hyperlysinemia.
We collected the clinical, biochemical and molecular data in a cohort of 8 hyperlysinemia patients with distinct neurological features.
We found novel causal mutations in AASS in all affected individuals, including 4 missense mutations, 2 deletions and 1 duplication. In two patients originating from one family, the hyperlysinemia was caused by a contiguous gene deletion syndrome affecting AASS and PTPRZ1.
Hyperlysinemia is caused by mutations in AASS. As hyperlysinemia is generally considered a benign metabolic variant, the more severe neurological disease course in two patients with a contiguous deletion syndrome may be explained by the additional loss of PTPRZ1. Our findings illustrate the importance of detailed biochemical and genetic studies in any hyperlysinemia patient.
Hyperlysinemia is an autosomal recessive inborn error of metabolism caused by a defect in the major catabolic pathway of the essential amino acid L-lysine. This pathway is primarily active in the liver and leads to the production of acetyl-CoA (Figure 1A). In the first step, lysine and α-ketoglutarate are converted into saccharopine by lysine-ketoglutarate reductase (LKR, EC 1.5.1.8). Saccharopine is then oxidized to α-aminoadipic semialdehyde and glutamate by saccharopine dehydrogenase (SDH, EC 1.5.1.9). In animals, but also other eukaryotes, both enzyme activities are catalyzed by a single mitochondrial bifunctional enzyme named α-aminoadipic semialdehyde synthase , which is encoded by the gene AASS. One mutation in AASS has been reported to cause hyperlysinemia (c.1601_1609del; p.C534X ).
Molecular and biochemical studies in hyperlysinemia patients. (A) Schematic representation of the lysine degradation pathway. Lysine can be degraded via two pathways. The pathway with L-pipecolic acid as an intermediate operates in brain and starts with oxidative deamination. The main pathway in other organs, however, proceeds via deamination with saccharopine as an intermediate. All genes known to operate in this pathway are indicated. ALDH7A1 is deficient in children with pyridoxine-dependent seizures . GCDH is deficient in glutaric aciduria type 1 . The intermediate 2-oxoadipate is metabolized by 2-oxoadipate dehydrogenase, resembling the TCA cycle enzyme complex 2-oxoglutarate dehydrogenase. The E1 subunit of this complex is encoded by DHTKD1 and is deficient in 2-aminoadipic and 2-oxoadipic aciduria . (B) Immunoblot analysis of fibroblast homogenates of hyperlysinemia cases. Cell lysates of 2 control subjects and hyperlysinemia cases were resolved by SDS-PAGE (30 μg of protein) blotted onto nitrocellulose and analyzed with a polyclonal antibody against AASS. (C) Relative expression levels of AASS in fibroblasts determined using qPCR with a primer sets specific for the 5′ (R) and 3′ (S) part of the cDNA. Average and SD are provided for 3 control fibroblasts. ND denotes not detectable. Expression was normalized to the level of cyclophilin B (PPIB). (D) Electropherogram showing that the heterozygous c.460G>A mutation in patient 5 appears homozygous at the cDNA level, indicating nonsense mediated decay of the other allele (c.2076dup).
Hyperlysinemia is characterized by elevated plasma lysine levels that exceed 600 μmol/L and can reach up to 2000 μmol/L (adult reference range 111–248 μmol/L) [6–9]. Cases in which the plasma lysine levels are elevated, but remain below 600 μmol/L, are often caused by decreased availability of α-ketoglutarate , which occurs in urea cycle disorders, pyruvate carboxylase deficiency, methylmalonic aciduria and propionic aciduria. As a consequence of the accumulating lysine, several alternative biochemical reactions take place. Lysine can be used in place of ornithine in the urea cycle resulting in the production of homoarginine . In addition, N-ε-acetyl-L-lysine, N-α-acetyl-L-lysine and pipecolic acid (Figure 1A) accumulate as a result of the use of alternative or detoxifying biochemical pathways [11, 12]. Hyperlysinemic individuals may also have saccharopinuria, when the SDH is deficient in combination with a preserved LKR activity (also known as hyperlysinemia type 2 ).
Although hyperlysinemia was initially associated with neurological damage and mental retardation, later reports questioned this relationship. This was mainly based on a review of 10 individuals identified with hyperlysinemia in newborn screening programs (4 cases), family surveys of a previously diagnosed case (4 cases) and during the investigation of a boy and his family for short stature (2 cases). Cases were rejected if the hyperlysinemia was diagnosed during investigation of a patient presenting with a neurological or intellectual impairment. In none of the identified 10 cases adverse effects could be attributed to hyperlysinemia . Furthermore, it is unclear whether dietary restriction of lysine is beneficial [11, 15], and a child with no clinical manifestations of hyperlysinemia has been born to an affected mother . These observations indicate that hyperlysinemia most likely represents a benign metabolic variant and illustrates that the association of nonspecific clinical signs and symptoms with biochemical abnormalities can be coincidental. Indeed it is currently unknown whether lysine or lysine-derived metabolites are toxic. In vitro, high concentrations of lysine (5 mM) induced oxidative damage to proteins and lipids, decreased oxidized glutathione and inhibited cytosolic creatine kinase activity [16, 17]. Intrastriatal injection of lysine in rats did not affect creatine kinase, but inhibited synaptic Na+,K+-ATPase activity, induced lipid peroxidation and decreased glutathione level . It is currently unclear how these findings can be related to clinical manifestations in patients with hyperlysinemia.
Despite this, biochemical diagnoses of hyperlysinemia are still made. Moreover, exome and whole genome sequencing projects are expected to identify variants in the AASS gene of unknown significance. To better define the genetic basis of hyperlysinemia, we collected clinical findings, and biochemical and molecular data in a cohort of 8 patients with distinct neurological features and hyperlysinemia.
The hyperlysinemia patients described here (Table 1) were collected over the years and material was sent to a laboratory for metabolic screening and confirmatory testing. In most cases, patients displayed neurological symptoms for which a metabolic cause was suspected or had to be excluded. The studies described in this report have been performed as part of patient care and according to Dutch law do not need additional approval of a medical ethical committee if used for retrospective anonymous evaluation.
Case 1 is the first child of non-consanguineous parents. He presented at age 6 months with psychomotor retardation and failure to thrive with vomiting due to severe gastro oesophageal reflux. In addition, there were craniosynostosis, microcephaly, a slightly dysmorphic face, and early development of spastic diplegia rapidly progressing to tetraparesis. Diagnosis of hyperlysinemia was established following the detection of elevated pipecolic acid. At age 4 years, motor development was severely retarded with inability to sit or stand. At this age, treatment with botulinum toxin was started and continued since then. Under this treatment, the patient learned to stand up and walk single steps with support. His expressive speech development is also largely retarded and he communicates with sign language. The EEG in this patient was normal as was the brain MR imaging at an age of 4 years. He is now 8 years old and severely affected by global retardation, spastic tetraparesis and microcephaly.
Case 2 is the younger brother of case 1 and showed a similar but less severe clinical course. At age 2 years, he walked on tiptoes as the first sign of a cerebral movement disorder. Treatment with botulinum toxin injections was started at the age of 4 years supporting the motor development. Currently at 7 years of age, the patient is able to walk and he can speak in full sentences. As in his older brother, the patient was affected by failure to thrive. Both brothers were treated with a lysine restricted diet, however, without any obvious benefit.
Case 3 is a boy of consanguineous parents (first degree cousins). He had an epileptic event during fever at the age of 6 months and was treated with anti-epileptic drugs for 2 months. From the age of 3 years developmental delay with spastic diplegia and behavioral disturbances became apparent. Magnetic resonance imaging (MRI) of the brain was normal. At the age of 4.5 years there was one single epileptic event without fever. A healthy sister did not have hyperlysinemia.
Case 4 is the third child of healthy consanguineous parents (first degree cousins). In two older healthy siblings hyperlysinemia was excluded. He came to clinical attention at the age of 10 months because of mild psychomotor retardation. Screening for urinary amino acids showed highly elevated lysine (7307 mmol/mol creatinine) in the absence of saccharopinuria. On physical examination, he displayed muscular hypotonia with brisk tendon reflexes. An EEG was normal. The patient was treated for three years with a strict low protein diet but this was relaxed and eventually stopped at age 5 years without obvious disadvantage to the neurological status. Currently at an age of 10 years, cognition is borderline normal with a debatable need for special education such as speech therapy and occupational and physiotherapy. The neurological examination including the muscle tone is normal.
Case 5 is the younger sister of a previously reported affected boy . Both were diagnosed with epilepsy, intellectual disability and behavioral problems. The third child in this sibship was healthy and had normal lysine levels. The patient came to the attention of a child neurologist at the age of two years because of seizures. Her EEG was abnormal with epileptic changes. A CT at the age of 18 showed widened ventricles. Several seizures were observed during childhood which responded well to standard anti-epileptic medication (valproate, carbamazepine). Her intelligence was low normal (IQ 86), but she was referred to an institution because of behavioral problems.
The patient had recurrent pneumonias as a result of atelectasis of the left lung due to a congenital hypoplasia of the left pulmonary artery. The left lung was surgically removed at the age of five. The pulmonary problems never resolved completely; at the age of 19, following influenza vaccination, she again developed a severe pneumonia and as a consequence of this a chronic polyneuropathy became manifest. Her physical inabilities at this stage necessitated admission to a rehabilitation center. After this episode, she was lost for follow-up.
Case 6 is a boy diagnosed with intellectual and motor disability of unknown cause. His development was impaired in all areas; motor development, language, and behavior. He was hyperactive and restless, but with little regulation. Attention deficit disorder was not excluded. He had strabism, microcephaly, small stigmata, thin eyebrows, a flat philtrum and a flat nose, but no syndrome could be attributed. Prenatal exposure of the child to toxic compounds was suspected. The child has been under the care of the youth welfare service since birth and was placed with foster parents before he was ten months old. It was the intention to let the child attend a kindergarten with special support. Urine lysine values were 2386–3196 mmol/mol creatinine. Saccharopine was noted in urine (11.0 mmol/mol creatinine) and serum (3.5 μmol/L).
Case 7 is a boy of consanguineous parents (first degree relatives). The first child of the parents was a healthy male. The patient was born after an uneventful pregnancy and delivery at 38 weeks of gestation. Birth weight and length were normal, but head circumference was 34 cm (< 5 p). He had no spontaneous breathing after birth and was admitted to the neonatal intensive care unit with seizures, respiratory difficulties, hypotonia, and bradycardia at 2 days of life. Physical examination revealed a prominent hypotonia, mild dehydration, increased deep tendon reflexes, absence of sucking, Moro, and grasping reflexes. He had dysmorphic features such as microcephaly, an underdeveloped antihelix and helix, hypotelorism and a high arched palate. Cranial MRI showed a subacute haemorrhage in the 4th and lateral ventricles, a mild subdural haemorrhage in the occipital lobe and haemorrhages in sinus transversus and sagittalis superior. The patient was diagnosed with hyperlysinemia and started a special diet containing 50 mg/kg/day lysine including 2–25 g/kg/day protein and 140–150 kcal/kg/day energy and was given antiepileptic drugs including phenobarbital. He had feeding and swallowing dysfunction and was fed with a nasogastric tube. Severe spasticity and opisthotonic posturing developed in the follow up period. Unfortunately, the patient did not respond to treatment and no improvement in his signs and symptoms occurred and he died at 6 months of age.
Case 8 was born as the first child of consanguineous parents with a birth weight of 2800 g after an uneventful pregnancy at 38 weeks. His twin died at 3 days of life due to pulmonary hemorrhage. He was the cousin of case 7. Pneumonia and convulsions of generalized tonic type manifested on the second day of life. During the follow up in a local hospital for 2 months he was treated with phenobarbital. At 16 months of age, the patient was referred to the metabolic unit. Physical examination revealed microcephaly, an enlarged right ear, a high palate, psychomotor retardation, increased deep tendon reflexes, and decreased subcutaneous fat tissue. The patient did have head control but could not sit with or without support. A brain MRI was normal. His diet contained protein and calories appropriate for his age and weight. At 4.5 years the boy was spastic and could sit with support for a short time. He is 13 years old now and seizures were controlled with anticonvulsants.
Primary skin fibroblasts from patients and controls were cultured in DMEM medium with 4.5 g/L glucose and L-glutamine (Lonza) supplemented with 10% fetal bovine serum (Lonza), 100 U/mL penicillin, 100 μg/mL streptomycin, fungizone (Life Technologies) and 25mM Hepes in a humidified atmosphere of 5% CO2 at 37°C.
Fibroblast pellets were resuspended in PBS and homogenized by sonication (twice on ice, 40J at 8W output). LKR was assayed spectrophotometrically at 340 nm by measuring the oxidation of NADPH. The reaction mixture contained 50 mM HEPES pH7.4, 10 mM α-ketoglutarate, 0.3 mM NADPH and 0.25% Triton X-100. The reaction was started with L-lysine (15 mM final concentration). SDH was assayed spectrophotometrically at 340 nm by measuring the formation of NADH. The reaction mixture contained 50 mM tricine pH8.5, 5 mM NAD and 0.1% Triton X-100. The reaction was initiated by adding saccharopine to a final concentration of 3.5 mM (stock solution of 35 mM in 100 mM tricine, pH 8.0). Both assays were performed kinetically on a COBAS FARA II centrifugal laboratory analyzer (Roche).
All exons, plus flanking intronic sequences of the AASS gene (NM_005763), were sequenced after amplification by PCR from genomic DNA. All forward and reverse primers (Sets A to Q, Table 2) were tagged with a –21M13 or M13rev sequence, respectively. PCR fragments were sequenced in two directions using –21M13 and M13rev primers by means of BigDye Terminator Cycle Sequencing (v1.1, Applied Biosystems, Foster City, CA) and analyzed on an Applied Biosystems 3130xl or 3730xl DNA analyzer.
1All forward and reverse primers were tagged with a –21M13 (5′-TGTAAAACGACGGCCAGT-3′) sequence or M13rev (5′-CAGGAAACAGCTATGACC-3′) sequence.
RNA was isolated from fibroblast pellets using Trizol extraction. cDNA was synthesized by using the Superscript II Reverse Transcriptase Kit (Invitrogen, Carlsbad, CA, USA). Quantitative real-time PCR analysis of AASS expression in fibroblasts was performed using the LC480 Sybr Green I Master mix (Roche) and primer sets R and S to amplify the 5′ and 3′ part of the AASS cDNA, respectively. In patient 1, 2 and 5 the complete AASS cDNA was amplified and sequenced using primer sets T and U (Table 2).
Comparative genomic hybridization (CGH) was performed using an Agilent 180K oligo-array (Amadid 023363, Agilent technologies Inc, Santa Clara, CA, USA) as described before . All genome coordinates mentioned are according to human genome build 19.
Fibroblast homogenates were prepared in PBS using sonication (twice on ice, 40J at 8W output). Samples were further prepared according to the instructions for electrophoresis of NuPAGE Bis-Tris mini gels (4–12%; Life Technologies) using sample buffer for denaturation and reduction of the protein disulfide bonds. Equal amounts of protein (30 μg) were loaded. A rabbit anti-AASS antibody (1 in 500 dilution) raised against amino acids 528 to 649 of the protein was obtained from Sigma-Aldrich (HPA020728). Antibodies were visualized using IRDye 800CW or IRDye 680RD anti-rabbit secondary antibodies and the Odyssey Infrared Imaging System (Li-Cor Biosciences).
Hyperlysinemia was diagnosed based on elevated plasma lysine levels in 8 patients with distinct neurological features whose material was sent to a laboratory for metabolic screening and confirmatory testing (Table 1). All patients had no detectable LKR and SDH activity in fibroblasts. For molecular genetic analysis, we sequenced all 24 exons including the flanking exon/intron boundaries of AASS by using standard Sanger sequencing techniques. To determine whether the identified mutations affect the AASS protein levels, we performed immunoblot analysis in fibroblast homogenates (Figure 1B).
Cases 1 and 2 are compound heterozygous for a transition c.194G>A in exon 2, and a transversion c.1256T>G in exon 11. Both substitutions change conserved amino acids, arginine at position 65 into glutamine (p.R65Q) and leucine at position 419 into arginine (p.L419R). In case 3 the c.194G>A mutation was homozygous, consistent with the reported consanguinity of the parents. Immunoblot analysis revealed that AASS protein was absent in case 1 and 3, indicating that both mutations primarily affect protein levels (Figure 1B). In case 4 no mutations were found in exons 2 to 24, but we failed to amplify exon 1 indicating the presence of a deletion. Indeed, no AASS cDNA and protein could be detected in this case (Figure 1B&C), indicating that this deletion interferes with expression of AASS. In case 5 we found two mutations, a heterozygous transition c.460G>A in exon 4 which changes a conserved alanine in the LKR domain into threonine (p.A154T), and a duplication of 1 basepair c.2076dup in exon 19, which creates a frame shift at amino acid position 693 resulting in a stop codon after 9 triplets (p.P693SfsX10). The c.460G>A mutation appeared homozygous at the cDNA level, indicating nonsense-mediated decay of the c.2076dup mRNA (Figure 1D). Indeed no immunoreactive protein with the predicted Mw of the truncated protein (78kDa) was observed upon immunoblotting. The detected AASS with a Mw of 102kDa is therefore the p.A154T mutant protein. In case 6, we found a homozygous transition c.2155A>G in exon 19, which changes threonine at position 719 into alanine (p.T719A). This mutation affects a highly conserved amino acid in the SDH domain of AASS. The activity of LKR is most likely at least partially conserved, which is evidenced by the fact that this patient displayed hyperlysinemia and saccharopinuria. Unfortunately, the available lymphoblasts of this patient were not suited for follow up analysis, because AASS activity and protein are undetectable in this cell type.
In cases 7 and 8 no mutations were found in exons 1 to 19, but we failed to amplify exon 20–24 indicating the presence of a large deletion. Despite the fact that the 5′ part of the AASS cDNA could be detected (Figure 1C), no AASS protein was present in both cases (Figure 1B). In order to determine the size of this deletion, we performed CGH in case 7. This analysis revealed a homozygous deletion of 126kb at 7q31.32 (karyotype arr7q31.32(121590497–121716631)x0) involving two genes, AASS and PTPRZ1. Although not exactly known, the deletion breakpoint for AASS must be located in intron 19 or exon 20. PTPRZ1 or protein tyrosine phosphatase, receptor-type, Z polypeptide 1 is encoded by 30 exons and spans 193 kbp. The breakpoint for PTPRZ1 lies in exon 2 or intron 2, which will prevent the expression of functional PTPRZ1. PTPRZ1 is a protein tyrosine phosphatase, which is mainly expressed in the developing and mature brain (astrocytes, oligodendrocyte precursors, immature and mature oligodendrocytes). Binding with a variety of cell adhesion and matrix molecules affect intracellular phosphatase activity [20, 21]. Although PTPRZ1 knockout mice have no gross anatomical alterations in their nervous system or other organs, they do display disturbed motor coordination and nociception and have decreased recovery from demyelinating lesions [22, 23]. Thus the physiological role of PTPRZ1 may be in oligodendrogenesis, promotion of neurite outgrowth and glial adhesion . Our data indicate that cases 7 and 8 have a novel contiguous gene deletion syndrome that was biochemically diagnosed as hyperlysinemia. We speculate that the severe neurological disease in these cases is caused by a loss of PTPRZ1 function.
In addition to the single mutation reported before, we now describe 7 novel mutations, one of which was present in two unrelated patients (p.R65Q). All missense mutations affect conserved amino acids and are not present in the SNP or 1000 genomes database. The causal nature of these mutations is further evidenced by deficient LKR and SDH activities in all patients' fibroblasts and the undetectable AASS protein levels in all but one case. In our cohort of patients, hyperlysinemia tracks with distinct neurological features. This could reflect the selection bias in our cohort, since amino acid analyses are mainly performed in patients with neurological abnormalities. Although, the neurological phenotype segregated with the biochemical abnormalities in all studied siblings, this is only weak evidence for causality in recessive disorders with single cases and consanguinity. In addition, there is a broad range of clinical phenotypes in the group of patients in which only AASS is defective. Patient 1 and 2 are more severely affected than patient 3 and 4, despite the fact that all cases appear to have no functional AASS protein. We suggest that the pathophysiology of AASS deficiency may be better addressed in a model organism such as an Aass knockout mouse. Population-based studies in which the prevalence of hyperlysinemia is measured (through metabolomics) in conjunction with genotyping and clinical phenotyping might provide additional insight.
We conclude that in our cohort of 8 cases, hyperlysinemia is caused by mutations in the AASS gene. In two patients originating from one family, the hyperlysinemia was caused by a contiguous gene deletion syndrome affecting AASS and PTPRZ1. Our findings illustrate the importance of detailed biochemical and genetic studies in any hyperlysinemia patient.
Protein tyrosine phosphatase, receptor-type, Z polypeptide 1.
This work was supported by the Netherlands Organisation for Scientific Research (VIDI-grant No. 016.086.336 to SMH). The authors thank Hans Waterham for helpful discussion and critical reading of the manuscript.
SH, RW and MD conceived and designed the study. SH drafted the manuscript. HtB carried out the molecular genetic studies. SD and JR carried out the biochemical studies. AK performed the CGH. JK, PA, MH, MB, TC, JZ, JOS, BT, RJ and MD were involved in the clinical evaluation, diagnosis and follow-up of the patients. All authors read and approved the final manuscript.


Social inequality has been a part of life for as long as humans have existed, with individuals from both sides of the coin striving to reduce it. Matt Barnes, the Chair at IFF's seminar last week on 'Dividing Lines – the Role of Evidence in Reducing Social Inequality' set a context for an interesting evening of discussions by taking us through a brief history in time of social inequality, starting 6,000 years ago when old agricultural land owners controlled access to weapons, taking in the Victorian era and Dickensian exposés of the gap between rich and poor and landing in the recent past when the Thatcher years saw the most marked and rapid increases in inequality in post-war Britain.
Indeed, the battle between the 'haves and have nots' has been a primary driver in British voting patterns throughout modern history with lower earners typically voting left and higher earners voting right. IFF's latest seminar provided a new, evidence heavy take on what this gap means in today's world and revealed that the research sector might benefit from widening its focus on this historic economic divide.
Most in the research and policy worlds will be familiar with the evidence of the economic story, showing that the gap between the highest and lowest earners has shot up in the last thirty years and that the UK ranks among the most unequal societies in the developed world (ranking 6th by the Gini coefficient in 2015). Most will be aware of the plethora of data behind Danny Dorling's powerful critiques of UK policy and the recent attacks on the richest 1%. Speaker, Matt Whittaker of the Resolution Foundation highlighted an additional layer to this analysis, demonstrating that although the extent of inequality has on the face of it remained broadly consistent over the last twenty years, if we look at income after housing costs then it has in fact continued to rise. This is compounded by a slowdown in economic growth since the 2008 financial crisis which has seen average annual income decrease in real-terms for the poorest households and lowered the general mood of the country.
Slide shared by Matthew Whittaker of the Resolution Foundadtion during his event presentation.
Building on the economic story, IFF's own Alistair Kuechel showed us how the financial services market and the government-led UK Financial Capability Strategy have attempted to address the impact of economic inequality on the financially squeezed portion of the public, offering support to improve the individual's ability and confidence to manage their money more effectively through free online banking products like Pockit, and by using regulation to reduce the 'poverty premium' (the idea that poorer people pay more for essential goods and services, for example from higher fuel tariffs and up-front payment methods). While these new initiatives were warmly received, Thursday's audience reverted back to the core problem of the income gap and why the public and policy makers are failing to take notice of it.
Awareness of the poverty premium among the public at large is low, and graphs of the Gini coefficient rarely make the front pages. Indeed, it was the lack of traction gained by the extensive evidence on the issue, diligently produced by the research sector, that emerged as the over-arching theme of Thursday night's seminar. While Guardian columnist and broadcaster (and the most emotive speaker at IFF's seminar) Polly Toynbee accepted that most politicians are conscious of the issue (look at Theresa May's 'burning social injustices' speech on the steps of Downing Street) they are failing to use the wealth of evidence available to shape new policies.
So why aren't people listening? Perhaps this is a symptom of Trump's post-truth world. Perhaps Gove was right and people really have 'had enough of experts'. The feeling from Polly Toynbee was that the research world is failing to tell the economic story in a human way, to really engage people on an individual level. Matt Whittaker however took this one step further, revealing through his Brexit analysis that actually there are other stories at play, which researchers and policy-makers alike need to explore and employ before we can have a real impact.
Brexit's shock result has shone a light on new dividing lines that go beyond economic inequality and cut across income differences and left/right voting patterns. While income was a factor, it was intertwined with other divides between, to name a few, students and workers, home owners and renters, and those who perceive that their communities are getting along or drifting apart. Perhaps the most important factor straddling all these issues, was whether or not voters had a degree. Importantly, while we have a wealth of evidence on economic inequality, this is only one of a multitude of inequalities that the individual perceives as relevant to them today and questions remain unanswered about how these other factors affect individual choices. Matt went as far as to suggest that if the remain campaign had identified and engaged with these lesser-known divides, the referendum result could have swung the other way.
When it comes to increasing the impact of research, we were left with the feeling that it is less an issue of poor story-telling, and more an issue of telling the wrong story. If we want evidence about social inequality to cut through the untruths, maybe we need to leave Danny Dorling's graphs on the shelf and tell the stories that speak to what else really matters to voters now. As IFF perpetually endeavours to do, we need to improve our understanding of the new lines that are changing behaviour today.


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Health U.S. Wire
New Mexico governor closes all roads to city of 22,000, forces strict lockdown
By Erin Coates, The Western Journal
Invoking the state's Riot Control Act on Friday, New Mexico Gov. Michelle Lujan Grisham essentially locked down the city of Gallup.
All roads into Gallup were closed at 12 p.m. on Friday "to mitigate the uninhibited spread of COVID-19 in that city."
"Vehicles may only have a maximum of two individuals. Residents of the city should remain at home except for emergency outings and those essential for health, safety and welfare," a media release from the Democratic governor's office read.
The city of 22,000 people, located 100 miles west of Albuquerque, has been hit hard by the coronavirus, CBS News reported.
As of Saturday morning, 1,064 of the 3,513 total confirmed cases of COVID-19 in New Mexico were in McKinley County, where Gallup is located, according to the data from Johns Hopkins.
"The virus is running amok there. It must be stopped, and stricter measures are necessary," Lujan Grisham said.
"A problem in one part of our state, with a virus this dangerous and this contagious, is a problem for our entire state."
The Riot Control Act gives the governor the authority to prohibit people from being out on public streets and can limit the use of certain streets and highways, according to the media release.
"I recognize this request is unusual and constitutes a drastic measure, and the emergency powers set out under the Riot Control Act should be invoked sparingly," Gallup Mayor Louis Bonaguidi said.
"However, the COVID-19 outbreak in the city of Gallup is a crisis of the highest order. Immediate action is necessary."
The emergency order was put in place in response to near-identical letters from outgoing Gallup Mayor Jackie McKinney and Bonaguidi, his successor.
"The virus has caused many deaths, stretched medical facilities and resources to their capacity, and adversely impacted the welfare of the City of Gallup," McKinney wrote on Thursday, hours before his term officially ended.
"Our community is unable to adequately address the outbreak without the imposition of certain restrictions necessary to regulate social distancing, public gatherings, sales of good, and the use of public streets."
The order in Gallup will expire at 12 p.m. on Monday, May 4.
The governor has also acted to extend the state's emergency public health order through May 15.
Elsewhere in the state, Grants Mayor Martin Hicks and a group of supporters rallied on Monday to encourage business owners to defy the governor's lockdown order.
"The governor is killing the state over a little bug," he said, according to CBS News.
Erin Coates, The Western Journal

redpajama_set_name: RedPajamaCommonCrawl


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Immune system protein in semen boosts HIV spread in female genital tissue
NIH study suggests virus uses protein to spread.
An immune system protein normally found in semen appears to enhance the spread of HIV to tissue from the uterine cervix, according to researchers at the National Institutes of Health.
The protein interleukin 7 (IL-7) belongs to a family of proteins that regulate the immune response. IL-7 is present in normal semen, and occurs at especially high levels in the semen of men with HIV.
The researchers developed a culture system of small pieces of tissue from the cervix and used this system to simulate male-to-female transmission of HIV, which causes AIDS. They observed the spread of the virus in cervical tissue under controlled laboratory conditions. In the presence of IL-7 at levels typically found in semen of men with HIV, the virus spreads to the tissue more readily than it spreads to tissue not treated with IL-7.
According to the study authors, the finding raises the possibility that IL-7, alone or in combination with other molecules, can foster male-to-female transmission of HIV. Similarly, they note, it's possible that the level of IL-7 in semen may determine how infectious a particular HIV-positive male is for a female sexual partner. Also, researchers may one day be able to prevent or delay the spread of HIV by blocking seminal IL-7.
The major targets for HIV infection are T cells, a type of immune cell that normally marshal the body's defenses against disease-causing organisms. Generally, when these cells become infected with HIV, they quickly die before the virus can produce a large number of copies of itself. However, the researchers found that in isolated pieces of cervical tissue, HIV-infected T cells in the presence of IL-7 live longer and so continued to produce the virus. IL-7 also stimulated uninfected T cells to divide thus increasing their number. These new T-cells would provide additional targets for the virus, potentially increasing its spread.
Researchers have long known that biological interactions that take place in the laboratory may not always occur in the more complex environment of a living organism. For this reason, Dr. Margolis noted that additional studies would be needed to confirm what he and his coworkers observed in the laboratory.
"These experiments show us again how vicious HIV is," said senior author Leonid Margolis, Ph.D., head of the Section on Intercellular Interactions at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), where the research was conducted. "The virus is able to commandeer an immune protein for its own benefit."
The paper was co-authored by Andrea Introini, Christophe Vanpouille, Ph.D., Andrea Lisco, M.D., Ph.D., Jean-Charles Grivel, Ph.D., and Leonid Margolis, Ph.D., all of the NICHD. Mr. Introini also is a Ph.D student at the University of Milan, Italy.
Their findings appear in PLOS Pathogens.
Based on their results with IL-7, Dr. Margolis said, his team plans to investigate whether other immune system proteins present in semen are involved in HIV transmission.
About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute's website at http://www.nichd.nih.gov.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Robert Bock


Thanks to Cathy K and Linda for the wonderful book blocks! The prints used are really great. Cathy, I really appreciate the fabric from Africa – it is beautiful and I'll try to do something wonderful with it.


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Washington State of the State Address
2020-01-16T11:44:47-05:00https://images.c-span.org/Files/302/20200114153102012_hd.jpgGovernor Jay Inslee (D) delivered his state of the state address from the state capitol in Olympia, Washington. Governor Inslee explained his goal of reducing homelessness across the state by giving Washingtonians job assistance, affordable housing and programs to help the vulnerable. Governor Inslee also called for a clean fuel standard as part of the state's continued effort to combat climate change.
Governor Jay Inslee (D) delivered his state of the state address from the state capitol in Olympia, Washington. Governor Inslee explained his… read more
Governor Jay Inslee (D) delivered his state of the state address from the state capitol in Olympia, Washington. Governor Inslee explained his goal of reducing homelessness across the state by giving Washingtonians job assistance, affordable housing and programs to help the vulnerable. Governor Inslee also called for a clean fuel standard as part of the state's continued effort to combat climate change. close
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West Virginia State of the State Address
Governor Jim Justice (R-WV) delivered his annual state of the state address in Charleston, West Virginia. He outlined…
Governor Jay Inslee (D-WA) delivered his 2019 State of the State address in the state capital of Olympia. Governor Inslee reflected on…
Governor Inslee on Policy Issues in Washington
Washington Governor Jay Inslee (D) talked about policy issues in his state. He spoke via video uplink from aboard the C-SPAN Bus in…
Washington Governor Jay Inslee (D) delivered the State of the State address at the State Capitol in Olympia. Among the…
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text:
Ro Khanna, a rising star among progressive Democrats, navigates a careful pro-Israel line
By	Ron Kampeas	 September 19, 2019 3:24 pm
Ro Khanna in his congressional office, Sept. 17, 2019. The California congressman wants close U.S.-Israel ties to continue, but says that should not preclude the American government from using the relationship as leverage to push for changes in Israeli policy. (Ron Kampeas)
WASHINGTON (JTA) — Ro Khanna, a rising star among progressive Democrats, wants to make a point about how to be progressive and pro-Israel, so he quotes Alan Dershowitz.
Yes, that Alan Dershowitz, the Fox News habitue who has accused the Democratic Party of "tolerating anti-Semitism."
"I don't agree with all of Professor Dershowitz's book," the California congressman said, referring to "The Case for Israel," Dershowitz's 2003 effort to advance a liberal argument for Israel. "But where he makes that point about not singling out a country unfairly — you have to stand up for human rights consistently around the world."
Khanna, 43, whose House district encompasses much of Silicon Valley in Northern California, initiated an interview in his Capitol Hill office with The Jewish Telegraphic Agency.
Here's the point he wants to make: The United States and Israel have a "deeply intertwined" relationship that ought to continue, but that shouldn't preclude the American government from using the relationship as leverage to push for changes in Israeli policy.
"The vast majority of the Democratic Party wants this relationship to continue to succeed," he said, "[but] we want it to succeed on progressive values that bring peace and human rights."
It's a fine line to walk as Democrats grapple with accusations — including from within — that the party is drifting away from Israel, and as its progressive wing grows increasingly vocal in its criticism. Republicans, chief among them President Donald Trump, have sought to imprint the party with the stamp of four congresswomen known as "The Squad," two of whom back the boycott Israel movement: Ilhan Omar of Minnesota and Rashida Tlaib of Michigan. Trump has called the party anti-Semitic.
Yet Khanna, a seasoned Democratic activist and a formidable fundraiser able to tap the deep reserves of wealthy liberals in his district, is intent on establishing his approach to Israel as a valid position within his party's progressive wing. A senior adviser to the presidential campaign of Sen. Bernie Sanders of Vermont, Khanna is a rising star in the party, having ousted a veteran Democrat, Mike Honda, in 2016.
Born in Philadelphia to Indian immigrants, he has been ensconced in the party's progressive wing for decades, having campaigned as a University of Chicago student for Barack Obama's first run for state Senate in 1996. Khanna went on to earn a law degree at Yale and was named by Obama, during his first term, to a top Commerce Department role.
In 2011, Khanna started exploring a congressional run almost as soon as he arrived in Silicon Valley to practice and teach law. In 2016, the year he was elected to Congress, Khanna was among a handful of Democratic candidates who endorsed Sanders' bid for the party's presidential nomination.
One of the first things Khanna mentioned in the interview was the close ties between Silicon Valley and Israel's high-tech sector. In December, he moderated a panel discussion in his district titled "Israel-Silicon Valley Roundtable on Entrepreneurship." He praised Irwin Federman, a constituent and venture capitalist who has invested in Palestinian businesses in the West Bank.
On Israel issues, Khanna is closer to Squad member Ayanna Pressley of Massachusetts, who similarly represents a district with a large population of wealthy liberal Jews. Khanna and Pressley both voted for a House resolution condemning the Boycott, Divestment and Sanctions movement targeting Israel, and both said they were heeding the sensibilities of their Jewish constituents.
"We each take these votes alone but aim to represent the districts we serve," Pressley said on Twitter after the vote, responding to Israel-critical leftists who berated her for her vote. On Twitter, Khanna quoted Pressley's tweet and added: "I believe @AyannaPressley we can work on a progressive agenda for peace on these principles. 1) Halt all settlement growth; 2) Halt Palestinian home demolitions; 3) Ease the terms of the Gaza blockade."
In the JTA interview, Khanna said it makes sense to heed a minority in determining what constitutes bigotry — to a point. Though he opposes BDS, Khanna like many Democrats opposes bills that would penalize Israel boycotters.
"Every person needs to be very careful with the language and listen to the communities being impacted," he said. "That doesn't mean you suppress your political views."
Khanna declined to name Omar or Tlaib, or to directly address the comments that have drawn fierce criticism from some pro-Israel sources. In addition to backing BDS, both freshman lawmakers have fretted about what they see as excessive pro-Israel influence in terms that critics say are anti-Semitic. Omar has apologized for some of her statements.
"I don't want to re-litigate," Khanna said.
Instead, Khanna broadly called for toning down the rhetoric and fostering greater tolerance. He cited the cooperation between Tlaib and Andy Levin, a Jewish progressive representing a Detroit-area district neighboring hers as a model.
"What I would suggest is the Levin-Tlaib peace plan," he said.
Khanna's progressive bona fides would seem to repudiate the thesis advanced recently by New York Times columnist Bari Weiss, author of the new book "How to Fight Anti-Semitism," that leftists focus intently on the Palestinians but ignore the plight of oppressed Muslims elsewhere.
Khanna is co-sponsoring two separate bills that would counter China's treatment of Uighers, an oppressed Muslim minority in China that Weiss alleges progressives have ignored. And he has called repeatedly for an end to arm sales to Saudi Arabia over its war in Yemen.
"What would be hypocritical for me is not to speak out for the human rights concerns of Palestinians," he said.
Nonetheless, Khanna is sensitive to how pro-Israel Americans feel singled out, especially on college campuses.
"I've had students and their parents saying they're uncomfortable about going to Hillel or being open about their faith," he said. "Just like I think we shouldn't penalize boycotts, or speaking about Palestinian rights, we have to have equal respect for people who are practicing Jews or supportive of the U.S.-Israel relationship."
Khanna said his views hew close to younger Jewish Democrats in favoring a close U.S. relationship with "progressive values." Just as young Indian Americans like himself favor relations with India but long for peace with Pakistan, Jewish Democrats of his generation support the relationship with Israel but long for peace with the Palestinians. The political action committee affiliated with J Street, the liberal Israel lobby that supports a two-state solution to the Israeli-Palestinian conflict, has endorsed Khanna.
In an aside, Khanna said his brother was married in a Hindu-Jewish ceremony, noting that a combined chuppah-mandap (the wedding tent used by Hindus) is increasingly common.
"You can buy them online," he said.
Khanna backed a bill this year to consolidate U.S. defense aid to Israel at about $3.8 billion per year, but he also favors leveraging U.S. aid as a means of pressuring Israel to end Palestinian home demolitions, release imprisoned Palestinian minors and stop settlement building. During the interview, he whipped out his smartphone and Googled instances of presidents (Eisenhower, Carter, Reagan, Bush Sr., Obama) who had used American assistance to extract concessions from Israel on territory or other issues.
Khanna, who is gathering signatures for a letter calling on Israel to stop the demolitions in the West Bank, declined to go into specifics about what aid he would favor using as leverage.
"I support continued aid to Israel," Khanna said, "but the American president has a whole range of options."
Stav Shaffir, Israel's liberal rising star, is now in free fall
By	Marcy Oster	 January 17, 2020 11:52 am
At debate, Democrats blast Trump for leaving Iran nuclear deal
Obama's Middle East policy team has a new home in Elizabeth Warren's campaign


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:The CEO of the Ghana Tourism Authority, Akwesi Agyeman has encouraged Ghanaians to carry on the spirit of the Heritage month beyond the month of march, even though the celebrations officially ended .today/yesterday.
He said government will continue to roll out measures of such nature to help cement the " See Ghana, eat Ghana, feel Ghana and wear Ghana" agenda. Mr Agyeman was speaking at the Climax of the Heritage month celebrations of the End Time Revival Center, Assembles of God in Accra.
The month of March has been set aside by the government to celebrate Ghana's culture, heritage and to promote tourism. Institutions and Corporate organisations held events within the month to showcase Ghana's rich culture and associate themselves with the Government's agenda to make local goods and tourism attractive.
For the End Time Revival Center, Assemblies of God, sunday service is the best time to showcase the rich culture of members in line with the Heritage month celebrations. Members dressed in their traditional attire representing all 16 regions. Most of the men were spotted in their kente cloth with others in Fugu or Batakari with accompanying accessories.
The ladies on the other hand dazzled in their kente and African prints displaying traditional beads adorned on their neck and wrists with beautifully worn head gears of all shapes and sizes, all in merry making mood. CEO of the Ghana Tourism Authority Akwesi Agyeman commended the church for the initiative.
Also in attendance was GJA President Affail Monney and Dr Thomas Owusu Mensah, a Ghanaian-American-fibre optics inventor.


Ideal family or couples 'escape' location-skiing, boarding, Easy bike paths, or challenging mountain biking. Golf extraordinaire. Music lovers paradise.
Chalet #1(see photos 8-24)-Please note Chalet # 1 is only available occasionally as it is primarily the family chalet.
In the winter; Ski out your back door to the Nansen trail, & ski to the gondola at the base of the mountain.
In the summer, bike or hike from your back door or a 7 minute stroll to the village at the base of the mountain, for music, luge rides, shopping & fine dining. A 4 minute walk to a spectacular zip line & a 2 minute drive to 4 top rated golf courses.
Entertain yourself on the electronic keyboard.
All 4 bathrooms have been recently renovated.
Sectional couch with Queen "Hide-a Bed"
8 -10 min Walk to pedestrian village at base of mountain or free shuttle service.
Keywords: Presidents Week, Ironman, Snowboard Park, Golf & Biking, Music Festivals Blues Jazz Chalet, Hottub, Mont-Tremblant, mountain side, 5 bedroom, Summer fun vacation Ski in ski out during winter. NB Unless the quote specifically says CDN$ the quote provided is in US$.


If you're a fan of Disney, you've most likely seen Joe Dunn's work before. As a Marketing Art Director for Disney Feature Animation, Joe Dunn can be credited with the design of some of the Blu-Ray/DVD packaging, official posters, Disney convention booths, and even the Fix-It Felix Jr. arcade machine -- all these cool things!!!
This particular piece was originally made to be printed as a giclee, which Joe showed us back in February. We really dug the design and love that the villain of Big Hero 6 is featured on his own poster looking all villainous (as he should!). At the time we were just getting started on the Cyclops Print Works program and thought this piece would make a pretty awesome serigraph, with metallic inks printed on black paper. With that said the original design –since it was going to be a giclee — was actually over 50 different colors, though Eclipse Workshop managed to turn it in 18 with all the bells and whistles still in-tact!


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What Financial Executives Need to Lead
Research Participants
Leadership development is a challenge for all professionals. However, for finance executives, no book has been written, nor research undertaken, specifically addressing their behavioral or leadership development. This introduction to the book "Leverage Competencies" explains how it will correct these omissions.
Leverage Competencies: What Financial Executives Need to Lead
The mandate to transform finance into a force for organizational change and business effectiveness has clearly been issued. In response, the Financial Executives Research Foundation has conducted research that has changed the direction of financial practices. Beginning with Changing Roles of Financial Management: Getting Close to the Business (1990), and subsequently with The Empowered Organization: Redefining the Roles and Practices of Finance (1994), these studies have helped financial executives climb out of their silos and begin integrating themselves into the business lives of their organizations.
Although the leadership challenge for financial executives is now clear, uncertainty remains: Do financial executives really have the full range of competencies1 to make this leadership mandate a reality? Moreover, in our eagerness to embrace changing roles and a new mandate for finance—without fully addressing such competencies—are we actually setting the stage for future disappointments and failures? These concerns, expressed by corporate CEOs and CFOs alike, are increasingly rising to the surface.
One of the most noteworthy surveys of financial practices offers the following observation, critical to the future leadership success of all finance executives:2
We categorize the competencies CFOs require as foundation and leverage. Foundation competencies are professional, technical and control related—these are the minimum competencies for all CFOs. In contrast, leverage competencies3 allow CFOs to build both the business (strategic thinking, innovation, managing business risk and change) and personal relationships (teamwork and coaching, inspiring leadership). Our research shows that most, if not all, CFOs rate themselves competent in foundation attributes. But many see further scope for personal development in leverage competencies.... Of all business functions, finance tends to lead fastest to the boardroom. This leaves precious little time for planned personal development. The CFO's leverage competencies tend to be acquired haphazardly or neglected altogether. (Emphasis added.)
The importance of competencies, and the new challenge of leadership outlined above, is echoed by the following quote regarding the requirements of leadership in the twenty-first century:4
The truly successful managers and leaders of the next century will be determined not by what they know but by how fast they can learn.... They will excel not by possessing traditional skills and tools but by demonstrating a high degree of flexibility and adaptability in dealing with both technology and people and by being able to stay constantly meaningfully connected to others in the ever-changing world.
The difference between 1990 and 2000 will probably be less extreme than the differences between 2000 and 2010, as we experience a world that that is demanding not only of a rethinking of management competencies, but a fundamental redefinition of the social contract between employer and employee, between colleague and colleague, between worker and work itself.


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Movie Review: "Blended" (2014)
Movie: "Blended"
Jim (Adam Sandler) is a widower with 3 daughters. Lauren (Drew Barrymore) is a recent divorcee with 2 sons. The two go on a blind date from hell. Jim takes Lauren to a Hooters and prefers to watch whatever is on the television instead of making eye contact with her. She brushes him off as a big jerk. The two are thrown together many times before they both, unknowingly, end up on a romantic getaway at a resort in Africa meant for Jim's boss and his family and Lauren's best friend. The resort's purpose is to help "blended" families come together. Jim and Lauren begin to learn more about each other and become closer despite their seeming dislike for one another.
*double sigh*
Let me reiterate the sentiment from our last Adam Sandler movie post. His old stuff? Hilarious. We LOVE "The Wedding Singer." Drew Barrymore and Adam Sandler, weirdly, have great on-screen chemistry that works so well.
It almost saves them from this steaming pile of crap.
This isn't the absolute worst Adam Sandler movie in the past 15 years (for our review of said worst movie, click here), but it's still really bad. His feeble attempts at what passes for humor are the same rhinos humping/fart/making fun of girls that look like guys/offending every possible race/gender/sex/country out there that he always throws at audiences. And for some reason, THEY EAT IT UP. It's pretty obvious he is just getting a free annual vacation out of these movies now. This year, he chose Africa.
The only thing that saves this movie in the slightest is a liiiiiiiiiitle bit of schmaltzy sweetness and heart. I blame this on that weird chemistry between Sandler and Barrymore. They are cute together, but this movie is not. And making Sandler a widower is a cheap and lazy attempt at garnering sympathy for his otherwise dolt of a character.
There is a running "joke" in the movie where he treats his daughters like they are boys....how and why this is funny, we have no idea. They are mistaken for boys constantly and yet look extremely feminine! Why he thinks gender identity issues are something to poke fun at really puzzles me, and they have been a central theme in the last few of his movies. If I was his daughter and he made such mean jokes to me, I would have filed for emancipation, and not shrug it off as "oh, silly dad, my mom died, he uses air freshener as cologne, I understand!" This is just one of the examples of the many jokes that fall flat in this movie. Terry Crews pops up about a hundred times with a fake African accent and a bunch of singers who insert themselves into situations to create humor, but instead, just stink up the joint. Kevin Nealon and his new younger wife make it a point to always be touching or making out in every scene where they are featured, and it's awkward and forced and annoying. The hotel concierge, played by Abdoulaye NGom, makes it a point to always pronounce Sandler's fake last name wrong....a thousand damn times. WE GET IT, but the repetition of said "humor" into the ground DOESN'T MAKE YOUR CHEAP ASS JOKES FUNNY. Though we may have laughed here and there, the bad FAR outweighs the good.
Barrymore plays the stereotypical overprotective single mother who cannot control her kids and doesn't let them have any fun. She also has a complete jerk cheater ex-husband, played by Joel McHale, who doesn't want to spend any time with his kids. She also has a very stereotypically female job: a closet organizer, whereas Sandler works at a sporting goods store with the macho Shaquille O'Neal. It's all very rudimentary and conforming to set gender roles.
Is the public at large finally getting over Adam Sandler and his same offensive shtick? BigJ and I are not praying folk, but I will drop to my knees in prayer once he realizes that his days as a box office star are finally numbered.
Do we recommend this movie: No.
Posted by Lolo at Monday, June 09, 2014
Labels: 2010's, comedy, movie review, romance, year 2