Gene: Breast Cancer

It seemed like the scientists are finding more genes responsible for breast cancer susceptibility, as described here:

Four novel breast cancer susceptibility genes are identified in a study published online in Nature. The large, genome-wide association study also points to many more genetic markers that should be pursued for their link to the disease. Together with two related papers online in Nature Genetics, these findings increase our knowledge of the genetic component of breast cancer risk, much of which has remained uncharacterised.

Known susceptibility genes – such as BRCA1 and BRCA2 – account for less than 25% of the familial risk of breast cancer. It is believed that a combination of many additional genetic factors, each playing a smaller role, also contribute to the disease. To look for further susceptibility alleles Douglas F. Easton and colleagues conducted an analysis, as part of which 30 single nucleotide polymorphisms (SNPs) were tested in 21,860 patients and 22,578 controls. The authors identify four genes positively associated with genetic susceptibility to breast cancer (FGFR2, TNRC9, MAP3K1 and LSP1). Further investigation indicates that many additional susceptibility alleles of more modest effect may also be identifiable by this approach.

Most previously identified breast cancer susceptibility genes are involved in DNA repair, but the associations reported here appear to relate more to the control of cell growth or to cell signalling. Only one of the genes – FGFR2 – had a clear prior relevance to breast cancer.

In Nature Genetics, two studies provide further evidence of the risk for breast cancer. One paper, from David J. Hunter and colleagues, identifies alleles for the gene FGFR2 as being particularly associated with the risk of sporadic postmenopausal breast cancer. Another paper, from Simon Stacey, Kari Stefansson and colleagues, reports genetic variants on each of chromosomes 2 and 16, which both increase the risk of oestrogen-receptor-positive breast cancer. One of these variants is located in close proximity to the gene TNRC9, which was also identified in the study from Easton and colleagues.

Gene: Monogamous?

Source: Gene treatment stops frisky voles being love rats, 17-06-2004

Not done on human yet.

When the brains of male meadow voles, usually the most promiscuous of lovers, are enhanced with a gene called the vasopressin receptor, they instantly reform their loose ways and form lasting pair bonds instead.

Because vasopressin is also active in the human brain, the remarkable experiment at Emory University in Atlanta, suggests that differing levels of the hormone could explain why some people find it harder to stay faithful than others.

“It is intriguing to consider that individual differences in vasopressin receptors in humans might play a role in how differently people form relationships,” Larry Young, who led the research, said.

Vasopressin and its receptors may also be implicated in drug addiction and social disorders such as autism, both of which affect the brain’s reward centre.

The Emory experiment, details of which are reported today in the journal Nature, has now proved this theory beyond reasonable doubt. In the study Dr Young’s team took the gene for the vasopressin receptor from the prairie vole and bound it to a harmless virus.

Dr Young said that while more than one gene and hormone is probably involved in regulating human monogamy and pair-bonding, the results have powerful implications for understanding the biological and chemical origins of relationships. “Our study provides evidence in a comparatively simple animal model that changes in the activity of a single gene can profoundly change the fundamental social behaviour of an entire species,” he said.

Gene: Sporting Aptitude

Source: Gene test for child’s sporting chance, 20-12-2004

The test, available online in kit form for about A$110 (£43) uses a DNA sample taken from a mouth swab to detect variations of a gene known as ACTN3. Studies conducted by the Australian Institute of Sport, have linked this gene to sporting potential.

Deon Venter, a director of Genetic Technologies, said: “It’s not a test that says you are going to be a winner or a loser. It’s a test that appears, on the evidence we have so far, to head people into choosing the best event and in some cases the optimal sport.”

The test identifies variations in the two copies that everyone has of the ACTN3 gene. Professor Venter said those with the “normal” variation produced a protein found in “fast-twitch” muscle fibres, giving them an edge in sprinting and power sports, such as speed skating and short-distance swimming, track and cycling events.

Those with a variation of the gene known as R577X lacked the protein, making them more suited to events requiring endurance, such as rowing and longdistance events.

Gene: Vision Loss

Source: 3 Studies Link Variant Gene to Risk of Severe Vision Loss, 11-03-2005

Scientists say they have identified a genetic variation that substantially raises the risk of age-related macular degeneration, the leading cause of severe vision loss in the elderly.

The authors of the studies said the disease was more frequent among whites. Dr. Edwards‘s study was done by scientists at the University of Texas Southwestern Medical Center in Dallas, Boston University and Sequenom, a biotechnology company in San Diego. Dr. Edwards has since left the University of Texas to start the Institute for Retina Research at Presbyterian Hospital of Dallas.

The study led by Dr. Pericak-Vance was at Duke and Vanderbilt. The third was led by Dr. Josephine Hoh at Yale and included researchers from the National Eye Institute and the Rockefeller University.

The genetic finding adds strong confirmation to accumulating evidence that macular degeneration, much like atherosclerosis, is at least partly caused by inflammation.

All three studies pinpointed a single change in a letter of the genetic code in a gene that contains the code for a protein involved in the complement system, part of the body’s immune response to invading pathogens. The change in the DNA letter led to a change of a single amino acid in the protein, complement factor H. Complement factor H acts as a brake on the immune response and inflammation. The variant form of the protein may be a less effective brake.

Gene: Dementia

Source: Dementia gene is identified, 17-07-2006

A gene that may underlie the second most common form of dementia has been identified, offering new insights into the origins and treatment of the brain condition.

Two groups of scientists have found a link between a mutation in a gene called granulin and frontotemporal dementia (FTD), the most frequently diagnosed form of the neurological disorder after Alzheimer’s disease.

The findings, which are published in the online version of the journal Nature, will open a new approach to researching FTD, as no one had previously imagined that the granulin gene might be involved.

Gene: Muscle Wastage

Source: Pop a pill to keep a six-pack without even breaking sweat, 31-08-2006

Research into muscle wastage — intended primarily to treat weakness in the sick and elderly — could lead to therapies that enable healthy people to preserve a buffed look without lifting a finger. While muscles can be built up with exercise, they start to break down quickly without it, so it is necessary to keep exercising to prevent muscles wasting away.

Two independent teams, one at Harvard University and one from a pharmaceutical company called Regeneron, have identified genes named atrogin1 and muRF1 which are active only during muscle atrophy. In rats, when these are knocked out, the animals suffer much less muscle wastage from disease or disuse.

A third team, at Purdue University, Indiana, has found another gene, erg1, which also contributes to the process. Its influence can be affected by an existing drug called astemizole, although this has been withdrawn because it can interfere with healthy heart activity.

Such a drug would not remove the need to exercise to build up muscles, but it would protect existing muscles against subsequent wastage.

BBC link here.

Gene: Hearing Loss

Source: New Medical Research, 05-09-2006

Many cases of hearing loss may be attributable to flaws in a specific gene, claims research funded by the Royal National Institute for Deaf People, released last week. The study of 1,200 people, by the University of Antwerp, found that minor changes in a gene called KCNQ4 increase the risk for hearing loss above the age of 60.

More about this here.

Gene: Schizophrenia

Source: New Medical Research, 12-09-2006

Baby girls who possess a specific immune gene that too closely resembles their mothers’ immune gene are significantly more likely to develop schizophrenia later in life, say scientists at the University of California, Los Angeles. The gene, HLA-B, is linked to other prenatal complications such as pre-eclampsia and low birth weight, says a report in the American Journal of Human Genetics (Oct).

The whole article is here, and the abstract:

Schizophrenia and human leukocyte antigen (HLA) matching between couples or between mothers and offspring have independently been associated with prenatal/obstetric complications, including preeclampsia and low birth weight. Here, we report the results of a family-based candidate-gene study that brings together these two disparate lines of research by assessing maternal-fetal genotype matching at HLA-A, -B, and -DRB1 as a risk factor of schizophrenia. We used a conditional-likelihood modeling approach with a sample of 274 families that had at least one offspring with schizophrenia or a related spectrum disorder. A statistically significant HLA-B maternal-fetal genotype–matching effect on schizophrenia was demonstrated for female offspring (P=.01; parameter estimate 1.7 [95% confidence interval 1.22–2.49]). Because the matching effect could be associated with pregnancy complications rather than with schizophrenia per se, these findings are consistent with the neurodevelopmental hypothesis of schizophrenia and with accumulating evidence that the prenatal period is involved in the origins of this disease. Our approach demonstrates how genetic markers can be used to characterize the biology of prenatal risk factors of schizophrenia.

On the other hand, a method called Whole Genome Association (WGA) is used to determine potential susceptibility genes for the disease, from this article, 21-03-2007.

A genetic basis for schizophrenia found on both the X and Y chromosomes, is presented online in Molecular Psychiatry. Todd Lencz and colleagues examined over 500,000 genetic markers through WGA method.

The results from this analysis show a link with schizophrenia from a marker located in a chromosomal region called pseudoautosomal region 1 (PAR1), which is on both the X and Y chromosomes, and was located adjacent to two genes, CSF2RA and IL3RA. These genes, previously thought to play a role in inflammation and autoimmune disorders, produce receptors for two cytokines, GM-CSF and interleukin-3.

Abstract available online.

Gene: Don’t like to Eat Greens?

Source: Don’t eat greens? It’s all in the genes, 17-09-2006

In the new study Mari Hakala and Paul Breslin, of Monell Chemical Senses centre in Philadelphia, suggest that a dislike of certain vegetables has evolved in some people because their ancestors lived in areas where eating them was potentially damaging.

Glucosinolates, chemicals in vegetables such as broccoli, turnips and horseradish, can partially block the uptake of iodine into the thyroid gland. The element is vital to growth and sexual development. Among people with low iodine intakes — mainly in areas far from the sea, such as the Andes in South America — vegetables containing glucosinolates would increase the risk of stunted growth and mental retardation.

The findings showed that there were two versions of the gene, one sensitive and one insensitive. People with two sensitive genes found broccoli horribly bitter, while those with two insensitive ones enjoyed it.

The findings will be published this week in the journal Current Biology.

More information from other article:

In the new work, researchers were able to show that different genetic versions of this same receptor, known as hTAS2R38, specifically determine people’s perception of plants that synthesize glucosinolates. In their experiments, the researchers divided a test array of vegetables into those that contain glucosinolates, such as broccoli and turnips, and those that do not contain known glucosinolates. The researchers found that individuals possessing two copies of a “sensitive” version of the hTAS2R38 gene rated the glucosinolate-containing vegetables as 60% more bitter than did subjects possessing two copies of an “insensitive” version of the receptor gene. In comparison, individuals possessing one copy of each version of the gene rated the bitterness of glucosinolate-containing vegetables at an intermediate level.

The researchers found that the differences in bitterness perception by the “sensitive” and “insensitive” hTAS2R38 groups reached statistical significance for six vegetables: watercress, mustard greens, turnip, broccoli, rutabaga, and horseradish.

Gene: Intelligence and Schizophrenia

Source: That which makes us clever, make us mad , 09-02-2007

One of the most devastating types of mental illness could be a by-product of the evolution of human beings’ uniquely sophisticated intelligence, a new genetic study has suggested.

Scientists have discovered that a common version of a particular gene appears both to enhance a key thinking circuit in the brain, and to be linked to a raised risk of schizophrenia.

The findings, from a study by the US National Institute of Mental Health (NIMH), provide fresh evidence for the theory that schizophrenia is the price that some people pay for our species’s peculiarly advanced intellectual abilities.

In the study, the NIMH team examined a common variant of a gene called DARPP-32. Three quarters of the subjects studied had inherited at least one copy of the variant.

Daniel Weinberger, of NIMH, said it was possible that while a more efficient link between the prefrontal cortex and striatum normally improves cognitive ability, it may have a negative effect when other genetic and environmental factors interfere. The result could be a predisposition to schizophrenia, which is known to be caused by a combination of genes and a person’s environment.

Details of the study are published in the Journal of Clinical Investigation.

Gene: Breast Cancer

Source: Huge drug trial to defeat breast cancer , 09-02-2007

One of the first specific cancer genes to be identified, in 1994, was the rogue breast cancer gene BRCA1.

The discovery of BRCA1 was followed by BRCA2, and women who carry a faulty version of either gene have a much higher risk of developing the disease — about 50-80 per cent over their lifetime. Faults in these DNA-repair genes may account for 5-10 per cent of breast cancers. Women with a history of it in their family seem to have a big risk of developing it themselves if a close relative, such as a mother or sister, had it before 50, or if two or more relatives have been affected.

On another note, the gene involved in breast tumour is found: Gene hope for breast cancer.

Scientists from the University of South Alabama and the University of Wales College of Medicine have found that a gene involved in making cells stick together is less active in aggressive breast tumours than in those that develop more slowly. The gene, called ALCAM (activated leucocyte cell adhesion molecule) is linked with cell migration. The more free the cells are to move, the quicker the potential spread of the cancer.

Reporting in Breast Cancer Research, Dr Judy King and colleagues compared the expression of the ALCAM gene in normal breast tissue and in tissue samples from primary breast tumours.

Gene: Type 2 Diabetes

Source: Gene test to spot adults who might get diabetes , 12-02-2007

An international team of scientists has identified five different genetic variants that are linked to the condition, which is caused both by family inheritance and lifestyle factors such as poor diet, obesity and smoking. The five variants are thought together to account for about 70 per cent of the genetic risk of type 2 diabetes, the form of the disease that generally strikes in adulthood.

Such a test could be used in a screening programme to pick up those who are most at risk, who could then alter their diet and exercise patterns accordingly. Professor Philippe Froguel of Imperial College, London, one of the leaders of the study, said: “The two major reasons why people develop type 2 diabetes are obesity and a family link. Our new findings mean that we can create a good genetic test to predict people’s risk of developing this type of diabetes.

One of the five genes, SLC30A8, is involved in transporting the mineral zinc in the body, and is known to be involved in secreting insulin, a hormone that is important to metabolising sugar.

Gene: Eyes and Personality

Source: An instant guide to someone’s personality? The eyes have it,  18-02-2007

THE eyes are the window to the soul, it is said. Now scientists have found that the patterns in someone’s iris may give important clues about their personality, ranging from how warm and trusting they are to whether they are impulsive or neurotic.

“Our results suggest people with different iris features tend to develop along different personality lines,” said Mats Larsson, a behavioural scientist who led the study at Orebro University in Sweden.

For the new study, which is awaiting publication in the journal Biological Psychology, scientists at Orebro and at the Karolinska Institute in Stockholm analysed the eyes of 428 people and tested their personalities.

The researchers argue that as much as 90% of the differences in people’s irises are due to genetic variation and they are particularly interested in one gene called Pax6, which helps to set the formation of the iris in embryos. Other research has shown that a mutation in this gene is linked to impulsiveness and poor social skills.

Abstract here:

Variable and person-oriented analyses were used to explore the associations between personality and three previously untested general iris characteristics: crypts, pigment dots and contraction furrows. Personality data, as measured by the NEO PI-R and ratings of iris characteristics from 428 undergraduate students were collected. Crypts were significantly associated with five approach-related behaviors, i.e., feelings, tendermindedness, warmth, trust and positive emotions, whereas furrows were associated with impulsiveness. These findings suggest that because Pax6 induces tissue deficiencies in both the iris and the left anterior cingulate cortex, Pax6 may influence the extent people engage in approach-related behaviors. The results from using a person-oriented analysis suggested that people with different iris configurations tend to develop along different personality trajectories. Future longitudinal studies, twin-studies and genetic association studies, may benefit from collecting iris data and testing candidate genes for crypts and furrows.

Keywords: Personality; Iris characteristics/crypts/pigment dots/contraction furrows; Candidate genes/Pax6/Six3/Lmx1b; Anterior cingulate; Hemispheric asymmetries

Some blog discussed about it, like here and here.

Gene: Male Infertility

Source: Mutation Leads To Male Infertility, 19-04-2007.

A mutation in a gene called AURKC (Aurora Kinase C) has been identified in 14 infertile men of North African descent, reports a paper online this week in Nature Genetics. While deletions of some portion of the Y chromosome have been found in infertile men, this is a rare example in which a mutation in a single gene causes male infertility.

Estimates suggest that at least 80 million individuals worldwide are infertile. Pierre Ray and colleagues studied 14 men whose infertility seemed to have a similar origin. Their sperm were characterized by large heads, increased DNA content, and a variable number of flagella– the whip-like tails that propel the sperm. A genome-wide scan identified a mutation in AURKC that severely truncates the protein. AURKC encodes an enzyme that phosphorylates other proteins, and the authors show that the mutation abolishes this activity. An analysis of the genomic region around AURKC shows that these individuals have other markers in common, suggesting that this mutation appeared in a North African common ancestor approximately 1,500 years ago. The authors note that a larger study of the prevalence of this mutation in North Africans is now warranted.

Abstract available online.

More information from other article.

Gene: Suicidal Tendency

Source: Suicidal Tendency, 24-02-2007

Meanwhile, American researchers say they are on the trail of a gene that may predispose people to commit suicide. Scientists at John Hopkins University say they are examining an area of the genome on chromasome 2 that family studies reveal to be implicated in suicide.

They say that ultimately it may enable them to create a life-saving drug that blocks some suicidal predispositions.

More details from John Hopkins University Gazette:

“We’re hoping our findings will eventually lead to tests that can identify those at high risk for attempting suicide,” said lead author Virginia Willour, an assistant professor in the Department of Psychiatry at the School of Medicine. An estimated 4.6 percent of Americans ages 15 to 54 have tried to take their lives, according to Willour.

In the multi-institutional study, results of which appear in the March issue of Biological Psychiatry, the researchers examined data from 162 families with bipolar disorder. They looked at attempted suicide in this sample because it is an important clinical problem that tends to occur more often in some of these families than in others, suggesting a distinctive genetic basis, according to senior author James B. Potash, of the Department of Psychiatry. This technique of looking at sub-types of illness is used by genetic researchers as a way to reduce genetic complexity.

From the 162 families, the researchers selected 417 subjects who were diagnosed with schizoaffective/bipolar disorder, bipolar I disorder or bipolar II disorder.

Data for all 417 subjects was entered into a computer program that looks for genetic similarities between subjects with similar psychological profiles. Results indicated that family members with a history of attempted suicide and bipolar disorder showed a high degree of genetic similarity at a specific area — DNA marker D2S1777 — on a section of chromosome 2 referred to as 2p12. This is the same marker implicated in a 2004 study from the University of Pittsburgh School of Medicine that looked at attempted suicide and major depression. And it is close to another marker, D2S1790, located in the 2p11 region of chromosome 2, that was identified in a 2004 study from the University of Connecticut School of Medicine that looked at alcoholism and attempted suicide.

Willour says that although the Johns Hopkins-led study does not pinpoint a specific gene responsible for attempted suicide, it does suggest a “neighborhood” in which the gene might be found. She adds that the next step is to further narrow the search and find the “address.”

Gene: IQ

Source: Switched-on genes mean a higher IQ, 03-03-2007

A GENE that could make up to 20 points difference between people’s IQs has been identified by psychiatrists at Washington University.

The scientists examined a gene called CHRM2 and found that it influences a particular kind of intelligence, called performance IQ, which determines people’s ability to organise things logically and have good spatial awarness. People with high performance IQs tend to be whizzes at chess and puzzles.

The investigators report in Behavioral Genetics that the more “positive” variations on the gene a person has, the greater a beneficial effect it can have on your IQ. The gene activates a multitude of signalling paths in the brain involved in learning, memory and other higher brain functions. Each positive variation on CHRM2 seems to raise IQ by up to four points.

Professor Danielle Dick, the lead author, says that a person with all the positive variations switched on would have up to 20 points more IQ than someone who had them all turned off.

Professor Dick says that the possibility of two people with such extreme variations of the gene ever meeting, however, would be statistically unlikely. She adds that CHMR2 is most probably not the only gene involved in raising IQ: up to 100 more might yet be awaiting discovery.

More here.

Gene: Bad Chlolestrol

Source: Increasing Bad Cholesterol Levels, 19-04-2007

A study in the May issue of Nature Structural & Molecular Biology suggests how the gene PCSK9 maintains cholesterol balance in the body.

Low-density lipoproteins (LDLs, also known as “bad cholesterol”) are removed from the bloodstream by binding to LDL receptors (LDLRs) present on the surface of cells. After binding, cells internalize both the receptor and cholesterol, the cholesterol is processed by the cell and LDLR is recycled back to the surface, where it can bind new cholesterol molecules. The amount of surface LDLR is decreased by the PCSK9 protein, resulting in high blood cholesterol, but how PCSK9 does this was not known. Xiayang Qiu and colleagues have now found that PCSK9 binds very tightly to LDLR. This tight binding may lower LDLR levels on the cell surface by sequestering LDLRs inside cells, preventing their recycling back to the cell surface. A mutation in PCSK9 associated with high cholesterol shows even tighter binding to LDLR, supporting this model. These findings should improve our understanding of cholesterol regulation, and may help in the development of drugs to treat cardiovascular disease.

Author contact:

Xiayang Qiu (Pfizer, Groton, CT, USA)
E-mail: xiayang.qiu@pfizer.com

Abstract available online.

(C) Nature Structural & Molecular Biology press release.

Gene: Cardiovascular Disease

Source: Gene for cardiovascular disease, 27-03-2007

Geneticists collaborating at several universities in the US and the UK have discovered a gene that may put individuals at higher risk of developing cardiovascular disease. The identification of the gene, called kalirin, could lead to a test for assessing patients’ heart disease risk, says a report in the American Journal of Human Genetics (April). The research was sponsored by the US National Institutes of Health.

More details from this article:

Researchers at Duke University have identified a new gene that appears to put individuals at greater risk of developing cardiovascular disease. The gene, known as kalirin (KALRN), is located in chromosome 3 in a region that has been previously implicated in the development of coronary artery disease (CAD).

“We used an iterative approach to find a genetic association of kalirin with CAD,” investigator Dr Simon Gregory (Duke University Medical Center, Durham, NC) told heartwire. “The approach involved testing an increasing density of genetic markers from a previous linkage region on 3q13-21 within a population of unrelated case-control individuals. Markers that showed suggestive significance within the first CAD population were then typed in a second case-control population to establish replication of the initial results. Statistical analysis showed that kalirin was associated with CAD, particularly within individuals with early-onset CAD.”

The results of the study, led by Dr Liyong Wang (Duke University Medical Center), are published in the April 2007 issue of the American Journal of Human Genetics.

Gene: Bone

Source: Bone Gene Found, 02-04-2007

A gene has been identified by scientists in California that is believed to play a key role in osteoporosis, the crippling brittle bone disease. The gene, called DARC, is involved in the regulation of bone density. Low bone mineral density is the primary cause of the disease, which affects about one in twenty people in Britain.

More from this article, 13-04-2007:

The study, conducted by scientists at the Musculoskeletal Diseases Center of the Jerry L Pettis Memorial Veteran’s Affairs Medical Center at Loma Linda, shows convincing evidence that a gene called DARC negatively regulates bone density in mice. The report will appear online in Genome Research.

“If our finding using the mouse model is confirmed in humans, then we may be able to develop therapies that are based on inhibiting the function of the DARC gene,” explains Dr. Subburaman Mohan, Ph.D., a Senior Scientist at the Loma Linda VA Medical Center and a Professor of Medicine and Biochemistry at Loma Linda University. “We will also be able to develop genetic screens to identify individuals who are at risk for osteoporosis.”

In the current project, Mohan and his colleagues honed in on this region of chromosome 1 using a variety of molecular techniques, and they located a gene called DARC (Duffy Antigen Receptor for Chemokines) that exhibited different levels of expression in mice with higher BMD.

Gene: Prostate Cancer

Source: New Medical Research, 03-04-2007

Screening for prostate cancer may be improved by testing for the prostate cancer gene (PCA3) in the urine, say researchers at the University of California, Los Angeles. They report in Urology (March 27) how they tested for PCA3 in the urine of 233 men already identified as having elevated levels of prostate-specific antigen (PSA), a standard test for possible prostate cancer. They claim that raised PCA3 levels were more accurate than raised PSA levels at predicting whether a full biopsy would indicate the presence of cancer cells.

PCA3 info at GeneCards.

Update: More news on the research on Prostate Cancer genetic variants.

Several newly identified genetic variants on chromosome 8 are associated with increased risk of developing prostate cancer, according to three studies published online in Nature Genetics.

Last year scientists in Iceland reported that a variant on chromosome 8 is associated with elevated risk of prostate cancer. Three groups have now revisited this region on chromosome 8, and have found additional variants that independently contribute to prostate cancer susceptibility. One group, led by Kari Stefansson, reports that a second variant is associated with the disease in several populations. This variant is relatively uncommon in individuals of European descent, but quite common in African Americans, suggesting that it accounts for some of the higher risk for prostate cancer observed in individuals of African descent.

The second group, led by David Reich, identified this same variant, as well as five previously undescribed risk variants in populations representing five different ethnic backgrounds. Finally, the third group, led by Stephen Chanock, found one of the variants reported by the Broad study to be associated with elevated risk in five different populations.

Abstracts available online:
Paper 1. Paper 2. Paper 3.

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