Heart development

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Heart_development

Heart development

Development of the human heart during the first eight weeks (top), and the formation of the heart chambers (bottom). In this figure, the blue and red colors represent blood inflow and outflow (not venous and arterial blood). Initially, all venous blood flows from the tail/atria to the ventricles/head, a very different pattern from that of an adult. Heart development, also known as cardiogenesis, refers to the prenatal development of the heart. This begins with the formation of two endocardial tubes which merge to form the tubular heart, also called the primitive heart tube. The heart is the first functional organ in vertebrate embryos.

The tubular heart quickly differentiates into the truncus arteriosus, bulbus cordis, primitive ventricle, primitive atrium, and the sinus venosus. The truncus arteriosus splits into the ascending aorta and the pulmonary trunk. The bulbus cordis forms part of the ventricles. The sinus venosus connects to the fetal circulation.

The heart tube elongates on the right side, looping and becoming the first visual sign of left-right asymmetry of the body. Septa form within the atria and ventricles to separate the left and right sides of the heart.

Early development

The heart derives from embryonic mesodermal germ layer cells that differentiate after gastrulation into mesothelium, endothelium, and myocardium. Mesothelial pericardium forms the outer lining of the heart. The inner lining of the heart – the endocardium, lymphatic and blood vessels, develop from endothelium.

Endocardial tubes

In the splanchnopleuric mesenchyme on either side of the neural plate, a horseshoe-shaped area develops as the cardiogenic region. This has formed from cardiac myoblasts and blood islands as forerunners of blood cells and vessels. By day 19, an endocardial tube begins to develop in each side of this region. These two tubes grow and by the third week have converged towards each other to merge, using programmed cell death to form a single tube, the tubular heart.

From splanchnopleuric mesenchyme, the cardiogenic region develops cranially and laterally to the neural plate. In this area, two separate angiogenic cell clusters form on either side and coalesce to form the endocardial tubes. As embryonic folding starts, the two endocardial tubes are pushed into the thoracic cavity, where they begin to fuse together, and this is completed at about 22 days.

At around 18 to 19 days after fertilisation, the heart begins to form. Early in the fourth week, around day 22 the developing heart starts to beat and to pump circulating blood. The heart begins to develop near the head of the embryo in the cardiogenic area. Following cell signalling, two strands or cords begin to form in the cardiogenic region As these form, a lumen develops within them, at which point, they are referred to as endocardial tubes. At the same time that the tubes are forming other major heart components are also being formed. The two tubes migrate together and fuse to form a single primitive heart tube which quickly forms five distinct regions. From head to tail, these are the truncus arteriosus, bulbus cordis, primitive ventricle, primitive atrium, and the sinus venosus. Initially, all venous blood flows into the sinus venosus, and contractions propel the blood from tail to head, or from the sinus venosus to the truncus arteriosus. The truncus arteriosus will divide to form the aorta and pulmonary artery; the bulbus cordis will develop into the right ventricle; the primitive ventricle will form the left ventricle; the primitive atrium will become the front parts of the left and right atria and their appendages, and the sinus venosus will develop into the posterior part of the right atrium, the sinoatrial node and the coronary sinus.

Heart tube position

The central part of cardiogenic area is in front of the oropharyngeal membrane and the neural plate. The growth of the brain and the cephalic folds push the oropharyngeal membrane forward, while the heart and the pericardial cavity move first to the cervical region and then into the chest. The curved portion of the horseshoe-shaped area expands to form the future ventricular infundibulum and the ventricular regions, as the heart tube continues to expand. The tube starts receiving venous drainage in its caudal pole and will pump blood out of the first aortic arch and into the dorsal aorta through its polar head. Initially the tube remains attached to the dorsal part of the pericardial cavity by a mesodermal tissue fold called the dorsal mesoderm. This mesoderm disappears to form the two pericardial sinuses the transverse and the oblique pericardial sinuses, which connect both sides of the pericardial cavity.

The myocardium thickens and secretes a thick layer of rich extracellular matrix containing hyaluronic acid which separates the endothelium. Then mesothelial cells form the pericardium and migrate to form most of the epicardium. Then the heart tube is formed by the endocardium, which is the inner endothelial lining of the heart, and the myocardial muscle wall which is the epicardium that covers the outside of the tube.

Heart folding

The heart tube continues stretching and by day 23, in a process called morphogenesis, cardiac looping begins. The cephalic portion curves in a frontal clockwise direction. The atrial portion starts moving in a cephalically and then moves to the left from its original position. This curved shape approaches the heart and finishes its growth on day 28. The conduit forms the atrial and ventricular junctions which connect the common atrium and the common ventricle in the early embryo. The arterial bulb forms the trabecular portion of the right ventricle. A cone will form the infundibula blood of both ventricles. The arterial trunk and the roots will form the proximal portion of the aorta and the pulmonary artery. The junction between the ventricle and the arterial bulb will be called the primary intra-ventricular hole. The tube is divided into cardiac regions along its craniocaudal axis: the primitive ventricle, called primitive left ventricle, and the trabecular proximal arterial bulb, called the primitive right ventricle. This time no septum is present in heart.

Heart chambers

Sinus venosus

In the middle of the fourth week, the sinus venosus receives venous blood from the poles of right and left sinus. Each pole receives blood from three major veins: the vitelline vein, the umbilical vein and the common cardinal vein. The sinus opening moves clockwise. This movement is caused mainly by the left to right shunt of blood, which occurs in the venous system during the fourth and fifth week of development.

When the left common cardinal vein disappears in the tenth week only the oblique vein of the left atrium and the coronary sinus remain. The right pole joins the right atrium to form the wall portion of the right atrium. The right and left venous valves fuse and form a peak known as the septum spurium. At the beginning, these valves are large, but over time the left venous valve and the septum spurium fuse with the developing atrial septum. The upper right venous valve disappears, while the bottom venous valve evolves into the inferior valve of the vena cava and the coronary sinus valve.

Heart wall

The main walls of the heart are formed between day 27 and 37 of the development of the early embryo. The growth consists of two tissue masses actively growing that approach one another until they merge and split light into two separate conduits. Tissue masses called endocardial cushions develop into atrioventricular and conotroncal regions. In these places, the cushions will help in the formation of auricular septum, ventricular conduits, atrio-ventricular valves and aortic and pulmonary channels.

Atria

Further information: Interatrial septum § Development

The developing heart at day 30. The septum primum (top, middle) develops downwards to separate the initially joined primitive atrium into left and right atria.

At the end of the fourth week, a crest grows that leaves the cephalic part. This crest is the first part of the septum primum. The two ends of the septum extend into the interior of the endocardial cushions in the atrioventricular canal. The opening between the bottom edge of the septum primum and endocardial cushions is the ostium primum (first opening). The extensions of the upper and lower endocardial pads grow along the margin of the septum primum and close the ostium primum. Coalescence of these perforations will form the ostium secundum (second opening), which allows blood to flow freely from the right atrium to the left.

When the right of the atrium expands due to the incorporation of the pole of the sinus, a new fold appears, called the septum secundum. At its right side it is fused with the left venous valve and the septum spurium. A free opening will then appear, called the foramen ovale. The remains of the upper septum primum, will become the valves of the foramen ovale. The passage between the two atrial chambers consists of a long oblique slit through which blood flows from the right atrium to the left.

Ventricles

Initially, a single pulmonary vein develops in the form of a bulge in the back wall of the left atrium. This vein will connect with the veins of the developing lung buds. As development proceeds, the pulmonary vein and its branches are incorporated into the left atrium and they both form the smooth wall of the atrium. The embryonic left atrium remains as the trabecular left atrial appendage, and the embryonic right atrium remains as the right atrial appendage.

Septum formation of the atrioventricular canal

At the end of the fourth week, two atrioventricular endocardial cushions appear. Initially the atrioventricular canal gives access to the primitive left ventricle, and is separated from arterial bulb by the edge of the ventricular bulb. In the fifth week, the posterior end terminates in the center part of the upper endocardial cushion. Because of this, blood can access both the left primitive ventricle and the right primitive ventricle. As the anterior and posterior pads project inwardly, they merge to form a right and left atrioventricular orifice.

Atrioventricular valves

When forming intra-atrial septa, atrio-ventricular valves will begin to grow. A muscular interventricular septum begins to grow from the common ventricle to the atrio-ventricular endocardial cushions. The division begins in the common ventricle where a furrow in the outer surface of the heart will appear the interventricular foramen eventually disappears. This closure is achieved by further growth of the muscular interventricular septum, a contribution of trunk crest-conal tissue and a membranous component.

Valves and outflow tracts

Truncus septum formation and arterial cone

The arterial cone is closed by the infundibular cushions. The trunk cones are closed by the forming of an infundibulotroncal septum, which is made from a straight proximal portion and distal spiral portion. Then, the narrowest portion of the aorta is in the left and dorsal portion. The distal portion of the aorta is pushed forward to the right. The proximal pulmonary artery is right and ventral, and the distal portion of the pulmonary artery is in the left dorsal portion.

Pacemaker and conduction system

The rhythmic electrical depolarization waves that trigger myocardial contraction is myogenic, which means that they begin in the heart muscle spontaneously and are then responsible for transmitting signals from cell to cell. Myocytes that were obtained in the primitive heart tube, start beating as they connect together by their walls in a syncytium. Myocytes initiate rhythmic electrical activity, before the fusion of the endocardial tubes. The heartbeat begins in the region of the pacemaker which has a spontaneous depolarization time faster than the rest of myocardium.

The primitive ventricle acts as initial pacemaker. But this pacemaker activity is actually made by a group of cells that derive from the sinoatrial right venous sinus. These cells form an ovoid sinoatrial node (SAN), on the left venous valve. After the development of the SAN, the superior endocardial cushions begin to form a pacemaker also known as the atrioventricular node. With the development of the SAN, a band of specialized conducting cells start to form creating the bundle of His that sends a branch to the right ventricle and one to the left ventricle. Most conduction pathways originate from the cardiogenic mesoderm but the sinus node may be derived from the neural crest.

The human embryonic heart begins beating approximately 21 days after fertilization, or five weeks after the last normal menstrual period (LMP), which is the date normally used to date pregnancy in the medical community. The electrical depolarizations that trigger cardiac myocytes to contract arise spontaneously within the myocyte itself. The heartbeat is initiated in the pacemaker regions and spreads to the rest of the heart through a conduction pathway. Pacemaker cells develop in the primitive atrium and the sinus venosus to form the sinoatrial node and the atrioventricular node respectively. Conductive cells develop the bundle of His and carry the depolarization into the lower heart. Cardiac activity is visible beginning at approximately 5 weeks of pregnancy.

The human heart begins beating at a rate near the mother’s, about 75-80 beats per minute (BPM). The embryonic heart rate (EHR) then accelerates linearly for the first month of beating, peaking at 165-185 BPM during the early 7th week, (early 9th week after the LMP). This acceleration is approximately 3.3 BPM per day, or about 10 BPM every three days, an increase of 100 BPM in the first month.

After peaking at about 9.2 weeks after the LMP, it decelerates to about 150 BPM (+/-25 BPM) during the 15th week after the LMP. After the 15th week the deceleration slows reaching an average rate of about 145 (+/-25 BPM) BPM at term.

Imaging

See also: Medical imaging in pregnancy

 

Device for obstetric ultrasonography including usage in 1st trimester.

 

Transvaginal ultrasonography of an embryo at 5 weeks and 5 days of gestational age, with discernible cardiac activity (arrow).

In the first trimester, the heartbeat can be visualized, and the heart rate quantified by obstetric ultrasonography. A study of 32 normal pregnancies showed that a fetal heartbeat was visible at a mean human chorionic gonadotropin (hCG) level of 10,000 UI/l (range 8650-12,200). Obstetric ultrasonography can also use Doppler technique on key vessels such as the umbilical artery to detect abnormal flow.

Doppler fetal monitor

In later stages of pregnancy, a simple Doppler fetal monitor can be used to quantify the fetal heart rate.

During childbirth, the parameter is part of cardiotocography, which is where the fetal heartbeat and uterine contractions are continuously recorded.

Heart rates

Starting at week 5 the embryonic heart rate accelerates by 3.3 bpm per day for the next month. Before this, the embryo possesses a tubular heart.

The embryonic heart begins to beat at approximately the same rate as the mother's, which is typically 80 to 85 bpm. The approximate fetal heart rate for weeks 5 to 9 (assuming a starting rate of 80):

• Week 5 starts at 80 and ends at 103 bpm
• Week 6 starts at 103 and ends at 126 bpm
• Week 7 starts at 126 and ends at 149 bpm
• Week 8 starts at 149 and ends at 172 bpm
• At week 9 the embryonic heart tends to beat within a range of 155 to 195 bpm.

By the end of week 9, the embryonic heart has developed septa and valves, and has all four chambers.

At this point, the fetal heart rate begins to decrease, and generally falls within the range of 120 to 160 bpm by week 12.

Obstetric ultrasonography of an embryo of 8 weeks with visible heartbeat.

Additional images

• 

  M-mode sonography measuring embryonic heart rate.

• 

  Blood flow in a neonate

• 

  Human embryo, 38 mm, 8–9 weeks–anterior view, heart is visible.

Irreligion in India

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Atheism and agnosticism have a long history in India and flourished within the Śramaṇa movement. Indian religions like Jainism, Hinduism and Buddhism consider atheism to be acceptable. India has produced some notable atheist politicians and social reformers. According to the 2011 Census of India, 99.76% of Indians identified with a religion while 0.24% did not state their religious identity. According to the 2012 WIN-Gallup Global Index of Religion and Atheism report, 81% of Indians were religious, 13% were non-religious, 3% were convinced atheists, and 3% were unsure or did not respond.

History

Ancient India

See also: Śramaṇa

Several śramaṇa movements are known to have existed in India before the 6th century BCE (pre-Buddha, pre-Mahavira), and these influenced both the āstika and nāstika traditions of Indian philosophy. Martin Wiltshire states that the Śramaṇa tradition evolved in India over two phases, namely Paccekabuddha and Savaka phases, the former being the tradition of individual ascetic and latter of disciples, and that Buddhism and Jainism ultimately emerged from these as sectarian manifestations. These traditions drew upon already established Brahmanical concepts, states Wiltshire, to formulate their own doctrines. Reginald Ray concurs that Śramaṇa movements already existed and were established traditions in pre-6th century BCE India, but disagrees with Wiltshire that they were nonsectarian before the arrival of Buddha.

Schools of Philosophy

See also: Indian philosophy

In Indian philosophy, there are six major orthodox (astika) schools of Hindu philosophy—Nyaya, Vaisheshika, Samkhya, Yoga, Mīmāṃsā and Vedanta, and five major heterodox (nāstika) schools of Śramaṇa —Jain, Buddhist, Ajivika, Ajñana, and Cārvāka. The four most studied Nāstika schools, those rejecting the doctrine of Vedas, are Jainism, Buddhism, Cārvāka, and Ājīvika.

Charvaka

Main article: Charvaka

There is no heaven, no final liberation, nor any soul in another world, Nor do the actions of the four castes, orders, etc., produce any real effect.

— from the Sarvadarśanasaṅ̇graha, attributed to Brhaspati

The Cārvāka school originated in India around the 6th century BCE. It is classified as a nāstika school. It is noteworthy as evidence of a materialistic movement in ancient India. Followers of this school only accepted pratyakşa (perception) as a valid pramāna (evidence). They considered other pramāna like sabda (testimony), upamāna (analogy), and anumāna (inference) as unreliable. Thus, the existence of a soul (ātman) and God were rejected, because they could not be proved by perception. They also considered everything to be made of four elements: earth, water, air and fire. The Cārvāka pursued enjoyment of life and elimination of physical pain. So, they can be considered hedonistic. All of the original Cārvāka texts are considered lost. A much quoted sūtra (Barhaspatya sutras) by Brhaspati, who is considered the founder of the school, is thought to be lost. The Tattvopaplavasimha by Jayarāśi Bhaṭṭa (8th century CE) and the Sarvadarśanasaṅ̇graha by Madhavacarya (13th century) are considered important secondary Cārvāka texts.

Samkhya

Main article: Samkhya

Sāṃkhya is an āstika school, but has some atheistic elements. Sāṃkhya is a radically dualist philosophy. They believed that the two ontological principles, puruṣa (consciousness) and prakriti (matter), to be the underlying foundation of the universe. The objective of life is considered the achievement of separation of pure consciousness from matter (kaivalya). The reasoning within this system led to the Nir-isvara Sāṃkhya (Sāṃkhya without God) philosophy, which deemed the existence of God as unnecessary. There is the opposing reasoning which accepts God, called Sesvara Sankhya (Sāṃkhya with God). Samkhya Karika (c. 350 CE) is the earliest known systematic text of this philosophy.

Mīmāṃsā

Main article: Mīmāṃsā

Mīmāṃsā (meaning exegesis) is also an astika school. They believed the Vedas to be author-less and self-authenticating. They did not accept the Vedas as being composed by any ṛishi (saint), they considered them to not be authored by anyone (apauruṣeya). They accepted the minor deities of the Vedas but resisted any notion of a Supreme Creator. They only concentrated on upholding the ṛta (order) by following the duties of the Vedas. The foundational text of this school is the Mīmāṃsā Sutra by Jaimini (c. 200 BCE - 200 CE).

Ājīvika

Main article: Ājīvika

Ājīvika is yet another nastika school with an atheistic outlook. None of their scriptures survive and there is some question as to whether or not the accounts of them in secondary sources (often hostile) are accurate. They believed in a naturalistic atomic theory and held that the consequence of natural laws led to a deterministic universe. They denied karma, but upheld the atman. They lived in ascetic communities and existed in southern India until at least the 14th century.

Buddhism and Jainism

See also: God in Buddhism and God in Jainism

Jainism rejects the idea of a creator deity responsible for the manifestation, creation, or maintenance of this universe. According to Jain doctrine, the universe and its constituents (soul, matter, space, time, and principles of motion) have always existed. All the constituents and actions are governed by universal natural laws and an immaterial entity like God cannot create a material entity like the universe. Jainism offers an elaborate cosmology, including heavenly beings (devas), but these beings are not viewed as creators; they are subject to suffering and change like all other living beings, and must eventually die. Jains define godliness as the inherent quality of any soul characterising infinite bliss, infinite power, Kevala Jnana (pure infinite knowledge) and Perfect peace. However, these qualities of a soul are subdued due to karmas of the soul. One who achieves this state of soul through right belief, right knowledge and right conduct can be termed a god. This perfection of soul is called kevalin. A soul thus becomes a liberated soul – liberated of miseries, cycles of rebirth, world, karmas and finally liberated of body as well. This is called moksha.

Gautama Buddha rejected the existence of a creator deity, refused to endorse many views on creation and stated that questions on the origin of the world are not ultimately useful for ending suffering. Buddhism instead emphasises the system of causal relationships underlying the universe, pratītyasamutpāda, which constitute the dhamma and source of enlightenment. No dependence of phenomena on a supernatural reality is asserted in order to explain the behaviour of matter.

Philosophers and ancient texts

Ajita Kesakambali was a materialist philosopher. He is mentioned in the Samaññaphala Sutta. He rejected gods, an afterlife and karma. Payasi is a character, referred to as a prince, who appears in the Buddhist text Digha Nikaya in the Payasi Sutta. He didn't believe in rebirth or karma. He debated Kassapa, a disciple of Buddha, and lost according to Buddhist sources.

Jabali's speech from the Ramayana

See also: Jabali

In the Hindu epic Ramayana (Ayodhya Khanda), when Bharata goes to the forest to convince Rama to return home, he was accompanied by a sophist called Jabali ("जाबालिः"). Jabali uses nihilistic reasoning to convince Rama. He also says that rituals are a waste of food and scriptures were written by smart men so that people will give alms. But Rama calls him a deviant from the path of dharma ("धरमपथात"), refuses to accept his "nastika" views and blame his own father for taking Jabali into service. He also equates the Buddha to a thief. On hearing Rama's retort, Jabali retracts his statements, saying that he was merely arguing like a nihilist. However, these verses referring to the Buddha are considered a later interpolation, as those verses use a different metre.

The Carvaka incident in the Mahabharata

A character described as a Carvaka briefly appears in the Mahabharata (in the Shanti Parva). As Yudhishthira enters the city of Hastinapur, a brahmin, referred to as Carvaka, accuses him of killing his own kinsmen and says that he would suffer for it. The accuser is revealed to a rakshasa in disguise, who was a friend of Duryodhana. He had existed since the Satya Yuga by virtue of a boon from the god Brahma, that he could only be killed when he is showing contempt towards brahmins. He was killed by other brahmins by the chanting of sacred hymns and Yudhishthira was assured that his actions were within the kshatriya code. This event may be a possible denigration of the Carvaka philosophy.

Medieval India

In the 9th century CE, Jain philosopher Jinasena wrote the Mahapurana. The book contains the following often quoted words,

Some foolish men declare that a creator made the world. The doctrine that the world was created is ill-advised, and should be rejected. If God created the world, where was he before creation? If you say he was transcendent then, and needed no support, where is he now?

This quote was also featured later in Carl Sagan's book, Cosmos. In the 14th century, philosopher Madhavacarya wrote the Sarvadarśanasaṅ̇graha, which is a compilation of all Indian philosophies, including Carvaka, which is described in the first chapter.

Modern India

19th century

Between 1882 and 1888, the Madras Secular Society published a magazine called The Thinker (Tattuvavivesini in Tamil) from Madras. The magazine carried articles written by anonymous writers and republished articles from the journal of the London Secular Society, which the Madras Secular Society considered itself affiliated to.

20th century

The Yukthivadi in 1929 was the first atheist/rationalist magazine published in Malayalam.

Periyar E. V. Ramasamy (1879 - 1973) was an atheist and rationalist leader of Self-Respect Movement and Dravidar Kazhagam. His views on the irreligion are based on the eradication of the caste system, religion must be denied to achieve the obliteration of caste system.

Vinayak Damodar Savarkar (1883 –1966) was an eminent Hindu nationalist leader of the Indian independence movement. He was also an atheist and a staunch rationalist who disapproved of orthodox Hindu belief, dismissing cow worship as superstitious. Being Hindu, for him, was a cultural and political identity.

Meghnad Saha (1893 – 1956) was an atheist astrophysicist best known for his development of the Saha equation, used to describe chemical and physical conditions in stars.

Jawaharlal Nehru (1889–1964), India's first Prime Minister was a self-described scientific humanist. He wrote in his autobiography, Toward Freedom (1936), about his views on religion and superstition.

Bhagat Singh (1907-1931), an Indian revolutionary and socialist nationalist who was hanged for using violence against British government officials, was a staunch atheist. He laid out his views in the essay Why I Am an Atheist, written in jail shortly before his execution.

Goparaju Ramachandra Rao (1902-1975), better known by his nom de guerre "Gora," was a social reformer, anti-caste activist, atheist and desciple of Mahatma Gandhi. He and his wife, Saraswathi Gora (1912-2007) who was also an atheist and social reformer, founded the Atheist Centre in 1940. The Atheist Centre is an institute working for social change. Gora expounded his philosophy of positive atheism as a way of life. He later wrote more about positive atheism in his 1972 book, Positive Atheism. Gora also organised the first World Atheist Conference in 1972. Subsequently, the Atheist Centre has organised several World Atheist Conferences in Vijayawada and other locations.

Khushwant Singh (1915-2014), a prominent and prolific writer, of Sikh extraction, was avowedly non-religious.

In 1997, the Federation of Indian Rationalist Associations was founded.

21st century

E.A.Jabbar and M. M. Akbar during the debate, Adv Anil Kumar,President Kerala Yukthivadi Sangham in middle

 

Declaration of Ex-Muslims day by Ex-Muslims of Kerala, From left 1.Jazla Madassery,2.Mini,3.Liyakkathali CM,4.Arif Hussain,5.Shafeeq

 

Askar Ali (Hudavi),a 24 year old Muslim maulvi from Kerala who was also an imam at a mosque, who left Islam and become a rationalist and freethinker.He faced murder attempts from Muslims and goondas of Islamic ummah of his native place Malappuram.His video has got one million views on YouTube in a week it has published

Amartya Sen (1933-), an Indian economist, philosopher and Nobel laureate, is an atheist and he holds that this can be associated with one of the atheist schools in Hinduism, the Lokayata.

Sunday Sapiens, the successor of Maharashtra Rationalist Association, is actively involved in developing scientific temper and eradicating superstition.

In 2008, the website Nirmukta was founded. It later became an organisation aiming to promote free thought and secular humanism in India.

In 2009, historian Meera Nanda published a book entitled "The God Market". It examines how Hindu religiosity is gaining more popularity among the rising middle class, as India is liberalising the economy and adopting globalisation.

In March 2009, in Kerala, a pastoral letter addressing the laity was issued by the Kerala Catholic Bishops' Council urging the members to not vote for political parties which advocate atheism. In July 2010, another similar letter was issued.

On 10 March 2012, Sanal Edamaruku investigated a so-called miracle in Vile Parle, where a Jesus statue had started weeping and concluded that the problem was caused by faulty drainage. Later that day, during a TV discussion with some church members, Edamaruku accused the Catholic Church of miracle-mongering. On 10 April, Angelo Fernandes, President of the Maharashtra Christian Youth Forum, filed a police complaint against Edamaruku under the Indian Penal Code Section 295A. In July while on a tour in Finland, Edamaruku was informed by a friend that his house was visited by the police. Since the offence is not bailable, Edamaruku stayed in Finland.

On Friday 7 July 2013, the first "Hug an Atheist Day" was organised in India by Nirmukta. The event aimed to spread awareness and reduce the stigma associated with being an atheist.

On 20 August 2013, Narendra Dabholkar, a rationalist and anti-superstition campaigner, was shot dead by two unknown assailants, while he was out on a morning walk.

On 9th Jan 2021, E.A.Jabbar, freethinker, atheist, and rationalist from Kerala and Islamic preacher M.M. Akbar were engaged in a debate on Quran. Both sides claimed to have defeated the other debater even as there was no clear verdict. Manoj John, an internationally reputed atheist activist, was dragged into a controversy after Liyakhathali CM alleged that the former took money from M.M. Akbar to tilt the debate in Akbar's favour. International atheist organisations immediately conducted a four-month long investigation and absolved Manoj John of having any link with Islamic organisations or having accepted money from them. It later turned out to be a false allegation to tarnish Manoj John's rising reputation and recognition in the global freethought movement, showing at the same time the dissaray among the irreligion camp in Kerala state of India.

In August 2021, Abdul Khader Puthiyangadi, an Indian citizen, a rationalist from Kerala, He was arrested by UAE police in 2021 without bail and sentenced to prison in UAE for 3 years for criticizing Islam on social media in his native language Malayalam. Liyakhathali CM, who was working towards the release of Puthiyangadi without authorisation by the latter's family, has been accused of unauthorised and intransparent fund collection for this purpose by many secular activists but the allegations have not yet been proven.

On 10 January 2022, ex-Muslim rationalist Aneesh Jasy from Tamil Nadu was arrested without bail over his Facebook posts against Islam. 

Rise of ex-Muslims of Kerala

In 2021 in Kerala, several ex-Muslims formed an organisation called Ex-Muslims of Kerala. It is an organisation founded in 2021 by E. A. Jabbar, Liyakkathali CM, Arif Hussain, and a few others who left Islam in Kerala. The organisation gives support to those who left Islam, a minority that is facing persecution from the Islamic community, just because they left the religion. The organisation conducts debates with Islamic scholars and fundamentalists on various topics. Ex-Muslim of Kerala observes 9 January as ex-Muslim day, by conducting seminars on atheism and Islam.

Legal status, rights and laws

Atheism and irreligion are not officially recognised in India. Apostasy is allowed under the right to freedom of religion in the Constitution, and the Special Marriage Act, 1954 allows the marriage of people with no religious beliefs, as well as non-religious and non-ritualistic marriages. However, there are no specific laws catering to atheists and they are considered as belonging to the religion of their birth for administrative purposes. In forms, the box in which you need to fill in 'caste' and 'religion' is still present in a lot of forms. Some of these boxes on forms are also compulsory, and you do not always have the option of leaving them empty. The closest option you get is 'Choose not to say' or 'Other' as an answer to these boxes.

Ravi Kumar, an atheist from Haryana is another person who is struggling and fighting to be officially and legally irreligious and caste-less in India. He went to court to declare him officially atheist and he got one certificate in which it was mentioned that he had "No Caste, No Religion, & No God". Later, Justice Tejinder Singh Dhindsa of the Punjab and Haryana High Court said they had exceeded their authority and asked heim to return the certificate; he refused to do so. The Fatehabad district authorities who issued the cewrtificate wthdrew it in April 2019. Kumar plans to continue his quest to be officially declared an atheist.

Sneha Parthibaraja, a lawyer from Vellore was the first citizen in India to get an official 'no religion, no caste' certificate. She won this right on February 5, 2019, after a 9-year court battle. Indian actor Kamal Haasan, who is known for his atheism, congratulated her on Twitter for this achievement.

Hate speech laws and irreligion

Main article: Hate speech laws in India

Notable verdicts

On 29 October 2013, the Bombay High Court judged in favour of an atheist school teacher from Nashik. Sanjay Salve had been employed by the state-funded Savitribai Phule Secondary School since 1996. In June 2007, during a prayer session, Salve didn't fold his hands during the pledge or prayer. The school management called this indiscipline and refused him a higher pay grade in 2008 when Salve became eligible for it. Salve sought legal recourse citing the article 28 (a) of the Constitution which states "no person attending any educational institution recognised by the State or receiving aid out of State funds shall be required to take part in any religious instruction that may be imparted in such institution or to attend any religious worship that may be conducted in such institution". The court ruled in Salve's favour and directed the school to release his dues by 31 January 2014.

On 23 September 2014, the Bombay High Court declared that the government cannot force a person to state a religion on any document or form. The court also stated any citizen has the right to declare that he/she doesn't belong to any religion. The decision came in response to a Public Interest Litigation (PIL) filed by Ranjit Mohite, Kishore Nazare and Subhash Ranware, representing an organisation called Full Gospel Church of God, after the Maharashtra state printing press refused to issue them a gazette notification stating that they belonged to no religion. The petitioners stated that the organisation had 4000 members, and that they believe in Jesus Christ but they do not follow Christianity or any religion. Responding to the petition, the Maharashtra and the central governments had stated that "no religion" cannot be treated as a religion on official forms. The court cited the Article 25 of the Constitution, which guarantees right to freedom of conscience, while passing the verdict.

Persecution and attacks

See also: Discrimination against atheists

Narendra Nayak, an advocate of atheism, has claimed to have been attacked three times and had his scooter damaged twice, with one of the attacks leaving him with head injuries. This compelled him to take self-defence lessons and carry a nunchaku. Megh Raj Mitter's house was surrounded by a mob after he debunked the Hindu milk miracle, forcing him to call the police.

On 15 March 2007, a bounty of ₹700,000 (equivalent to ₹1.8 million or US$24,000 in 2020) was announced on atheist Bangladeshi author Taslima Nasrin, while living in India, by a Muslim cleric named Maulana Tauqeer Raza Khan for allegedly writing derogatory statements about Prophet Mohammad in her work. In December 2013, an FIR was filed against Nasrin in Bareilly by a cleric named Hasan Raza Khan, for hurting religious sentiments. Nasrin had allegedly tweeted on Twitter that "In India, criminals who issue fatwas against women don't get punished." Raza Khan said that by accusing clerics of being criminals, Nasrin had hurt religious sentiments.

On 2 July 2011, the house of U. Kalanathan, secretary of the Kerala Yukthivadi Sangham, was attacked in Vallikunnu after he suggested on television that the temple treasures of Padmanabhaswamy Temple should be used for public welfare. On 20 August 2013, Narendra Dabholkar, a rationalist and anti-superstition campaigner, was assassinated.

On 16 February 2015, rationalist Govind Pansare and his wife were attacked by unknown gunmen. He later died from the wounds on 20 February. On 30 August 2015, M. M. Kalburgi, a scholar and rationalist, was shot dead at his home. He was known for his criticism of superstition and idol worship. Soon afterwards, another rationalist and author, K. S. Bhagwan, received a threatening letter. He had offended religious groups by criticizing the Gita.

In March 2017, 31-year-old A Farooq, an Indian Muslim youth from Coimbatore who became an atheist, was killed by members of a Muslim radical group.

Demographics

Indian government census

The Indian census does not explicitly count atheists. In the 2011 Census of India, the response form required the respondent to choose from six options under religion. The "Others" option was meant for minor or tribal religions as well as atheists and agnostics.

The religion data from 2011 Census of India was released in August 2015. It revealed that about 2,870,000 people had stated no religion in their response, about 0.27% of the nation's population. However, the number included atheists, rationalists and also those who believed in a higher power. K. Veeramani, a Dravidar Kazhagam leader, said that it was the first time the number of non-religious people was recorded in the census. However, he added that he believed that the number of atheists in India was actually higher as many people don't reveal their atheism out of fear.

Different surveys

World Values Survey (2006)

According to the 2006 World Values Survey, conducted by the Dentsu Communication Institute Inc, Japan Research Center (2006), 6.6% of Indians stated that they had no religion.

WIN-Gallup Global Index of Religion and Atheism

According to the 2005 Global Index of Religion and Atheism report from WIN-Gallup, 87% of Indians were religious and 4% called themselves atheists. According to the 2012 report by the same organisation, 81% of Indians were religious, 13% were non-religious, 3% were convinced atheists and 3% were unsure or did not respond.

Worldviews and Opinions of Scientists in India (2007)

In 2007, a survey was conducted by the Institute for the Study of Secularism in Society and Culture of the Trinity College with the help of Center for Inquiry (India) called Worldviews and Opinions of Scientists in India. 1100 scientists surveyed from 130 institutes. Most of them identified themselves as secular (59%) or somewhat secular (16%) but refused to be labelled irreligious. 83% defined secularism, as it appears in the Indian constitutions, as the separation of state and religion. But, 93% also defined it as tolerance of other religious philosophies. 20% equated secularism to atheism. Only 11% called themselves completely not spiritual. However, 8% reportedly said they would refuse to do stem cell research based on religious or moral convictions. Y. S. Rajan commented on this saying that most Indians don't feel there is a conflict between science and religion. Other the hand, Innaiah Narisetti, chairman of Centre for Inquiry (India) and Pushpa Bhargava, the former director of the Centre for Cellular and Molecular Biology, pointed out the lack of scientific temper among Indian scientists.

Religion Among Scientists in an International Context (2014)

In a survey conducted by Elaine Howard Ecklund of Rice University, it was found that:

	India	United Kingdom
Scientists who identified as nonreligious	6%	65%
Scientists who attend religious services on a regular basis (once a month or more)	32%	12%
Scientists who never attend religious services	19%	68%
Scientists who believe that there are basic truths in many religions	73%	49%
Scientists who believe in God	27%	11%
Scientists who believe in a higher power of some kind	38%	8%

The ongoing study has surveyed 1,581 scientists from UK and 1,763 from India.

Neuroepigenetics

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Neuroepigenetics 

Neuroepigenetics is the study of how epigenetic changes to genes affect the nervous system. These changes may effect underlying conditions such as addiction, cognition, and neurological development.

Mechanisms

Neuroepigenetic mechanisms regulate gene expression in the neuron. Often, these changes take place due to recurring stimuli. Neuroepigenetic mechanisms involve proteins or protein pathways that regulate gene expression by adding, editing or reading epigenetic marks such as methylation or acetylation. Some of these mechanisms include ATP-dependent chromatin remodeling, LINE1, and prion protein-based modifications. Other silencing mechanisms include the recruitment of specialized proteins that methylate DNA such that the core promoter element is inaccessible to transcription factors and RNA polymerase. As a result, transcription is no longer possible. One such protein pathway is the REST co-repressor complex pathway. There are also several non-coding RNAs that regulate neural function at the epigenetic level. These mechanisms, along with neural histone methylation, affect arrangement of synapses, neuroplasticity, and play a key role in learning and memory.

Methylation

DNA methyltransferases (DNMTs) are involved in regulation of the electrophysiological landscape of the brain through methylation of CpGs. Several studies have shown that inhibition or depletion of DNMT1 activity during neural maturation leads to hypomethylation of the neurons by removing the cell's ability to maintain methylation marks in the chromatin. This gradual loss of methylation marks leads to changes in the expression of crucial developmental genes that may be dosage sensitive, leading to neural degeneration. This was observed in the mature neurons in the dorsal portion of the mouse prosencephalon, where there was significantly greater amounts of neural degeneration and poor neural signaling in the absence of DNMT1. Despite poor survival rates amongst the DNMT1-depleted neurons, some of the cells persisted throughout the lifespan of the organism. The surviving cells reaffirmed that the loss of DNMT1 led to hypomethylation in the neural cell genome. These cells also exhibited poor neural functioning. In fact, a global loss of neural functioning was also observed in these model organisms, with the greatest amounts neural degeneration occurring in the prosencephalon.

Other studies showed a trend for DNMT3a and DNMT3b. However, these DNMT's add new methyl marks on unmethylated DNA, unlike DNMT1. Like DNMT1, the loss of DNMT3a and 3b resulted in neuromuscular degeneration two months after birth, as well as poor survival rates amongst the progeny of the mutant cells, even though DNMT3a does not regularly function to maintain methylation marks. This conundrum was addressed by other studies which recorded rare loci in mature neurons where DNMT3a acted as a maintenance DNMT. The Gfap locus, which codes for the formation and regulation of the cytoskeleton of astrocytes, is one such locus where this activity is observed. The gene is regularly methylated to downregulate glioma related cancers. DNMT inhibition leads to decreased methylation and increased synaptic activity. Several studies show that the methylation-related increase or decrease in synaptic activity occurs due to the upregulation or downregulation of receptors at the neurological synapse. Such receptor regulation plays a major role in many important mechanisms, such as the 'fight or flight' response. The glucocorticoid receptor (GR) is the most studied of these receptors. During stressful circumstances, there is a signaling cascade that begins from the pituitary gland and terminates due to a negative feedback loop from the adrenal gland. In this loop, the increase in the levels of the stress response hormone results in the increase of GR. Increase in GR results in the decrease of cellular response to the hormone levels. It has been shown that methylation of the I7 exon within the GR locus leads to a lower level of basal GR expression in mice. These mice were more susceptible to high levels of stress as opposed to mice with lower levels of methylation at the I7 exon. Up-regulation or down-regulation of receptors through methylation leads to change in synaptic activity of the neuron.

Hypermethylation, CpG islands, and tumor suppressing genes

CpG Islands (CGIs) are regulatory elements that can influence gene expression by allowing or interfering with transcription initiation or enhancer activity. CGIs are generally interspersed with the promoter regions of the genes they affect and may also affect more than one promoter region. In addition they may also include enhancer elements and be separate from the transcription start site. Hypermethylation at key CGIs can effectively silence expression of tumor suppressing genes and is common in gliomas. Tumor suppressing genes are those which inhibit a cell's progression towards cancer. These genes are commonly associated with important functions which regulate cell-cycle events. For example, PI3K and p53 pathways are affected by CGI promoter hypermethylation, this includes the promoters of the genes CDKN2/p16, RB, PTEN, TP53 and p14ARF. Importantly, glioblastomas are known to have high frequency of methylation at CGIs/promoter sites. For example, Epithelial Membrane Protein 3 (EMP3) is a gene which is involved in cell proliferation as well as cellular interactions. It is also thought to function as a tumor suppressor, and in glioblastomas is shown to be silenced via hypermethylation. Furthermore, introduction of the gene into EMP3-silenced neuroblasts results in reduced colony formation as well as suppressed tumor growth. In contrast, hypermethylation of promoter sites can also inhibit activity of oncogenes and prevent tumorigenesis. Such oncogenic pathways as the transformation growth factor (TGF)-beta signaling pathway stimulate cells to proliferate. In glioblastomas the overactivity of this pathway is associated with aggressive forms of tumor growth. Hypermethylation of PDGF-B, the TGF-beta target, inhibits uncontrolled proliferation.

Hypomethylation and aberrant histone modification

Global reduction in methylation is implicated in tumorigenesis. More specifically, wide spread CpG demethylation, contributing to global hypomethylation, is known to cause genomic instability leading to development of tumors. An important effect of this DNA modification is its transcriptional activation of oncogenes. For example, expression of MAGEA1 enhanced by hypomethylation interferes with p53 function.

Aberrant patterns of histone modifications can also take place at specific loci and ultimately manipulate gene activity. In terms of CGI promoter sites, methylation and loss of acetylation occurs frequently at H3K9. Furthermore, H3K9 dimethylation and trimethylation are repressive marks which, along with bivalent differentially methylated domains, are hypothesized to make tumor suppressing genes more susceptible to silencing. Abnormal presence or lack of methylation in glioblastomas are strongly linked to genes which regulate apoptosis, DNA repair, cell proliferation, and tumor suppression. One of the best known examples of genes affected by aberrant methylation that contributes to formation of glioblastomas is MGMT, a gene involved in DNA repair which encodes the protein O6-methylguanine-DNA methyltransferase. Methylation of the MGMT promoter is an important predictor of the effectiveness of alkylating agents to target glioblastomas. Hypermethylation of the MGMT promoter causes transcriptional silencing and is found in several cancer types including glioma, lymphoma, breast cancer, prostate cancer, and retinoblastoma.

Neuroplasticity

Neuroplasticity refers to the ability of the brain to undergo synaptic rearrangement as a response to recurring stimuli. Neurotrophin proteins play a major role in synaptic rearrangement, amongst other factors. Depletion of neurotrophin BDNF or BDNF signaling is one of the main factors in developing diseases such as Alzheimer's disease, Huntington's disease, and depression. Neuroplasticity can also occur as a consequence of targeted epigenetic modifications such as methylation and acetylation. Exposure to certain recurring stimuli leads to demethylation of particular loci and remethylation in a pattern that leads to a response to that particular stimulus. Like the histone readers, erasers and writers also modify histones by removing and adding modifying marks respectively. An eraser, neuroLSD1, is a modified version of the original Lysine Demethylase 1(LSD1) that exists only in neurons and assists with neuronal maturation. Although both versions of LSD1 share the same target, their expression patterns are vastly different and neuroLSD1 is a truncated version of LSD1. NeuroLSD1 increases the expression of immediate early genes (IEGs) involved in cell maturation. Recurring stimuli lead to differential expression of neuroLSD1, leading to rearrangement of loci. The eraser is also thought to play a major role in the learning of many complex behaviors and is way through which genes interact with the environment.

Neurodegenerative diseases

Main article: Epigenetics of neurodegenerative diseases

Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disease known to progressively affect memory and incite cognitive degradation. Epigenetic modifications both globally and on specific candidate genes are thought to contribute to the etiology of this disease. Immunohistochemical analysis of post-mortem brain tissues across several studies have revealed global decreases in both 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in AD patients compared with controls. However, conflicting evidence has shown elevated levels of these epigenetic markers in the same tissues. Furthermore, these modifications appear to be affected early on in tissues associated with the pathophysiology of AD. The presence of 5mC at the promoters of genes is generally associated with gene silencing. 5hmC, which is the oxidized product of 5mC, via ten-eleven-translocase (TET), is thought to be associated with activation of gene expression, though the mechanisms underlying this activation are not fully understood.

Regardless of variations in results of methylomic analysis across studies, it is known that the presence of 5hmC increases with differentiation and aging of cells in the brain. Furthermore, genes which have a high prevalence of 5hmC are also implicated in the pathology of other age related neurodegenerative diseases, and are key regulators of ion transport, neuronal development, and cell death. For example, over-expression of 5-Lipoxygenase (5-LOX), an enzyme which generates pro-inflammatory mediators from arachidonic acid, in AD brains is associated with high prevalence of 5hmC at the 5-LOX gene promoter region.

Amyotrophic Lateral Sclerosis

DNA modifications at different transcriptional sites have been shown to contribute to neurodegenerative diseases. These include harmful transcriptional alterations such as those found in motor neuron functionality associated with Amyotrophic Lateral Sclerosis (ALS). Degeneration of upper and lower motor neurons, which contributes to muscle atrophy in ALS patients, is linked to chromatin modifications among a group of key genes. One important site that is regulated by epigenetic events is the hexanucleotide repeat expansion in C9orf72 within the chromosome 9p21. Hypermethylation of the C9orf72 related CpG Islands is shown to be associated with repeat expansion in ALS affected tissues. Overall, silencing of the C9orf72 gene may result in haploinsufficiency, and may therefore influence the presentation of disease. The activity of chromatin modifiers is also linked to prevalence of ALS. DNMT3A is an important methylating agent and has been shown to be present throughout the central nervous systems of those with ALS. Furthermore, over-expression of this de novo methyl transferase is also implicated in cell death of motor-neuron analogs.

Mutations in the FUS gene, that encodes an RNA/DNA binding protein, are causally linked to ALS. ALS patients with such mutations have increased levels of DNA damage. The protein encoded by the FUS gene is employed in the DNA damage response. It is recruited to DNA double-strand breaks and catalyzes recombinational repair of such breaks. In response to DNA damage, the FUS protein also interacts with histone deacetylase I, a protein employed in epigenetic alteration of histones. This interaction is necessary for efficient DNA repair. These findings suggest that defects in epigenetic signalling and DNA repair contribute to the pathogenesis of ALS.

Neuro-oncology

A multitude of genetic and epigenetic changes in DNA profiles in brain cells are thought to be linked to tumorgenesis. These alterations, along with changes in protein functions, are shown to induce uncontrolled cell proliferation, expansion, and metastasis. While genetic events such as deletions, translocations, and amplification give rise to activation of oncogenes and deactivation of tumor suppressing genes, epigenetic changes silence or up-regulate these same genes through key chromatin modifications.

Neurotoxicity

Neurotoxicity refers to damage made to the central or peripheral nervous systems due to chemical, biological, or physical exposure to toxins. Neurotoxicity can occur at any age and its effects may be short-term or long-term, depending on the mechanism of action of the neurotoxin and degree of exposure.

Certain metals are considered essential due to their role in key biochemical and physiological pathways, while the remaining metals are characterized as being nonessential. Nonessential metals do not serve a purpose in any biological pathway and the presence and accumulation in the brain of most can lead to neurotoxicity. These nonessential metals, when found inside the body compete with essential metals for binding sites, upset antioxidant balance, and their accumulation in the brain can lead to harmful side effects, such as depression and intellectual disability. An increase in nonessential heavy metal concentrations in air, water and food sources, and household products has increased the risk of chronic exposure.

Acetylation, methylation and histone modification are some of the most common epigenetic markers. While these changes do not directly affect the DNA sequence, they are able to alter the accessibility to genetic components, such as the promoter or enhancer regions, necessary for gene expression. Studies have shown that long-term maternal exposure to lead (Pb) contributes to decreased methylation in areas of the fetal epigenome, for example the interspaced repetitive sequences (IRSs) Alu1 and LINE-1. The hypomethylation of these IRSs has been linked to increased risk for cancers and autoimmune diseases later in life. Additionally, studies have found a relationship between chronic prenatal Pb exposure and neurological diseases, such as Alzheimer's and schizophrenia, as well as developmental issues. Furthermore, the acetylation and methylation changes induced by overexposure to lead result in decreased neurogenesis and neuron differentiation ability, and consequently interfere with early brain development.

Overexposure to essential metals can also have detrimental consequences on the epigenome. For example, when manganese, a metal normally used by the body as a cofactor, is present at high concentrations in the blood it can negatively affect the central nervous system. Studies have shown that accumulation of manganese leads to dopaminergic cell death and consequently plays a role in the onset of Parkinson's disease (PD). A hallmark of Parkinson's disease is the accumulation of α-Synuclein in the brain. Increased exposure to manganese leads to the downregulation of protein kinase C delta (PKCδ) through decreased acetylation and results in the misfolding of the α-Synuclein protein that allows aggregation and triggers apoptosis of dopaminergic cells.

Research

The field has only recently seen a growth in interest, as well as in research, due to technological advancements that facilitate better resolution of the minute modifications made to DNA. However, even with the significant advances in technology, studying the biology of neurological phenomena, such as cognition and addiction, comes with its own set of challenges. Biological study of cognitive processes, especially with humans, has many ethical caveats. Some procedures, such as brain biopsies of Rett Syndrome patients, usually call for a fresh tissue sample that can only be extricated from the brain of deceased individual. In such cases, the researchers have no control over the age of brain tissue sample, thereby limiting research options. In case of addiction to substances such as alcohol, researchers utilize mouse models to mirror the human version of the disease. However, the mouse models are administered greater volumes of ethanol than humans normally consume in order to obtain more prominent phenotypes. Therefore, while the model organism and the tissue samples provide an accurate approximation of the biology of neurological phenomena, these approaches do not provide a complete and precise picture of the exact processes underlying a phenotype or a disease.

Neuroepigenetics had also remained underdeveloped due to the controversy surrounding the classification of genetic modifications in matured neurons as epigenetic phenomena. This discussion arises due to the fact that neurons do not undergo mitosis after maturation, yet the conventional definition of epigenetic phenomena emphasizes heritable changes passed on from parent to offspring. However, various histone modifications are placed by epigenetic modifiers such as DNA methyltransferases (DNMT) in neurons and these marks regulate gene expression throughout the life span of the neuron. The modifications heavily influence gene expression and arrangement of synapses within the brain. Finally, although not inherited, most of these marks are maintained throughout the life of the cell once they are placed on chromatin.