Generally, disease susceptibility is determined based on changes not only in DNA sequences but also in the activities of genes and chromosomal regions. Epigenetic regulation has attracted attention as a mechanism underlying changes of activities of genes and chromosomal regions. Epigenetic modification regulates gene activity and is essential for cell division and histogenesis. Genetically, phenotype diversity of identical cells is thought to be caused by differences in epigenetic profiles. Epimutations have also recently been recognized as the first step of tumorigenesis of cancers and are thought to be direct dispositions to cancers .
Epimutation affects one or both alleles and decreases the gene product by inhibiting transcription. Tumor cells are typical examples of the results of epimutation that occurs at a high frequency in mammals. Epimutation in cancer generally occurs in somatic cells with tumor progression. Various epimutations are present in cancers and are frequently observed in tumor suppressor genes [1-4].
Germline epimutation which occurs in germ cells is defined as those changes maintained in fertilization and embryogenesis and present in all somatic cells in the mature body. Transmission of epigenetic characteristics through generations has been reported. The cancer risk is similar in individuals carrying a germline epimutation. However, epimutation is not necessarily inherited, and inheritance patterns that do not follow Mendel's laws have been reported [5-8]. Complete elimination of epimutation in spermatogenesis has also been shown . Only inheritance of maternal epimutation has been confirmed, suggesting that elimination of epimutation in oogenesis is less likely to occur [8-9]. Several genomic imprinting-associated somatic cell abnormalities are thought to be caused by germline epimutation . Constitutional epimutation is defined as those changes observed in all tissues in the body due to occurrence in an early step of embryogenesis before differentiation into the three germ layers. Not all cells possess this type of epimutation, leading to a mosaic pattern at the cell level, and it is unclear if this epimutation is transmitted from the previous generation. All epimutation types are a first step leading to tumorigenesis and may be direct causes of carcinogenesis .
Epimutation is not only involved in cancer, but is also observed in genomic imprinting (Table 1). Since a gene transmitted from one parent is selectively expressed in genomic imprinting, a hereditary disease develops when the gene is defective, even though the allelic gene is normal. The characteristic phenotype of genomic imprinting is maintained by imprinting control centers (ICs). ICs are short sequences present in the gene to be imprinted. Hemiallelic methylation of ICs results in transcription of the other allele, controlling imprinting . Diverse gene aberrations in these ICs, such as micro defects, have been discovered, and these are considered to be the causes of epimutations observed in very rare neurobehavioral congenital familial diseases such as Angelman syndrome (AS), Prader-Willi syndrome (PWS), and Beckwith-Wiedemann syndrome (BWS). PWS is characterized by hypotonia in the neonatal period, increased appetite, overeating and subsequent obesity after infancy, characteristic desires, mild mental retardation, and hypoplasia of the external genitalia. In contrast, AS is characterized by severe mental retardation, epilepsy, and awkward movement. However, the causative genetic locus is located in the q11-q13 region on the long arm of chromosome 15 in both diseases. PWS and AS are caused by chromosomal 15q11q13 deletion in many cases, but there are a few cases of imprinting mutation causing abnormal genomic imprinting. In imprinting mutation, the parental chromosome is normal, but the imprinting of 15q11-q13 is changed to the opposite pattern. Familial cases of imprinting mutations are known, and minute deletions upstream of the SNURF-SNRPN gene, which has ICs in PWS and AS, have been described . However, ICs are resistant to minute changes or contain several extra elements, and most imprinting mutations are thought to occur due to epimutation after fertilization .
BWS is a congenital disease with a high reported risk of embryonal fetal tumors, such as Wilms tumor, hepatoblastoma, and rhabdomyosarcoma. The p15.5 region on the short arm of chromosome 11 (11p15.5) has been identified as the causative locus. There are two imprinting domains in 11p15.5: the Cyclin-dependent kinase inhibitor 1C/KCNQ1 opposite antisense transcript 1(CDKN1C/KCNQ1OT1) domain and the Insulin-like growth factor 2(IGF2)/H19 domain, and expression of the imprinting gene near the domain is controlled by the respective imprinting regulation region. CDKN1C expression is decreased due to DNA hypomethylation of the CDKN1C/KCNQ1OT1 domain in about 30-50% of BWS cases, and IGF2 expression is enhanced due to DNA hypermethylation of the IGF2/H19 domain in about 5-10% . Silver-Russell syndrome (SRS) is characterized by intrauterine growth restriction and severe failure to thrive after birth, and epimutation of the H19 gene in 11p15.5 is the cause of this disease . IGF2 and H19 are regulated by a common enhancer present in the terminal end of the short arm of chromosome 11. Normally, sperm-derived H19–DMR is methylated and ovum-derived H19–DMR is not methylated. The enhancer acts on IGF2 because CTCF protein cannot bind to methylated DMR in the former case, whereas it acts on H19 because CTCF protein binds to non-methylated DMR in the latter. Hypomethylation of sperm-derived H19-DMR due to epimutation causes the gene to behave similarly to the maternal domain and induces underexpression of IGF2 and overexpression of H19, causing SRS due to IGF2 underexpression . Thus, these diseases are thought to develop due to aberration in ICs.
Epimutation also occurs due to genomic changes, such as insertion, deletion, and changes in the length of tandem repeat sequences, which are termed copy number variations (CNVs) . In α-thalassemia, another well-known epimutation-associated disease, the deleted region of the LUC7-like (LUC7L) gene is close to an α-globin gene, hemoglobin alpha 2 (HBA2), leading to methylation of the HBA2 gene promoter .
A study on familial cancer showed that a gene group inactivated by mutation in characteristic regions produces a predisposition to cancer. Mutation of a tumor suppressor gene, Retinoblastoma (RB), provided the first evidence of a causative gene in hereditary cancer . Subsequently, Nishishou et al. reported mutation of Adenomatous polyposis coli (APC) in familial adenomatous polyposis  and Hussussian et al. found mutation of Cyclin-dependent kinase inhibitor2A (CDKN2A) in familial melanoma . As more mutations have been identified in tumor suppressor genes, the various cancer-associated mechanisms of these genes have been elucidated. Relationships of Breast cancer susceptibility gene 1(BRCA1), MutL protein homolog 1 (MLH1), and MutS homologue 2 (MSH2), all of which are DNA repair genes (DNA mismatch repair: MMR), with predispositions to familial cancers have also been found. Mutation-induced gene inactivation in hereditary cancer is recessively inherited and many carriers have no abnormal phenotype. However, the cancer prevalence shows marked dominant inheritance because mutation, inactivation, and loss of heterozygosity readily occur in the normal allele .
Methylation of RB was the first reported cancer-inducing epimutation [19-20]. Later, methylation of many other oncogenes, such as Von Hippel-Lindau (VHL), MLH1, APC, and BRCA1, was shown in sporadic cancers [22-24]. VHL mutation is related to primary ciliary function, hemostasis of the extracellular matrix, tumor metabolism, and particularly to clear cell carcinoma . Vaziri et al. examined the VHL gene in an analysis of the clonal relationship between the primary tumor and metastatic lesions of clear cell carcinoma in 10 patients. The gene status differed between the primary tumor and the metastatic lesions in 4 patients. In addition, even when the VHL genotype differed in another renal primary tumor or among several metastatic lesions within a patient, the VHL germline genotype in adjacent normal tissue was always the wild-type germline VHL gene in the primary tumor. These findings indicated that the status of VHL may differ between the primary tumor and metastatic lesions in clear cell carcinoma .
Regarding DNA repair genes, methylation of MLH1 and MSH2 has been reported to cause Lynch syndrome (hereditary non-polyposis colorectal cancer (HNPCC)). This methylation is also known as a predisposition to characteristic cancers, such as those in the endometrium, small intestine, and ovary, in addition to colon cancer. Both genes encode mismatch repair proteins and inactivation of these proteins is thought to induce microsatellite instability (MSI) in tumors . MSI frequently occurs in endometrial cancer and accumulation of MSI-induced gene mutations plays a major role in carcinogenesis . It has since been discovered that MLH1 may also be methylated in sporadic colorectal cancer. In an investigation of methylation of the MLH1 promoter in 110 patients with sporadic early-onset colorectal cancer, Auclair et al. found methylation in 55 (50%) and also observed decreased MLH1 expression due to hypermethylation, which was present in 7.4% of all patients, suggesting that constitutional epimutation is the fundamental mechanism inducing early-onset colorectal cancer . The phenotype of sporadic colorectal cancer with MLH1 methylation is the same as that of mismatch repair defects, and the clinicopathological characteristics are similar to those of a hereditary tumor. MLH1 methylation occurs in sporadic colorectal cancer at a high frequency  and is strongly related to cancers showing the CpG island methylator phenotype (CIMP). Methylation of CpG islands, which are characteristic of promoter regions, has been shown to occur at a high frequency in CIMP-positive cancer . These cancers arise mainly from the ascending colon and have a particularly high incidence in elderly women.
Gazzoli et al. first demonstrated that MLH1 may be methylated in peripheral blood, as in tumors, in colorectal cancer patients . In an investigation of 14 Lynch syndrome patients with MSI, no mismatch repair gene methylation was noted in any patient, but hypermethylation (about 50%) of MLH1 was discovered in normal blood DNA in a 25-year-old female patient . This allelic methylation in unrelated tissue derived from the embryologically different germ layer indicated that the methylation may be constitutional or germline. No conclusion could be reached with regard to the heredity of this epimutation because no mutation was detected in parental tissue, but the occurrence of methylation so early in life is of interest. A later study clarified that constitutional methylation occurs in colorectal cancer patients with hemiallelic methylation of MLH1 , in 2 colorectal cancer patients. Tissues from parents were unavailable, but no methylation was observed in tissues in 4 of 5 children of these patients.
It remains unclear whether constitutional epimutation is transmitted from the mother or father or occurs de novo in early embryogenesis . Crepin et al. investigated constitutional epimutations of MLH1 and MSH2 and defective EPCAM in 134 germline mutation-free patients with suspected Lynch syndrome, and found MLH1 constitutional epimutation in 2 patients. One was a female patient, and her 2 children (one male and one female) developed early-onset colorectal cancer, suggesting that MLH1 constitutional epimutation is related to inheritance. In addition, somatic cell BRAF mutation was found in one child, indicating that cancers in patients with MLH1 constitutional epimutation are similar to MSI-high sporadic cancers . In addition to reports supporting inheritance from the mother, Goel et al. described cases of epimutation of the paternal allele, in which analysis of the genotype showed that the inactivated T allele was inherited from the father . Miyukura et al. showed that complete methylation of the MLH1 promoter region plays an important role in inactivation of MLH1 in sporadic colorectal cancer patients with high MSI . This complete methylation was induced in both alleles, and methylation upstream of the MLH1 promoter region was also observed in normal large intestinal mucosa adjacent to the cancer in one-third of colorectal cancer patients with complete methylation . Subsequently, Miyukura et al. surveyed methylation of the MLH1 promoter region in peripheral blood lymphocytes in 30 patients with sporadic early-onset colorectal cancer or multiple primary cancers, and found complete methylation of the MLH1 promoter region in peripheral blood lymphocytes (PBLs) in 4 patients (early-onset sporadic colorectal cancer: 2, multiple cancers including colorectal cancer: 1, multiple cancers including cancer of the uterine body: 1) . This was hemiallelic methylation. In one of the patients with early-onset sporadic colorectal cancer, no methylation was detected in a sister's PBLs. MSI was confirmed in all patients and methylation was also observed in the normal large intestine, gastrointestinal mucosa, endometrium, and bone marrow in 3. Interestingly, loss of heterozygosity (LOH), loss of the G allele of the MLH1 locus in somatic cells, and biallelic methylation were observed when both alleles of MLH1 in colorectal cancer were investigated, and these findings are consistent with the germline epimutation-associated cancerization mechanism based on Knudsen's "two hit" hypothesis proposed by Suter et al. (Figure 1) . Furthermore, according to Kantelinen et al., variants of uncertain significance (VUS) of the mature hereditary MMR gene present in some colorectal cancer patients may form pairs with other MMR gene VUS and indirectly induce MMR deficiency. An analysis of 8 pairs of MMR gene mutations carried by cancer patients showed aberrations in 2 pairs. Pairs with MSH2 may increase the cancer risk by reducing the repair ability of the wild-type MSH2 by half. Two MSH6 mutations were MMR defects . MLH1 VUS has also been reported to influence mRNA transcription and impair MMR activity .
Mechanisms of epimutation in induction of cancer. (A) Germ cell mutation of tumor suppressor genes. (B) Germ cell epimutation of tumor suppressor genes. Somatic cell mutation, heterozygote loss, and other allele epimutations are triggers that induce tumorigenesis.
Allelic methylation is noted in many cases of Lynch syndrome, but there are some exceptions. Wu et al. investigated germline methylation of MLH1 in 140 gastric cancer patients with a familial medical history. MLH1 promoter methylation was detected in peripheral blood DNA in only 0.7% of the gastric cancer patients, and the methylation pattern of these patients was mosaic. Mosaic germline epimutation of MLH1 occurs in familial gastric cancer, although the incidence is low . Hitchins et al. found allelic MLH1 epimutation in 2 cases in an investigation of constitutional MLH1 methylation in white blood cell DNA in 122 ethnically diverse South African subjects aged ≤50 years old with early-onset colorectal cancer, with a few alleles showing a mosaic pattern .
Epimutation is not always inherited and inheritance patterns that do not follow Mendel's laws have been reported [5-8]. Complete elimination of epimutation in spermatogenesis has also been shown. Only inheritance of maternal epimutation has been found in previous reports, suggesting that elimination of epimutation in oogenesis is less likely to occur [8-9]. In a cohort study of 160 Lynch syndrome patients without germline mutation of mismatch repair genes, constitutive MLH1 methylation was induced in only one patient, and no MLH1 methylation was found in the parents or siblings of this patient, indicating that clinicopathological characteristics are better indices than familial medical history for identification of constitutional epimutation of tumor suppressor genes in cancer patients . In addition, Pineda et al. reported that it is useful to screen for MLH1 methylation in lymphocyte DNA in patients with Lynch syndrome-related tumor with early MLH1 methylation to judge the presence of epimutation .
Epimutation is also related to chronic lymphocytic leukemia (CLL), in which apoptosis of leukemia cells is strongly inhibited. Apoptosis inhibition in CLL is caused by enhanced B-cell lymphoma 2 (BCL2) production and methylation of the Death-associated protein kinase1 (DAPK1) promoter region . DAPK1 was identified as a familial tumor suppressor gene and the DAPK1 promoter region is methylated in CLL . This methylation increases Homeobox B7 (HOXB7) protein binding upstream of the promoter region and 75% of DAPK1 genes in the allele are downregulated. Methylation-induced DAPK1 inactivation causes both familial and sporadic CLL, whereas hypomethylation of DAPK1 in peripheral blood mononuclear cells (PBMCs) of healthy subjects has been reported . An association of this hypomethylation with CLL has yet to be shown.
A recent study showed that a specific MMR gene is involved in regulation of cellular dynamics, such as apoptosis. Therefore, the action of specific MMR gene expression of MSH2 and MLH1 may also be important in resistance to cytotoxic drugs used in chemotherapy, such as cisplatin . However, it has also been shown that MMR inactivation is not related to inherent cisplatin resistance of cells, suggesting that MMR inactivation may have a role in acquired drug resistance . Involvement of impairment of the MMR pathway in aging of hematopoietic stem and precursor cells has also been reported. Kenyon et al. investigated MSI and MMR gene expression in hematopoietic stem, precursor, and colony-forming cells, and found that there were many CD34(+) precursors with MSI lacking MLH1 expression and protein in hematopoietic colony-forming cells in subjects aged ≥45 years old, compared to younger subjects .
There have been many reports on the relationship of breast cancer with BRCA1 mutation. Armes and Lakhani et al. showed that breast cancer arising in patients with germline BRCA1 mutation has histological characteristics such as a high mitotic count and lymphocyte infiltration. This morphology is now referred to as the basal-like type, and Foulkes et al. found that this type accounted for 80-90% of cancers arising in germline BRCA1 mutation carriers . Methylation in the BRCA1 promoter region in sporadic breast cancer was subsequently discovered  and this led to many studies on the association between BRCA1 mutation and methylation. Under the hypothesis that a sporadic tumor with BRCA1 methylation should be similar to tumors with BRCA1 mutation if BRCA1 methylation induces tumorigenesis, Cattear and Morris et al. reported that sporadic tumors with BRCA1 methylation have pathological characteristics similar to those of hereditary breast cancer with BRCA1 mutation . Hedenfalk et al. also showed that the overall phenotypes of the gene were similar between the two breast cancer types . Tumors accompanied by BRCA1 methylation have a high grade, are negative for estrogen and progesterone receptors, and have a high incidence in young women. These features are referred to as BRCA1-like characteristics. Hedenfalk et al. also found BRCA1 methylation at high frequencies of 67% in medullary carcinoma and 55% in mucinous carcinoma, and these histologic types were noted at high frequency in family lines carrying BRCA1 mutations . Recently, Snell et al. discovered methylation of the BRCA1 promoter region in normal tissue of breast cancer patients with the BRCA1-like characteristic histologic type . No germline mutation of BRCA1 or BRCA2 was detected in these patients. These findings suggest constitutional epimutation of BRCA1 in breast cancer patients. It is thought that BRCA1 methylation is the first hit and subsequent deletion of both BRCA1 genes then leads to the characteristic tumor pathology .
MMR gene mutation-induced breast cancer in Lynch syndrome has also recently been described by Buerki et al.  in an investigation of 70 unrelated families with Lynch syndrome. The subjects were 632 females, of whom 51 and 40 carried MLH1 and MSH2 mutations, respectively. MMR impairment was detected in 85.7% (6/7) of molecular test-applicable breast cancer patients. Combined with information from related reports, MSI was present in 70.3% (26/37) of breast cancer patients with MLH1 or MSH2 mutation, and altered MMR protein expression was noted in 72.7% (16/22) . Lotsair et al. also found that the ratio of breast cancer cases with MMR protein deficiency and MSI-induced MMR impairment was markedly higher in MMR mutant cases than in a non-mutant group. These findings suggest that MMR dysfunction is closely related to the development of breast cancer in Lynch syndrome. However, the development pattern and onset age of breast cancer in patients with MMR mutation are similar to those in general breast cancer patients without mutation. Moreover, the frequency of MMR protein deficiency is lower than those in other Lynch syndrome-related cancers .
Lynch syndrome (HNPCC) is a typical familial tumor transmitted through autosomal dominant inheritance, and is observed in about 3% of cases of colorectal cancer . MMR gene aberration is involved in carcinogenesis in Lynch syndrome. Six types of MMR genes have been cloned: MSH2, MLH1, MutS protein homolog 3 (MSH3), MutS protein homolog 6 (MSH6), Postmeiotic segregation increased 1 (PMS1), and Postmeiotic segregation increased 1 (PMS2). Mutations of 3 of these genes (MSH2, MLH1, and MSH6) in family lines with Lynch syndrome have been reported , with MSH2 and MLH1 aberrations accounting for about 90%, and MSH6 and PMS2 gene aberrations accounted for only 7 and 1% of cases, respectively . Thus, MLH1 and MSH2 mutations are particularly associated with Lynch syndrome. These mutations are also predispositions to cancers in the endometrium, small intestine, and ovary . Both genes encode mismatch repair proteins, and inactivation of these proteins is thought to induce MSI in tumors . Since microsatellites (short-tandem repeats, STRs) are generally present in non-coding regions, mutations in STRs do not lead to abnormal protein production. However, some STRs are present in regions with important genes, such as those encoding BCL2-associated X protein (BAX), which is involved in apoptosis induction, Insulin-like growth factor 2 receptor (IGF2R), which is associated with inhibition of cell proliferation, and mutations in these regions are thought to be involved in cancerization of cells .
Typical cases of Lynch syndrome-related ovarian cancer develop early, and the tumor is FIGO cancer stage I and non-serous in many cases . Grindedal et al. reported that the prognosis of Lynch syndrome-related invasive ovarian cancer is better than that of invasive cancer in patients carrying a BRCA1/2 mutation . Regarding endometrial cancer, Shih et al. investigated MMR protein deficiency in 56 women aged ≤40 years old with endometrial cancer, and found abnormal MMR in 9 cases. The families of these 9 patients had a medical history of Lynch syndrome; the mean BMIs were 23.4 and 31.2 in the patients with and without abnormal MMR, respectively; the stage was I in 80% of the cases in the patients without abnormal MMR, but ≥II in 90% of those with abnormal MMR; muscular layer and lymph vascular invasions were noted in many cases with abnormal MMR; and the 5-year/5-year exacerbation-free survival rate was 70% . Many pathological aspects of familial endometrial cancer are unclear despite the high malignancy, and an effective screening method has yet to be established.
Lynch syndrome cases with epimutation of the MLH1 or MSH2 promoter region in blood cells without morbid MMR gene mutation have recently been discovered, showing that germline MLH1 epimutation causes Lynch syndrome. Takahashi et al. reported that MLH1 protein expression was deficient in Lynch syndrome patients carrying a germline mutation in the 5΄ splice site of MLH1, and that mutation of this intron of MLH1 induced aberrant splicing, influencing the onset of Lynch syndrome . In family lines with MSH2 methylation, germline mutation of the Epithelial cell adhesion molecule (EPCAM) gene present upstream of MSH2 has been reported to be the cause of epimutation. EPCAM is strongly expressed in epithelial tissue and cancers  and a defective 3΄-terminal of this gene causes read-through to MSH2, resulting in hypermethylation of the CpG island promoter . Interestingly, no MSH2 methylation in any other cancer has been reported to date. In contrast to the allelic methylation found in many patients with constitutional methylation of MLH1, allelic methylation of MSH2 occurs in only about 50%. This methylation level is also dependent on the tissues examined. Unlike MLH1 epimutation, inheritance of MSH2 methylation following Mendel's laws has been reported. In Lynch syndrome caused by these epimutations, methylation levels vary among epimutation carriers in the same family line and among tissues within the same patient . In addition, the MLH1 and MSH2 mutations show racial differences. In a comparison of Asian and Western subjects based on International Society of Gastrointestinal Hereditary (InSiGHT) data, Wei et al. found differences in mutations in the regions containing MLH1 and MSH2, with some mutations found to be more frequent or to be present only in Asian subjects . This indicates the importance of consideration of racial differences in evaluating mutations in screening .
Epimutation has diverse characteristics: some epimutations are inherited or eliminated in embryogenesis, while others are inherited in patterns that do not follow Mendel's laws. Cancers associated with epimutations include Lynch syndrome (HNPCC), familial colorectal cancer, CLL, breast cancer, and ovarian cancer. Defined histological characteristics of epimutation-associated tumors have been suggested, and it is possible that the histologic type of cancers will ultimately be identifiable based on the methylation pattern detected in normal tissue, which may reduce the need for invasive tests such as tumor tissue biopsy . Furthermore, elucidation of differences in the methylation pattern between healthy subjects and cancer patients may facilitate low-invasive cancer risk evaluation in healthy individuals.
To develop these techniques, it will be important to identify the causes of methylation. The extent of variation of methylation in normal somatic cell tissues within an individual is unclear, but conservation of the methylation pattern in an individual has been shown . Different DNA methylation patterns in monozygotic twins have been observed, and the difference increased as the twins lived in different environments . Aging-dependent methylation of non-methylated CpG islands has also been shown, and it has been suggested that metabolite ingestion can influence methyl metabolism, such as metabolism of folic acid, choline, vitamin B12, and betaine, and change the methylation pattern. In particular, the influence of environmental factors in early embryogenesis may serve as a predisposition to cancers and other diseases associated with epigenetic changes . Methylation is influenced by environmental factors and aging, in addition to inheritance, as described above, and further studies on the association of these factors with epimutation are required.
Improvement of epigenetic aberration has also been attempted through induction of re-expression of tumor suppressor genes, with some success using DNA methyltransferase (DNMT) inhibitors, azacitidine and decitabine, for blood malignant tumors . However, intense epigenetic therapy using a DNMT inhibitor and a histone deacetylase (HDAC) inhibitor concomitantly did not achieve complete chromosome remodeling, and stable gene re-expression was not obtained . Moreover, reinhibition of re-expressed genes has occurred after suspension of epigenetic therapy in many studies. These findings indicate that there are many problems to be overcome in development of epigenetic therapy.
The authors gratefully acknowledge grant support from the Japan Society for the Promotion of Science (JSPS) through a Grant-in-Aid for Scientific Research (KAKENHI), a Grant-in-Aid for Scientific Research (B) (22390313), a Grant-in-Aid for Scientific Research (C) (22591866), and a Grant-in-Aid for Young Scientists (B) (21791573); the Ichiro Kanehara Foundation; Kobayashi Foundation for Cancer Research; and the Keio University Medical Science Fund through a Research Grant for Life Sciences and Medicine.


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Venkata Mohan is the author of Sociological Thoughts: In the Light of J. Krishnamurti's Philosophy, Ethical Thought– Buddha Damasio, and two other non-fiction books. Hehas also penned his autobiography Marriage of a Monk A Story of My Ideas and Life. A B.Tech. from IIT-Madras,he is the director of Feynman IAS Institute, Hyderabadwhere he teaches Sociology, Ethics and Essay.
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Published Books 11
Caste and Religion in India
Books by Venkata Mohan
This book comprehensively deals with issues of caste and religion in the context of India, covering the UPSC syllabus for Sociology and Anthropology. It includes historical and ideological perspectives on the caste system presented by various thinkers and activists. It traces the philosophical connections across the major religions of India and describes their impact on the world.
IAS Ethics & Essay
Books by Feynman Ias
This book tells IAS aspirants what Essay and Ethics (GS-4) papers are about and how to score high in both the papers. The previous years' questions are listed topic-wise. The student gets to know what topics are important. This book provides the essential framework for exam preparation in Essay and Ethics.
IAS Sociology
This book tells IAS aspirants what sociology is and how to score high in this paper. The previous years' questions from 2012 are listed topic-wise. They are classified in such a way that the student gets to know the linkages across the topics. This book provides the essential framework for exam preparation in sociology.
IAS Anthropology
This book tells IAS aspirants what anthropology is and how to score high in this paper. The previous years' questions from 2009 are listed topic-wise. They are classified in such a way that the student gets to know the linkages across the topics. This book provides the essential framework for exam preparation in anthropology.
The book introduces you to anthropology, covers research methods, gender-based issues, economic and political organisations and religion. It can serve as a good textbook for students of anthropology, while also helping sociology students. It gives latest research and India specific examples.
Lectures on Andhra Pradesh Economy
Amaravati is exclusive, alienating to other regions and damaging to the ecology. The Polavaram dam is insensitive to lakhs of people, environmentally destructive and, what is worse, unsafe. The first government of AP obviously got its priorities wrong. Instead of discussing these priorities, the people got busy blaming the Centre and making unfair demands on it. This book, apart from critiquing the priorities set by AP's first government, argues for an eco-frie
Amaravati is exclusive, alienating to other regions and damaging to the ecology. The Polavaram dam is insensitive to lakhs of people, environmentally destructive and, what is worse, unsafe. The first government of AP obviously got its priorities wrong. Instead of discussing these priorities, the people got busy blaming the Centre and making unfair demands on it. This book, apart from critiquing the priorities set by AP's first government, argues for an eco-friendly and inclusive economic model giving primacy to agriculture.
What Is Wrong with Advaita?
This is a book for the students of enlightenment, as well as its seekers. It examines the issues related to enlightenment in the light of Antonio Damasio's scientific findings. It attempts answers to questions such as 'Is self an illusion? Is there consciousness outside body-mind?'
Anthropological Thought
Praise for Sociological Thought
"Venkata Mohan's Sociological Thought: In the Light of J. Krishnamurti's is an exceptional and brilliant contribution of the author whom I consider as a unique academic intellectual of contemporary times. I am sure no one in the academic sphere has so far attempted to explain social Thought the way the author has analyzed and presented."
G. Satyanarayana,
Emeritus professor of Sociologyat
at Osmania University, Hyderabad.
What is culture? How should one study it? Is a science of culture possible? And what is science anyway? Many thinkers have been attempting to answer these questions. This book covers the answers provided by anthropologists ranging from classical evolutionists to postmodernists
Why Bruce Lee on the cover Page? The reason is...
Sociological Thought
"This book, Sociological Thought: In the Light of J. Krishnamurti's Philosophy, is an exceptional and brilliant contribution of the author whom I consider as a unique academic intellectual of contemporary times. I am sure no one in the academic sphere has so far attempted to explain Social Thought the way the author has analyzed and presented."
Emeritus professor of Sociology at Osmania University
Emeritus professor of Sociology at Osmania University, Hyderabad.
This book first covers the basic ideas in Sociological Thought from Comte to postmodernism. It comprehensively discusses Marx, Weber, Durkheim and Parsons, giving prominent place to Marx. It then takes Thought to its philosophical roots and also widens it by bringing in Kant, Nietzsche and Freud.
Why J. Krishnamurti here? Well, that is a way of bringing the Buddha to the discussion.
Ethical Thought
Why is a certain behavior considered ethical? By what processes does a certain behavior become ethical? Why are some people more capable of behaving ethically? This book discusses questions such as these with the help of the perspectives drawn from three distinct fields: Religion, Philosophy and Neuroscience. Theorists from the ancient to the recent – from the Buddha and Socrates to Antonio Damasio – are covered.
Marriage of a Monk
An IIT graduate, who always dreamt of becoming a monk, married an IAS officer. Both thought they understood each other, as well as their priorities in life, so well that neither her commitment to work nor his pursuit of Truth would be affected by the marriage.
What they did not know was that life does not oblige mortal's plans…
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SportsHockeyNew York Rangers
Rangers' Sammy Blais remains optimistic despite inability to score
Sammy Blais #91 of the New York Rangers checks Connor Murphy #5 of the Chicago Blackhawks during the third period at Madison Square Garden on Saturday, Dec. 3, 2022 in New York City. Credit: Jim McIsaac
By Colin Stephensoncolin.stephenson@newsday.comColinSNewsday Updated December 10, 2022
DENVER — Sammy Blais had some excellent scoring chances in Wednesday's game in Las Vegas but was unable to convert. As the Rangers entered the finale of their two-game road trip Friday night in Colorado, he still had not scored a goal this season or in his 39-game Rangers career.
"For sure, it's in the back of my head a little bit,'' Blais said. "But you know, I just try not to think about it a lot. When I think about it too much, it won't come, you know? So I just try to stay positive, and I'm doing some good stuff out there. Like I'm one of the most physical guys in the league right now, so I'm just trying to keep doing that.''
The 6-2, 205-pound Blais entered Friday ninth in the NHL in hits with 88. His hits per 60 minutes (21.3) ranked third in the league.
"It's always been in my game [and] I'm on the fourth line, so I try to bring physicality, and I try not to think about scoring a goal too much, but for sure it would be fun,'' he said. "I'm not gonna lie to you.''
Blais was asked if he has a special celebration planned for whenever he gets his first goal.
"No,'' he said with a laugh, "I'm just putting my hands in the air.''
Notes & quotes: Coach Gerard Gallant used the same lineup as he did in Wednesday's game in Vegas, meaning rookie forward Vitali Kravtsov was a healthy scratch for the second straight game. Gallant used Barclay Goodrow in that spot.
"I'm comfortable with what our lineup is right now,'' Gallant said. "I like Goodrow up there, he's played great hockey for us all year long . . . nothing against Kravy. It's just, I like the lineup right now.''
The other scratch was D Ben Harpur, who has yet to play since being called up from AHL Hartford last Saturday.
C Ryan Carpenter, who had been placed on waivers Thursday, cleared and was assigned to Hartford.
By Colin Stephenson
colin.stephenson@newsday.comColinSNewsday
Colin Stephenson covers the Rangers for Newsday. He has spent more than two decades covering the NHL and just about every sports team in the New York metropolitan area.
Rangers' Trocheck confident new line pairing with Kreider, Vesey will work
Zibanejad, Panarin score in shootout as Rangers beat Avs
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The Rotary Club of Whitby Sunrise is a diverse and dynamic, fast-paced club located in Whitby, Ontario Canada. Dedicated Whitby Sunrise Rotarians meet weekly on Wednesday mornings for fellowship, and to learn and practice the Rotary motto of "Service Above Self". Taking part in both local and International projects, every member can find a way to take part and "give back" to the community and the world. Check out our YouTube channel to see some of our initiatives.


Plan started working in Myanmar in 2008 following Cyclone Nargis, which tore through the country's southern coast killing 140,000 people. Together with local partners, our post-Nargis activities included emergency relief, disaster risk reduction, early childhood care and development, and school construction.
GDP per Capita: U.S. $1,700.
In July 2012 Plan entered into a new, longer-term commitment in Myanmar with the signing of a Memorandum of Agreement with the Ministry of Social Welfare, Relief and Resettlement.
Our initial target areas include the regions/states of Ayeyarwady, Sagaing, Rakhine and Mandalay, although we are investigating the possibility of expanding into other areas including Kayah and Kayin State. Plan Myanmar is primarily implementing programmes in partnership with local organisations and has not yet started any sponsorship activities.
Plan's programmes in Myanmar will include early childhood care and development; maternal and neonatal health with an emphasis on nutrition; water, sanitation and hygiene; disaster risk management; and child protection. At present Plan is undertaking a sector situation analysis in these areas and also selecting specific townships in which to implement programmes.
Plan's work has so far directly benefited over 194,000 people.


Do We Need a Revolutionary Approach to Bring Creativity into Education?
Creative Contradictions in Education is a provocative collection of essays by international experts who tackle difficult questions about creativity in education from a cross-disciplinary perspective. The contributors to this volume examine and provide fresh insights into the tensions and contradictions that researchers and educators face when attempting to understand and apply creativity in educational contexts. Creativity in education is surrounded by many contradictions. Teachers generally value creativity, but question the role it can and should play in their classroom. Many educators find themselves feeling caught between the push to promote students' creative thinking skills and the pull to meet external curricular mandates, increased performance monitoring, and various other curricular constraints. This book brings together leading experts who provide fresh, cross-disciplinary insights into how creative contradictions in education might be addressed. Contributors will draw from existing empirical and theoretical work, but push beyond "what currently is" and comment on future possibilities. This includes challenging the orthodoxy of traditional conceptions of creativity in education or making a case for maintaining particular orthodoxies.


Current reporting partners include WNYC, WHYY, WBGO, NJ Spotlight, The Record of the USA Today Network and New America Media; additional reporting partners will be added this summer. Editorial components of the project are being coordinated by the Center for Cooperative Media at Montclair State University, and audience engagement is being coordinated by Reveal from The Center for Investigative Reporting.
Current reporting partners include WYNC, WHYY, NJ Spotlight, The Record of the USA Today Network and New America Media; additional reporting partners will be added this summer. Editorial components of the project are being coordinated by the Center for Cooperative Media at Montclair State University, and audience engagement is being coordinated by Reveal from The Center for Investigative Reporting.
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Picrasma tetramera är en bittervedsväxtart som först beskrevs av Ignatz Urban, och fick sitt nu gällande namn av W.W.Thomas, J.D.Mitch. & A.Noa. Picrasma tetramera ingår i släktet Picrasma och familjen bittervedsväxter. Inga underarter finns listade i Catalogue of Life.

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tetramera

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ISO standards (International Organization for Standardization)
Omni Processor - Landscaping and Standards Development (TÜV SÜD Asia Pacific Pte Ltd)
TuvSudWS
WASH Programme Manager, Water Services, TÜV SÜD Singapore. (Former roles: Hydrogeologist & exploration geologist in Pilbara and Department of Water, Western Australia)
17 Oct 2018 11:57	#26276 by TuvSudWS
Today I would like to introduce a project that you that I lead here at TÜV SÜD Asia Pacific Pte Ltd in Singapore. It is funded by the Bill & Melinda Gates Foundation and I had previously talked about it here in this thread: forum.susana.org/iso-standards-internati...on-treatment-systems .
By the way, TÜV SÜD is also in the process of becoming a SuSanA partner organization.
Title: Omni Processor - Landscaping and Standards Development
To develop a private technical standard that will lead to an International Workshop Agreement for safe and sustainable off-grid community scale sanitation technologies to ensure safe and sustainable solutions for the poor in developing countries
The Omni-Processor program aims to develop low-cost approaches for processing fecal sludge and the combined processing of fecal sludge and solid waste. The goal is to develop processors that are smaller than traditional treatment plants, with each processor supporting some 1,000 to 100,000 residents. Ideally, processed waste will be converted into products, forms of energy, or fertilizers and other soil amendments, which can generate revenue and thereby offset waste collection costs and increase people's standard of living. Currently, there is no single international accepted and applicable standard available for Omni Processor type technologies – community scale, non-centralized, sustainable, sewage & solid-waste treatment systems – targeted at developing countries. These low-cost approaches should result in systems which are smaller than traditional waste treatment plants should help in addressing fecal sludge management where the failure of the traditional centralized/sewered and existing decentralized sanitation ecosystem results in risks to human and environmental health and safety. The lack of a standard results in scattered technology development, failure of installed systems, the pursuit of non-suitable technologies and the lack of innovative solutions or ability to compare the promise of possible solutions.
The development of a private technical standard that will lead to an International Workshop Agreement for safe and sustainable off-grid community scale sanitation technologies and will help ensure that only safe and sustainable solutions are being procured, installed and used for the benefit of the poor in developing countries.
The technical standard will ensure that a certified system will meet a clear set of health and environmental safety and regulatory parameters and support the comparison of performance enabling informed decisions. The standard will also provide a common, transparent basis that promotes both technology development and commercial adoption.
Research or implementation partners:
TÜV SÜD initially developed a private technical standard with a selected group of experts, which was taken as the basis for an ISO International Workshop Agreement (IWA 28:2018, published in April 2018) document. Supported by American National Standards Institute (ANSI), Association Sénégalaise de Normalisation (ASN) and the foundation as the Chairman for Project Committee (PC) 318, IWA 28 is currently under development into a full ISO standard.
ISO PC 318 is lead by Raymond Lee, TÜV SÜD as Project Leader, Mr Sun Kim, Bill and Melinda Gates Foundation as Chairman, Sally Seitz, ANSI and Mr. El Hadji Abdourahmane Ndione, ASN as Secretary.
Biggest successes so far:
The formation of PC 318 follows the successful publication of International Workshop Agreement (IWA) 28, Faecal sludge treatment units – Energy independent, prefabricated, community-scale resource-recovery units – Safety and performance, in April 2018. Supported through a grant from the Bill and Melinda Gates Foundation, TÜV SÜD led the development of the private standard that served as the basis for the IWA. TÜV SÜD will now serve as the Secretariat of the Singapore National Mirror Committee, which will represent Singapore in providing input on the developing standard.
Singapore delegation represented by TÜV SUD colleagues
Main challenges / frustration:
Getting the right technical experts on board, getting consensus amongst the diverse stakeholders, working on an aggressive timeline
The first ISO PC-318 meeting was held in Dakar 16 - 19th July 2018, attended by over 25 countries to review and draft on the published IWA 28 document "Faecal sludge treatment units – Energy independent, prefabricated, community-scale resource-recovery units – Safety and performance
Grant size: USD $2,011,387
If you want to access some additional links for this project, please see here in the SuSanA project database: www.susana.org/en/knowledge-hub/projects/database/details/293
(scroll down to the end of the project description)
I'd also be happy to answer your questions or field your comments in this thread.
I am going to introduce two more of our projects in the next few days.
Mei Yee Chan
Previous WASH experience:
World Toilet Organization - Programme Manager - Developed and led China Rainbow School Toilet Project & Floating toilet for floating school on Tonle Sap Lake, Cambodia.
Master research, Cranfield University, in Sanitation Ownership and Servicing: Access and Affordability in Antananarivo, Madagascar - The effective demand of a Loowatt toilet.
Publications: A systematic review of success factors in the community management of rural water supplies over the past 30 years
20180716_153222.jpg (Filesize: 101KB)
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Last Edit: 18 Oct 2018 14:24 by TuvSudWS.	Reason: add caption
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The Student Printz is the award-winning, student-run newspaper at The University of Southern Mississippi in Hattiesburg, Mississippi. We publish every Wednesday morning and online daily at www.studentprintz.com.
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The newspaper changed its name to the Student Printz in 1927, by campus referendum. The name was chosen because it sounded like the name of a popular contemporary musical, The Student Prince, which opened on Broadway in 1924.
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redpajama_set_name: RedPajamaGithub


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Elon Musk Turned Down Uber's Self-Driving Partnership Offer
'Elon spent the rest of the call convincing me that it's too far out,' Travis Kalanick said.
Image credit: Beck Diefenbach/Reuters via engadget
Steve Dent
This story originally appeared on PCMag
A new book on Uber by Fortune's Adam Lashinsky is coming out soon, but Bloomberg has revealed one juicy anecdote ahead of time. CEO Travis Kalanick reportedly called up Tesla CEO Elon Musk to propose a partnership on self-driving cars, but Musk rebuffed the offer and even tried to talk him out of it.
"I said, 'Look man, we should partner,' " Kalanick stated in the book. "Elon spent the rest of the call convincing me that it's too far out, and it's not realistic, that I should just stick to what we do best and be focused, or I'm going to fuck it all up. That's when I knew Tesla was competing."
Kalanick wasn't aware that Tesla was already working on autonomous vehicle tech, even though it had unveiled its "Autopilot" driving assistant hardware. Shortly afterwards, Musk detailed a master plan for self-driving Tesla cars, including an autonomous ride-hailing service that would directly compete with Uber. Tesla has done perhaps the most impressive fully autonomous demo yet, steering a car from a customer's house to Tesla offices and parking without any human intervention.
Uber, meanwhile, has been mired in problems. It was sued by Google's Waymo self-driving division for intellectual property theft and now risks a criminal prosecution. On top of that, it recently demoted self-driving lead Anthony Levandowski, who was subsequently barred by a judge from working on any projects involving crucial LIDAR tech.
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Elon Musk Received the Highest CEO Compensation Package Ever, and 27 Other Crazy Things We've Learned About the SpaceX and Tesla CEO
Elon Musk Just Trolled Jeff Bezos on Twitter and It Could Reignite a Years-Old Feud Between the Billionaires
Tesla Investigated Elon Musk After He Reportedly Pushed a Former Employee
Elon Musk's Pentagon Security Clearance Is Under Review Over Marijuana Use
Making $1 Million: Here's How Long It Took the World's Super-Rich (Infographic)


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