Structure.

Connections.

The anterior part of the insula is subdivided by shallow sulci into three or four short gyri.  The anterior insula receives a direct projection from the basal part of the ventral medial nucleus of the thalamus and a particularly large input from the central nucleus of the amygdala. In addition, the anterior insula itself projects to the amygdala.  One study on rhesus monkeys revealed widespread reciprocal connections between the insular cortex and almost all subnuclei of the amygdaloid complex. The posterior insula projects predominantly to the dorsal aspect of the lateral and to the central amygdaloid nuclei. In contrast, the anterior insula projects to the anterior amygdaloid area as well as the medial, the cortical, the accessory basal magnocellular, the medial basal, and the lateral amygdaloid nuclei.  The posterior part of the insula is formed by a long gyrus.  The posterior insula connects reciprocally with the secondary somatosensory cortex and receives input from spinothalamically activated ventral posterior inferior thalamic nuclei. It has also been shown that this region receives inputs from the ventromedial nucleus (posterior part) of the thalamus that are highly specialized to convey homeostatic information such as pain, temperature, itch, local oxygen status, and sensual touch.  A human neuroimaging study using diffusion tensor imaging revealed that the anterior insula is interconnected to regions in the temporal and occipital lobe, opercular and orbitofrontal cortex, triangular and opercular parts of the inferior frontal gyrus. The same study revealed differences in the anatomical connection patterns between the left and right hemisphere.  The 'circular sulcus of insula' (or sulcus of Reil)is a semi-circular sulcus or "fissure" that separates the insula from the neighboring gyri of the operculum in the front, above, and behind.

Cytoarchitecture.

The insular cortex has regions of variable cell structure or cytoarchitecture, changing from granular in the posterior portion to agranular in the anterior portion. The insula also receives differential cortical and thalamic input along its length. The anterior insular cortex contains a population of spindle neurons (also called "von Economo neurons"), identified as characterising a distinctive subregion as the agranular frontal insula.

Development.

The insular cortex is considered a separate lobe of the telencephalon by some authorities. Other sources see the insula as a part of the temporal lobe. It is also sometimes grouped with limbic structures deep in the brain into a limbic lobe. As a paralimbic cortex, the insular cortex is considered to be a relatively old structure.

Function.

Multimodal sensory processing, sensory binding.

Functional imaging studies show activation of the insula during audio-visual integration tasks.

Taste.

The anterior insula is part of the primary gustatory cortex.

Interoceptive awareness.

There is evidence that, in addition to its base functions, the insula may play a role in certain higher-level functions that operate only in humans and other great apes. The spindle neurons found at a higher density in the right frontal insular cortex are also found in the anterior cingulate cortex, which is another region that has reached a high level of specialization in great apes. It has been speculated that these neurons are involved in cognitive-emotional processes that are specific to primates including great apes, such as empathy and metacognitive emotional feelings. This is supported by functional imaging results showing that the structure and function of the right frontal insula is correlated with the ability to feel one's own heartbeat, or to empathize with the pain of others. It is thought that these functions are not distinct from the lower-level functions of the insula but rather arise as a consequence of the role of the insula in conveying homeostatic information to consciousness. The right anterior insula aids interoceptive awareness of body states, such as the ability to time one's own heartbeat. Moreover, greater right anterior insular gray matter volume correlates with increased accuracy in this subjective sense of the inner body, and with negative emotional experience. It is also involved in the control of blood pressure, in particular during and after exercise, and its activity varies with the amount of effort a person believes he/she is exerting.  The insular cortex also is where the sensation of pain is judged as to its degree. Further, the insula is where a person imagines pain when looking at images of painful events while thinking about their happening to one's own body. Those with irritable bowel syndrome have abnormal processing of visceral pain in the insular cortex related to dysfunctional inhibition of pain within the brain.  Another perception of the right anterior insula is the degree of nonpainful warmth or nonpainful coldness of a skin sensation. Other internal sensations processed by the insula include stomach or abdominal distension. A full bladder also activates the insular cortex.  One brain imaging study suggests that the unpleasantness of subjectively perceived dyspnea is processed in the right human anterior insula and amygdala.  The cerebral cortex processing vestibular sensations extends into the insula, with small lesions in the anterior insular cortex being able to cause loss of balance and vertigo.  Other noninteroceptive perceptions include passive listening to music, laughter, and crying, empathy and compassion, and language.

Motor control.

In motor control, it contributes to hand-and-eye motor movement, swallowing, gastric motility, and speech articulation. It has been identified as a "central command” centre that ensures that heart rate and blood pressure increase at the onset of exercise. Research upon conversation links it to the capacity for long and complex spoken sentences. It is also involved in motor learning and has been identified as playing a role in the motor recovery from stroke.

Homeostasis.

It plays a role in a variety of homeostatic functions related to basic survival needs, such as taste, visceral sensation, and autonomic control. The insula controls autonomic functions through the regulation of the sympathetic and parasympathetic systems. It has a role in regulating the immune system.

Self.

It has been identified as playing a role in the experience of bodily self-awareness, sense of agency, and sense of body ownership.

Social emotions.

The anterior insula processes a person's sense of disgust both to smells and to the sight of contamination and mutilation — even when just imagining the experience. This associates with a mirror neuron-like link between external and internal experiences.  In social experience, it is involved in the processing of norm violations, emotional processing, empathy, and orgasms.  The insula is active during social decision making. Tiziana Quarto et al. measured emotional intelligence (EI) (the ability to identify, regulate, and process emotions of themselves and of others) of sixty-three healthy subjects. Using fMRI EI was measured in correlation with left insular activity. The subjects were shown various pictures of facial expressions and tasked with deciding to approach or avoid the person in the picture. The results of the social decision task yielded that individuals with high EI scores had left insular activation when processing fearful faces. Individuals with low EI scores had left insular activation when processing angry faces.

Emotions.

The insular cortex, in particular its most anterior portion, is considered a limbic-related cortex. The insula has increasingly become the focus of attention for its role in body representation and subjective emotional experience. In particular, Antonio Damasio has proposed that this region plays a role in mapping visceral states that are associated with emotional experience, giving rise to conscious feelings. This is in essence a neurobiological formulation of the ideas of William James, who first proposed that subjective emotional experience (i.e., feelings) arise from our brain's interpretation of bodily states that are elicited by emotional events. This is an example of embodied cognition.  In terms of function, the insula is believed to process convergent information to produce an "emotionally relevant context for sensory experience". To be specific, the anterior insula is related more to "olfactory, gustatory, viscero-autonomic, and limbic function", whereas the posterior insula is related more to "auditory-somesthetic-skeletomotor" function. Functional imaging experiments have revealed that the insula has an important role in pain experience and the experience of a number of basic emotions, including anger, fear, disgust, happiness, and sadness.  The anterior insular cortex (AIC) is believed to be responsible for emotional feelings, including maternal and romantic love, anger, fear, sadness, happiness, sexual arousal, disgust, aversion, unfairness, inequity, indignation, uncertainty, disbelief, social exclusion, trust, empathy, sculptural beauty, a ‘state of union with God’, and hallucinogenic states.  Functional imaging studies have also implicated the insula in conscious desires, such as food craving and drug craving. What is common to all of these emotional states is that they each change the body in some way and are associated with highly salient subjective qualities. The insula is well-situated for the integration of information relating to bodily states into higher-order cognitive and emotional processes. The insula receives information from "homeostatic afferent" sensory pathways via the thalamus and sends output to a number of other limbic-related structures, such as the amygdala, the ventral striatum, and the orbitofrontal cortex, as well as to motor cortices.  A study using magnetic resonance imaging found that the right anterior insula is significantly thicker in people that meditate. Other research into brain activity and meditation has shown an increase in grey matter in areas of the brain including the insular cortex.  Another study using voxel-based morphometry and MRI on experienced Vipassana meditators was done to extend the findings of Lazar et al., which found increased grey matter concentrations in this and other areas of the brain in experienced meditators.  The strongest evidence against a causative role for the insula cortex in emotion comes from Damasio et al. (2012) which showed that a patient who suffered bilateral lesions of the insula cortex expressed the full complement of human emotions, and was fully capable of emotional learning.

Salience.

Functional neuroimaging research suggests the insula is involved in two types of salience. Interoceptive information processing that links interoception with emotional salience to generate a subjective representation of the body. This involves, first, the anterior insular cortex with the pregenual anterior cingulate cortex (Brodmann area 33) and the anterior and posterior mid-cingulate cortices, and, second, a general salience network concerned with environmental monitoring, response selection, and skeletomotor body orientation that involves all of the insular cortex and the mid-cingulate cortex.  An alternative or perhaps complementary proposal is that the right anterior insular regulates the interaction between the salience of the selective attention created to achieve a task (the dorsal attention system) and the salience of arousal created to keep focused upon the relevant part of the environment (ventral attention system). This regulation of salience might be particularly important during challenging tasks where attention might fatigue and so cause careless mistakes but if there is too much arousal it risks creating poor performance by turning into anxiety.

Auditory perception.

Recent research indicates that the insular cortex is involved in auditory perception. Responses to sound stimuli were obtained using intracranial EEG recordings acquired from patients with epilepsy. The posterior part of the insula showed auditory responses that resemble those observed in Heschl’s gyrus, whereas the anterior part responded to the emotional contents of the auditory stimuli.  Direct recordings from the posterior part of the insula showed responses to unexpected sounds within regular auditory streams, a process known as auditory deviance detection. Researchers observed a mismatch negativity (MMN) potential, a well known event related potential, as well as the high frequency activity signals originating from local neurons.  Simple auditory illusions and hallucinations were elicited by electrical functional mapping.

Clinical significance.

Progressive expressive aphasia.

Progressive expressive aphasia is the deterioration of normal language function that causes individuals to lose the ability to communicate fluently while still being able to comprehend single words and intact other non-linguistic cognition. It is found in a variety of degenerative neurological conditions including Pick's disease, motor neuron disease, corticobasal degeneration, frontotemporal dementia, and Alzheimer's disease. It is associated with hypometabolism and atrophy of the left anterior insular cortex.

Addiction.

A number of functional brain imaging studies have shown that the insular cortex is activated when drug users are exposed to environmental cues that trigger cravings. This has been shown for a variety of drugs, including cocaine, alcohol, opiates, and nicotine. Despite these findings, the insula has been ignored within the drug addiction literature, perhaps because it is not known to be a direct target of the mesocortical dopamine system, which is central to current dopamine reward theories of addiction. Research published in 2007 has shown that cigarette smokers suffering damage to the insular cortex, from a stroke for instance, have their addiction to cigarettes practically eliminated. These individuals were found to be up to 136 times more likely to undergo a disruption of smoking addiction than smokers with damage in other areas. Disruption of addiction was evidenced by self-reported behavior changes such as quitting smoking less than one day after the brain injury, quitting smoking with great ease, not smoking again after quitting, and having no urge to resume smoking since quitting. The study was conducted on average eight years after the strokes, which opens up the possibility that recall bias could have affected the results. More recent prospective studies, which overcome this limitation, have corroborated these findings This suggests a significant role for the insular cortex in the neurological mechanisms underlying addiction to nicotine and other drugs, and would make this area of the brain a possible target for novel anti-addiction medication. In addition, this finding suggests that functions mediated by the insula, especially conscious feelings, may be particularly important for maintaining drug addiction, although this view is not represented in any modern research or reviews of the subject.  A recent study in rats by Contreras et al. corroborates these findings by showing that reversible inactivation of the insula disrupts amphetamine conditioned place preference, an animal model of cue-induced drug craving. In this study, insula inactivation also disrupted "malaise" responses to lithium chloride injection, suggesting that the representation of negative interoceptive states by the insula plays a role in addiction. However, in this same study, the conditioned place preference took place immediately after the injection of amphetamine, suggesting that it is the immediate, pleasurable interoceptive effects of amphetamine administration, rather than the delayed, aversive effects of amphetamine withdrawal that are represented within the insula.  A model proposed by Naqvi et al. (see above) is that the insula stores a representation of the pleasurable interoceptive effects of drug use (e.g., the airway sensory effects of nicotine, the cardiovascular effects of amphetamine), and that this representation is activated by exposure to cues that have previously been associated with drug use. A number of functional imaging studies have shown the insula to be activated during the administration of addictive psychoactive drugs. Several functional imaging studies have also shown that the insula is activated when drug users are exposed to drug cues, and that this activity is correlated with subjective urges. In the cue-exposure studies, insula activity is elicited when there is no actual change in the level of drug in the body. Therefore, rather than merely representing the interoceptive effects of drug use as it occurs, the insula may play a role in memory for the pleasurable interoceptive effects of past drug use, anticipation of these effects in the future, or both. Such a representation may give rise to conscious urges that feel as if they arise from within the body. This may make addicts feel as if their bodies need to use a drug, and may result in persons with lesions in the insula reporting that their bodies have forgotten the urge to use, according to this study.

Subjective certainty in ecstatic seizures.

A common quality in mystical experiences is a strong feeling of certainty which cannot be expressed in words. Fabienne Picard proposes a neurological explanation for this subjective certainty, based on clinical research of epilepsy. According to Picard, this feeling of certainty may be caused by a dysfunction of the anterior insula, a part of the brain which is involved in interoception, self-reflection, and in avoiding uncertainty about the internal representations of the world by "anticipation of resolution of uncertainty or risk". This avoidance of uncertainty functions through the comparison between predicted states and actual states, that is, "signaling that we do not understand, i.e., that there is ambiguity." Picard notes that "the concept of insight is very close to that of certainty," and refers to Archimedes' "Eureka!" Picard hypothesizes that during ecstatic seizures the comparison between predicted states and actual states no longer functions, and that mismatches between predicted state and actual state are no longer processed, blocking "negative emotions and negative arousal arising from predictive uncertainty," which will be experienced as emotional confidence. Picard concludes that "[t]his could lead to a spiritual interpretation in some individuals."

Other clinical conditions.

The insular cortex has been suggested to have a role in anxiety disorders, emotion dysregulation, and anorexia nervosa.

History.

The insula was first described by Johann Christian Reil while describing cranial and spinal nerves and plexuses. Henry Gray in Gray's Anatomy is responsible for it being known as the "Island of Reil". John Allman and colleagues showed that anterior insular cortex contains spindle neurons.

The insular cortex (also insula and insular lobe) is a portion of the cerebral cortex folded deep within the lateral sulcus (the fissure separating the temporal lobe from the parietal and frontal lobes) within each hemisphere of the mammalian brain.

岛叶(Insula)是大脑皮质的一部分。它是向内凹陷的皮层区域,被包埋在外侧裂之内,无法直接从完整的脑的外部观察到。它与额叶,<unk>叶和顶叶的皮层相连通。额叶,<unk>叶和顶叶在面向外侧裂,与岛叶相邻的部分叫做“岛盖”(Operculum)。岛叶有时也被称为“赖耳岛”(Island of Reil)。


OpenVZ compared to other virtualization technologies.

While virtualization technologies such as VMware, Xen and KVM provide full virtualization and can run multiple operating systems and different kernel versions, OpenVZ uses a single Linux kernel and therefore can run only Linux. All OpenVZ containers share the same architecture and kernel version. This can be a disadvantage in situations where guests require different kernel versions than that of the host. However, as it does not have the overhead of a true hypervisor, it is very fast and efficient.  Memory allocation with OpenVZ is soft in that memory not used in one virtual environment can be used by others or for disk caching. While old versions of OpenVZ used a common file system (where each virtual environment is just a directory of files that is isolated using chroot), current versions of OpenVZ allow each container to have its own file system.

Kernel.

The OpenVZ kernel is a Linux kernel, modified to add support for OpenVZ containers. The modified kernel provides virtualization, isolation, resource management, and checkpointing. As of vzctl 4.0, OpenVZ can work with unpatched Linux 3.x kernels, with a reduced feature set.

Virtualization and isolation.

Each container is a separate entity, and behaves largely as a physical server would. Each has its own:

Resource management.

OpenVZ resource management consists of four components: two-level disk quota, fair CPU scheduler, disk I/O scheduler, and user bean counters (see below). These resources can be changed during container run time, eliminating the need to reboot.

Two-level disk quota.

Each container can have its own disk quotas, measured in terms of disk blocks and inodes (roughly number of files). Within the container, it is possible to use standard tools to set UNIX per-user and per-group disk quotas.

CPU scheduler.

The CPU scheduler in OpenVZ is a two-level implementation of fair-share scheduling strategy.  On the first level, the scheduler decides which container it is to give the CPU time slice to, based on per-container cpuunits values. On the second level the standard Linux scheduler decides which process to run in that container, using standard Linux process priorities.  It is possible to set different values for the CPUs in each container. Real CPU time will be distributed proportionally to these values.  In addition to the above, OpenVZ provides ways to:

I/O scheduler.

Similar to the CPU scheduler described above, I/O scheduler in OpenVZ is also two-level, utilizing Jens Axboe's CFQ I/O scheduler on its second level.  Each container is assigned an I/O priority, and the scheduler distributes the available I/O bandwidth according to the priorities assigned. Thus no single container can saturate an I/O channel.

User Beancounters.

User Beancounters is a set of per-container counters, limits, and guarantees, meant to prevent a single container from monopolizing system resources. In current OpenVZ kernels (RHEL6-based 042stab*) there are two primary parameters (ram and swap, a.k.a. physpages and swappages), and others are optional.  Other resources are mostly memory and various in-kernel objects such as Inter-process communication shared memory segments and network buffers. Each resource can be seen from /proc/user_beancounters and has five values associated with it: current usage, maximum usage (for the lifetime of a container), barrier, limit, and fail counter. The meaning of barrier and limit is parameter-dependent; in short, those can be thought of as a soft limit and a hard limit. If any resource hits the limit, the fail counter for it is increased. This allows the owner to detect problems by monitoring /proc/user_beancounters in the container.

Checkpointing and live migration.

A live migration and checkpointing feature was released for OpenVZ in the middle of April 2006. This makes it possible to move a container from one physical server to another without shutting down the container. The process is known as checkpointing: a container is frozen and its whole state is saved to a file on disk. This file can then be transferred to another machine and a container can be unfrozen (restored) there; the delay is roughly a few seconds. Because state is usually preserved completely, this pause may appear to be an ordinary computational delay.

Limitations.

By default, OpenVZ restricts container access to real physical devices (thus making a container hardware-independent). An OpenVZ administrator can enable container access to various real devices, such as disk drives, USB ports, PCI devices or physical network cards.  /dev/loopN is often restricted in deployments (as loop devices use kernel threads which might be a security issue), which restricts the ability to mount disk images. A work-around is to use FUSE.  OpenVZ is limited to providing only some VPN technologies based on PPP (such as PPTP/L2TP) and TUN/TAP. IPsec is supported inside containers since kernel 2.6.32.  A graphical user interface called EasyVZ was attempted in 2007, but it did not progress beyond version 0.1. Up to version 3.4, Proxmox VE could be used as an OpenVZ-based server virtualization environment with a GUI, although later versions switched to LXC.

OpenVZ (Open Virtuozzo) is an operating-system-level virtualization technology for Linux. It allows a physical server to run multiple isolated operating system instances, called containers, virtual private servers (VPSs), or virtual environments (VEs). OpenVZ is similar to Solaris Containers and LXC.

OpenVZ是基于Linux内核的操作系统级虚拟化技术。OpenVZ允许物理服务器运行多个操作系统,该技术常用于虚拟专用服务器(VPS,Virtual Private Server)。


History.

In 1966 the Council of State made the decision to establish a School of Economics and Business Administration in Vaasa, and so Vaasa got its first institution of higher education which the region of Vaasa had worked for since the 1940s. The very next year the first students started their studies; 90 business and 60 correspondence students. The first principal to be chosen for the school was Tryggve Saxén and the first vice principal was, who later would become the longest serving principal the school has seen so far. The lectures were first held in a yard building of Vaasa Commercial College in Raastuvankatu street, but in its second year the school moved into the whole house as the commercial college moved to a new building.  In 1977 the school became a state institution along with all other academic institutions in Finland.  In 1980 education in Humanities (languages) began and so the school became a "School of higher education" (in Finland the term is "Korkeakoulu"). In 1983 studies in the Social Sciences began and in 1990 Technology studies began in connection with Helsinki University of Technology. In 1991 it changed its name to University of Vaasa. In 1992 the school was organised into four faculties; The Humanities, Business Administration, Accounting and Industrial Management, and Social Sciences. In 1994 the university moved into its new premises on Palosaari. The university got the right to award master's degrees in Technology in 2004. In 2010 the university also reorganized its faculties to three, namely Faculty of Business Studies, Faculty of Technology and Faculty of Philosophy which includes previous faculties of Humanities and Social Sciences. In 2018 the university reorganized its structure again. Instead of three faculties, the University of Vaasa has four different schools: the School of Accounting and Finance, the School of Management, the School of Marketing and Communication studies and the School of Technology and Innovations.

Campus.

The university can be found in the neighbourhood of Palosaari beside the city's old cotton mill, which also houses part of the university. Each building has its own name, like the main building of "Tervahovi" () and the governing building of "Luotsi" (). These buildings were finished in 1994 and planned in the spirit of the former county architect Carl Axel Setterberg who planned most of Vaasa's public buildings in 1860. The part of the university placed in the old mill is called "Fabriikki" (). There is also the academic library of Tritonia, which the university shares with the other academic institutions in the city, and the laboratory of Technobothnia, which is shared with the city's two universities of applied sciences. The whole campus is near the waterfront and surrounded by park areas. It is sometimes called the most beautiful campus in Finland.

Schools.

There are fours schools at the University of Vaasa:

Education and research.

The University of Vaasa is a business oriented and multi-disciplinary university. It offers education possibilities on the following levels: The strategic areas of research are management and change, energy and sustainable development and financing and economic decision making.

Honorary doctorates.

1988  1998  2006  2011  2018

The University of Vaasa (, ) is a multidisciplinary, business-oriented university in Vaasa, Finland. The campus of the university is situated by the Gulf of Bothnia adjacent to downtown Vaasa. The university has evolved from a school of economics founded in 1968 to a university consisting of four different schools: The School of Accounting and Finance, The School of Management, The School of Marketing and Communications and the School of Technology and Innovations. Philosophy and Faculty of Technology. University of Vaasa is one of the largest business universities in Finland. The university has personnel of around 500 which includes a teaching staff of 180 and 54 professors. Around 5000 students are currently studying in various degree programs at the university.

瓦萨大学(,),是位于芬兰共和国瓦萨市的一所大学,创立于1968年。瓦萨大学是一所多学科综合性大学,提供从学士到博士层次的教育。据2007年的统计数据,瓦萨大学有雇员456人,其中教授和教师214人。学生总数5055人,其中国际学生近400人(含交换生163人)。


Plot.

Barry Egan is a single man who owns a company that markets themed toilet plungers and other novelty items. He has seven overbearing sisters who ridicule and emotionally abuse him regularly, and he leads a lonely life punctuated by fits of rage and social anxiety. One day, he witnesses an inexplicable car accident, picks up an abandoned harmonium from the street, and encounters Lena Leonard, a coworker for one of his sisters, Elizabeth. Lena had orchestrated this meeting after seeing him in a family picture belonging to Elizabeth.  Barry goes to his sister's birthday party, where the rest of his sisters ridicule him. They bring up the times when they would call him "gay boy" until he got mad. They bring up an incident from when he was younger when he threw a hammer through their sliding glass window. He reacts angrily, shattering his sister's windows. He talks to his brother-in-law, where he asks if he can give him the phone number to a therapist.  Coping with his loneliness, Barry calls a phone-sex line, but the operator attempts to extort money and sends her four henchmen, who are brothers, to collect. This complicates his budding relationship with Lena, as well as his plan to exploit a loophole in a Healthy Choice promotion and amass a million frequent flyer miles by purchasing large quantities of pudding.  After Lena leaves for Hawaii on a business trip, Barry decides to follow her. He arrives and calls Elizabeth to find out where Lena is staying. When his sister starts abusing him again, Barry snaps and demands she give him the information, which she does. Lena is overjoyed to see Barry. They spend time together and make love. At first, Barry explains that he is in Hawaii on a business trip by coincidence, but he soon admits that he came only for her. When Barry's sister calls Lena in Hawaii, Lena tells her that she has not had any contact with Barry, loyally preserving his and their privacy. The romance develops further, and Barry finally feels some relief from the emotional isolation he has endured.  After they return home, the four brothers ram their car into Barry's, leaving Lena mildly injured. With his new-found freedom from loneliness in jeopardy, a surprisingly aggressive and poised Barry adeptly fights off all four of the goons in a matter of seconds, using a tire iron. Wanting to make sure Lena is recovered, Barry leaves her at the hospital and tries to end the harassment by calling the phone-sex line back and speaking to the "supervisor", who turns out to be Dean Trumbell, the owner of a mattress store in Provo, Utah. There, Barry confronts Dean face to face. Dean, at first trying to intimidate Barry, finds him more intimidating after he tells him that he is in love and it makes him stronger than anyone else. An end to the harassment is implied once Dean learns that Barry has come all the way from California, and confronts him instead of going to the police, though Dean tries to save face by getting in the last word.  Barry returns to Lena's apartment, and tells her everything, about the phone-sex episode, and Dean's goons, and begs her for forgiveness, pledging his loyalty and to use his frequent-flier miles to accompany her on all future business trips in just six to eight weeks after his pudding miles are processed. She was upset he left the hospital but eventually agrees, and they embrace happily. Some time later, Lena approaches Barry in his office while he plays the harmonium. She puts her arms around him and says, "So, here we go."

Production.

After the success of "Magnolia", Anderson stated that he would work with Adam Sandler and that he was determined to make his next film ninety minutes long.

Reception.

Box office.

The film received a limited domestic release with $17,791,032 in box office receipts on October 11, 2002. An international box office of about $6,800,000 resulted in a worldwide box office of $24,591,032.

Critical reception.

On review aggregator Rotten Tomatoes, the film has an approval rating of 79% based on 194 reviews, with an average rating of 7.43/10. The website's critical consensus states, "Odd, touching, and unique, "Punch-Drunk Love" is also delightfully funny, utilizing Adam Sandler's comic persona to explore the life of a lonely guy who finds love." On Metacritic, the film has a weighted average score of 78 out of 100, based on 37 critics, indicating "generally favorable reviews". The movie came in at #33 in The A.V. Club's "Top 50 films of the '00s".  Roger Ebert, who gave the film three-and-a-half stars out of four, praised Sandler's performance in his review for the "Chicago Sun-Times", saying, "Sandler, liberated from the constraints of formula, reveals unexpected depths as an actor. Watching this film, you can imagine him in Dennis Hopper roles. He has darkness, obsession and power. He can't go on making those moronic comedies forever, can he?" Sandler went on to win Best Actor at the Gijón International Film Festival for his performance and was also nominated for the Golden Globe Award for Best Actor – Motion Picture Musical or Comedy. Anderson won the award for Best Director at the 2002 Cannes Film Festival and the film was nominated for the Palme d'Or. The film was nominated for the Grand Prix of the Belgian Syndicate of Cinema Critics.  Filmmakers Lee Unkrich, Judd Apatow, Barry Jenkins and Taika Waititi, and actors Bill Nighy, Owen Wilson and Timothée Chalamet have cited it as one of their favorite films.

Home media.

The film was released on VHS and DVD by Columbia TriStar Home Entertainment on June 24, 2003.  The Criterion Collection released the film on Blu-ray in November 2016 with a restored HD transfer, the first time the company had done so for Anderson and Sandler. It has behind-the-scenes featurette about a recording session for the film's soundtrack, a Cannes press conference and deleted scenes.

Soundtrack.

The score to "Punch-Drunk Love" was composed by Jon Brion. As with "Magnolia", Brion and Anderson collaborated heavily for the production of the film's score. However, rather than scoring the film after rough footage had been shot, Brion made compositions while making the film. During the scoring process, Brion would experiment with tones and sounds, carefully making note of what Anderson would respond to. Anderson himself would create the vocal tempos he would envision in the score and use them on set, even to the extent of inspiring the pace of Sandler's performance.  The film's score features heavy use of the harmonium. Brion had introduced Anderson for it on "Magnolia", and Anderson knew he wanted it to feature heavily in the score. Many scenes between Sandler's character and the instrument were inspired by Brion. For instance, Brion once found a harmonium with a hole in its bellows before going on tour with Aimee Mann. To fix the problem, he covered the hole with duct tape. The situation is mirrored in the film.

Punch-Drunk Love is a 2002 American romantic comedy film written and directed by Paul Thomas Anderson, and starring Adam Sandler, Emily Watson, Philip Seymour Hoffman, Luis Guzmán and Mary Lynn Rajskub. Sandler plays an entrepreneur with severe social anxiety who is set up on a date with his sister's co-worker. The two immediately fall in love, but he is forced to defend his new love interest and himself from extortionists.

《恋爱鸡尾酒》(英语:Punch-Drunk Love)是2002年的爱情喜剧电影,由美国导演保罗·汤玛斯·安德森执导,本片获选为第55届戛纳影展正式竞赛片,最终获得最佳导演奖。


Introduction.

Some forms of chemical biology attempt to answer biological questions by directly probing living systems at the chemical level. In contrast to research using biochemistry, genetics, or molecular biology, where mutagenesis can provide a new version of the organism, cell, or biomolecule of interest, chemical biology probes systems "in vitro" and "in vivo" with small molecules that have been designed for a specific purpose or identified on the basis of biochemical or cell-based screening (see chemical genetics).  Chemical biology is one of several interdisciplinary sciences that tend to differ from older, reductionist fields and whose goals are to achieve a description of scientific holism. Chemical biology has scientific, historical and philosophical roots in medicinal chemistry, supramolecular chemistry, bioorganic chemistry, pharmacology, genetics, biochemistry, and metabolic engineering.

Systems of interest.

Enrichment techniques for proteomics.

Chemical biologists work to improve proteomics through the development of enrichment strategies, chemical affinity tags, and new probes. Samples for proteomics often contain many peptide sequences and the sequence of interest may be highly represented or of low abundance, which creates a barrier for their detection. Chemical biology methods can reduce sample complexity by selective enrichment using affinity chromatography. This involves targeting a peptide with a distinguishing feature like a biotin label or a post translational modification. Methods have been developed that include the use of antibodies, lectins to capture glycoproteins, and immobilized metal ions to capture phosphorylated peptides and enzyme substrates to capture select enzymes.

Enzyme probes.

To investigate enzymatic activity as opposed to total protein, activity-based reagents have been developed to label the enzymatically active form of proteins (see Activity-based proteomics). For example, serine hydrolase- and cysteine protease-inhibitors have been converted to suicide inhibitors. This strategy enhances the ability to selectively analyze low abundance constituents through direct targeting. Enzyme activity can also be monitored through converted substrate. Identification of enzyme substrates is a problem of significant difficulty in proteomics and is vital to the understanding of signal transduction pathways in cells. A method that has been developed uses "analog-sensitive" kinases to label substrates using an unnatural ATP analog, facilitating visualization and identification through a unique handle.

Glycobiology.

While DNA, RNA and proteins are all encoded at the genetic level, glycans (sugar polymers) are not encoded directly from the genome and fewer tools are available for their study. Glycobiology is therefore an area of active research for chemical biologists. For example, cells can be supplied with synthetic variants of natural sugars to probe their function. Carolyn Bertozzi's research group has developed methods for site-specifically reacting molecules at the surface of cells via synthetic sugars.

Combinatorial chemistry.

Chemical biologists used automated synthesis of diverse small molecule libraries in order to perform high-throughput analysis of biological processes. Such experiments may lead to discovery of small molecules with antibiotic or chemotherapeutic properties. These combinatorial chemistry approaches are identical to those employed in the discipline of pharmacology.

Employing biology.

Many research programs are also focused on employing natural biomolecules to perform biological tasks or to support a new chemical method. In this regard, chemical biology researchers have shown that DNA can serve as a template for synthetic chemistry, self-assembling proteins can serve as a structural scaffold for new materials, and RNA can be evolved "in vitro" to produce new catalytic function. Additionally, heterobifunctional (two-sided) synthetic small molecules such as dimerizers or PROTACs bring two proteins together inside cells, which can synthetically induce important new biological functions such as targeted protein degradation.

Peptides synthesis.

Chemical synthesis of proteins is a valuable tool in chemical biology as it allows for the introduction of non-natural amino acids as well as residue specific incorporation of "posttranslational modifications" such as phosphorylation, glycosylation, acetylation, and even ubiquitination. These capabilities are valuable for chemical biologists as non-natural amino acids can be used to probe and alter the functionality of proteins, while post translational modifications are widely known to regulate the structure and activity of proteins. Although strictly biological techniques have been developed to achieve these ends, the chemical synthesis of peptides often has a lower technical and practical barrier to obtaining small amounts of the desired protein.  In order to make protein-sized polypeptide chains via the small peptide fragments made by synthesis, chemical biologists use the process of native chemical ligation. Native chemical ligation involves the coupling of a C-terminal thioester and an N-terminal cysteine residue, ultimately resulting in formation of a "native" amide bond. Other strategies that have been used for the ligation of peptide fragments using the acyl transfer chemistry first introduced with native chemical ligation include expressed protein ligation, sulfurization/desulfurization techniques, and use of removable thiol auxiliaries. Expressed protein ligation allows for the biotechnological installation of a C-terminal thioester using inteins, thereby allowing the appendage of a synthetic N-terminal peptide to the recombinantly-produced C-terminal portion. Both sulfurization/desulfurization techniques and the use of removable thiol auxiliaries involve the installation of a synthetic thiol moiety to carry out the standard native chemical ligation chemistry, followed by removal of the auxiliary/thiol.

Directed evolution.

A primary goal of protein engineering is the design of novel peptides or proteins with a desired structure and chemical activity. Because our knowledge of the relationship between primary sequence, structure, and function of proteins is limited, rational design of new proteins with engineered activities is extremely challenging. In directed evolution, repeated cycles of genetic diversification followed by a screening or selection process, can be used to mimic natural selection in the laboratory to design new proteins with a desired activity.  Several methods exist for creating large libraries of sequence variants. Among the most widely used are subjecting DNA to UV radiation or chemical mutagens, error-prone PCR, degenerate codons, or recombination. Once a large library of variants is created, selection or screening techniques are used to find mutants with a desired attribute. Common selection/screening techniques include FACS, mRNA display, phage display, and "in vitro" compartmentalization. Once useful variants are found, their DNA sequence is amplified and subjected to further rounds of diversification and selection.  The development of directed evolution methods was honored in 2018 with the awarding of the Nobel Prize in Chemistry to Frances Arnold for evolution of enzymes, and George Smith and Gregory Winter for phage display.

Bioorthogonal reactions.

Successful labeling of a molecule of interest requires specific functionalization of that molecule to react chemospecifically with an optical probe. For a labeling experiment to be considered robust, that functionalization must minimally perturb the system. Unfortunately, these requirements are often hard to meet. Many of the reactions normally available to organic chemists in the laboratory are unavailable in living systems. Water- and redox- sensitive reactions would not proceed, reagents prone to nucleophilic attack would offer no chemospecificity, and any reactions with large kinetic barriers would not find enough energy in the relatively low-heat environment of a living cell. Thus, chemists have recently developed a panel of bioorthogonal chemistry that proceed chemospecifically, despite the milieu of distracting reactive materials "in vivo".  The coupling of an probe to a molecule of interest must occur within a reasonably short time frame; therefore, the kinetics of the coupling reaction should be highly favorable. Click chemistry is well suited to fill this niche, since click reactions are rapid, spontaneous, selective, and high-yielding. Unfortunately, the most famous "click reaction," a [3+2] cycloaddition between an azide and an acyclic alkyne, is copper-catalyzed, posing a serious problem for use "in vivo" due to copper's toxicity. To bypass the necessity for a catalyst, Carolyn R. Bertozzi's lab introduced inherent strain into the alkyne species by using a cyclic alkyne. In particular, cyclooctyne reacts with azido-molecules with distinctive vigor.  The most common method of installing bioorthogonal reactivity into a target biomolecule is through metabolic labeling. Cells are immersed in a medium where access to nutrients is limited to synthetically modified analogues of standard fuels such as sugars. As a consequence, these altered biomolecules are incorporated into the cells in the same manner as the unmodified metabolites. A probe is then incorporated into the system to image the fate of the altered biomolecules. Other methods of functionalization include enzymatically inserting azides into proteins, and synthesizing phospholipids conjugated to cyclooctynes.

Discovery of biomolecules through metagenomics.

The advances in modern sequencing technologies in the late 1990s allowed scientists to investigate DNA of communities of organisms in their natural environments ("eDNA"), without culturing individual species in the lab. This metagenomic approach enabled scientists to study a wide selection of organisms that were previously not characterized due in part to an incompetent growth condition. Sources of eDNA include soils, ocean, subsurface, hot springs, hydrothermal vents, polar ice caps, hypersaline habitats, and extreme pH environments. Of the many applications of metagenomics, researchers such as Jo Handelsman, Jon Clardy, and Robert M. Goodman, explored metagenomic approaches toward the discovery of biologically active molecules such as antibiotics. Functional or homology screening strategies have been used to identify genes that produce small bioactive molecules. Functional metagenomic studies are designed to search for specific phenotypes that are associated with molecules with specific characteristics. Homology metagenomic studies, on the other hand, are designed to examine genes to identify conserved sequences that are previously associated with the expression of biologically active molecules. Functional metagenomic studies enable the discovery of novel genes that encode biologically active molecules. These assays include top agar overlay assays where antibiotics generate zones of growth inhibition against test microbes, and pH assays that can screen for pH change due to newly synthesized molecules using pH indicator on an agar plate. Substrate-induced gene expression screening (SIGEX), a method to screen for the expression of genes that are induced by chemical compounds, has also been used to search for genes with specific functions. Homology-based metagenomic studies have led to a fast discovery of genes that have homologous sequences as the previously known genes that are responsible for the biosynthesis of biologically active molecules. As soon as the genes are sequenced, scientists can compare thousands of bacterial genomes simultaneously. The advantage over functional metagenomic assays is that homology metagenomic studies do not require a host organism system to express the metagenomes, thus this method can potentially save the time spent on analyzing nonfunctional genomes. These also led to the discovery of several novel proteins and small molecules. In addition, an "in silico" examination from the Global Ocean Metagenomic Survey found 20 new lantibiotic cyclases.

Kinases.

Posttranslational modification of proteins with phosphate groups by kinases is a key regulatory step throughout all biological systems. Phosphorylation events, either phosphorylation by protein kinases or dephosphorylation by phosphatases, result in protein activation or deactivation. These events have an impact on the regulation of physiological pathways, which makes the ability to dissect and study these pathways integral to understanding the details of cellular processes. There exist a number of challenges—namely the sheer size of the phosphoproteome, the fleeting nature of phosphorylation events and related physical limitations of classical biological and biochemical techniques—that have limited the advancement of knowledge in this area.  Through the use of small molecule modulators of protein kinases, chemical biologists have gained a better understanding of the effects of protein phosphorylation. For example, nonselective and selective kinase inhibitors, such as a class of pyridinylimidazole compounds are potent inhibitors useful in the dissection of MAP kinase signaling pathways. These pyridinylimidazole compounds function by targeting the ATP binding pocket. Although this approach, as well as related approaches, with slight modifications, has proven effective in a number of cases, these compounds lack adequate specificity for more general applications. Another class of compounds, mechanism-based inhibitors, combines knowledge of the kinase enzymology with previously utilized inhibition motifs. For example, a "bisubstrate analog" inhibits kinase action by binding both the conserved ATP binding pocket and a protein/peptide recognition site on the specific kinase. Research groups also utilized ATP analogs as chemical probes to study kinases and identify their substrates.  The development of novel chemical means of incorporating phosphomimetic amino acids into proteins has provided important insight into the effects of phosphorylation events. Phosphorylation events have typically been studied by mutating an identified phosphorylation site (serine, threonine or tyrosine) to an amino acid, such as alanine, that cannot be phosphorylated. However, these techniques come with limitations and chemical biologists have developed improved ways of investigating protein phosphorylation. By installing phospho-serine, phospho-threonine or analogous phosphonate mimics into native proteins, researchers are able to perform in vivo studies to investigate the effects of phosphorylation by extending the amount of time a phosphorylation event occurs while minimizing the often-unfavorable effects of mutations. Expressed protein ligation, has proven to be successful techniques for synthetically producing proteins that contain phosphomimetic molecules at either terminus. In addition, researchers have used unnatural amino acid mutagenesis at targeted sites within a peptide sequence.  Advances in chemical biology have also improved upon classical techniques of imaging kinase action. For example, the development of peptide biosensors—peptides containing incorporated fluorophores improved temporal resolution of in vitro binding assays. One of the most useful techniques to study kinase action is Fluorescence Resonance Energy Transfer|FRET. To utilize FRET for phosphorylation studies, fluorescent proteins are coupled to both a phosphoamino acid binding domain and a peptide that can by phosphorylated. Upon phosphorylation or dephosphorylation of a substrate peptide, a conformational change occurs that results in a change in fluorescence. FRET has also been used in tandem with Fluorescence Lifetime Imaging Microscopy (FLIM) or fluorescently conjugated antibodies and flow cytometry to provide quantitative results with excellent temporal and spatial resolution.

Biological fluorescence.

Chemical biologists often study the functions of biological macromolecules using fluorescence techniques. The advantage of fluorescence versus other techniques resides in its high sensitivity, non-invasiveness, safe detection, and ability to modulate the fluorescence signal. In recents years, the discovery of green fluorescent protein (GFP) by Roger Y. Tsien and others, hybrid systems and quantum dots have enabled assessing protein location and function more precisely. Three main types of fluorophores are used: small organic dyes, green fluorescent proteins, and quantum dots. Small organic dyes usually are less than 1 kDa, and have been modified to increase photostability and brightness, and reduce self-quenching. Quantum dots have very sharp wavelengths, high molar absorptivity and quantum yield. Both organic dyes and quantum dyes do not have the ability to recognize the protein of interest without the aid of antibodies, hence they must use immunolabeling. Fluorescent proteins are genetically encoded and can be fused to your protein of interest. Another genetic tagging technique is the tetracysteine biarsenical system, which requires modification of the targeted sequence that includes four cysteines, which binds membrane-permeable biarsenical molecules, the green and the red dyes "FlAsH" and "ReAsH", with picomolar affinity. Both fluorescent proteins and biarsenical tetracysteine can be expressed in live cells, but present major limitations in ectopic expression and might cause a loss of function.  Fluorescent techniques have been used assess a number of protein dynamics including protein tracking, conformational changes, protein–protein interactions, protein synthesis and turnover, and enzyme activity, among others. Three general approaches for measuring protein net redistribution and diffusion are single-particle tracking, correlation spectroscopy and photomarking methods. In single-particle tracking, the individual molecule must be both bright and sparse enough to be tracked from one video to the other. Correlation spectroscopy analyzes the intensity fluctuations resulting from migration of fluorescent objects into and out of a small volume at the focus of a laser. In photomarking, a fluorescent protein can be dequenched in a subcellular area with the use of intense local illumination and the fate of the marked molecule can be imaged directly. Michalet and coworkers used quantum dots for single-particle tracking using biotin-quantum dots in HeLa cells. One of the best ways to detect conformational changes in proteins is to label the protein of interest with two fluorophores within close proximity. FRET will respond to internal conformational changes result from reorientation of one fluorophore with respect to the other. One can also use fluorescence to visualize enzyme activity, typically by using a quenched activity based proteomics (qABP). Covalent binding of a qABP to the active site of the targeted enzyme will provide direct evidence concerning if the enzyme is responsible for the signal upon release of the quencher and regain of fluorescence.

Chemical biology is a scientific discipline spanning the fields of chemistry and biology. The discipline involves the application of chemical techniques, analysis, and often small molecules produced through synthetic chemistry, to the study and manipulation of biological systems. In contrast to biochemistry, which involves the study of the chemistry of biomolecules and regulation of biochemical pathways within and between cells, chemical biology deals with chemistry "applied to" biology (synthesis of biomolecules, simulation of biological systems etc.).

化学生物学(英语:Chemical Biology)是哈佛大学的斯图亚特·L·施莱伯等人所提倡,利用分子生物学的手法,搭配有机化学的方式,探讨细胞内核酸或是蛋白质等生物体内分子的功能或是反应。Schreiber等人指出:“化学生物学是对分子生物学的有力补充,化学生物学是采用化学的手段,如运用小分子或人工设计合成的分子作为配体来直接改变生物分子的功能。


Pyramids.

So far, more than 35 pyramids grouped in five sites were discovered in Sudan. They were constructed in Nubia over a period of a few hundred years to serve as tombs for the kings and queens and wealthy citizens of Napata and Meroë.  The first three sites are located around Napata in Lower Nubia, near the modern town of Karima.  The first of these was built at the site of el-Kurru, including the tombs of King Kashta and his son Piye, together with Piye's successors Shabaka, Shabataka, and Tanwetamani. Fourteen pyramids were constructed for their queens, several of whom were renowned warrior queens. This can be compared to approximately 120 much larger pyramids that were constructed in Ancient Egypt over a period of 3000 years.  Later Napatan pyramids were sited at Nuri, 10 km north on the opposite bank of the Nile. This necropolis was the burial place of 21 kings and 52 queens and princes including Anlami and Aspelta. The bodies of these kings were placed in huge granite sarcophagi. Aspelta's weighed 15.5 tons, and its lid weighed four tons. The oldest and largest pyramid at Nuri is that of the Napatan king and Twenty-fifth Dynasty pharaoh Taharqa.  Another small group of 9 pyramids is located next to Jebel Barkal itself.  The most extensive Nubian pyramid site is at Meroë, which is located between the fifth and sixth cataracts of the Nile, approximately north of Khartoum. During the Meroitic period, over forty queens and kings were buried there.  Between 2009 and 2012 the new group of pyramids was discovered near the village Sedeinga.  The physical proportions of Nubian pyramids differ markedly from the Egyptian edifices: they are built of stepped courses of horizontally positioned stone blocks and range approximately in height, but rise from fairly small foundation footprints that rarely exceed in width, resulting in tall, narrow structures inclined at approximately 70°. Most also have offering temple structures abutting their base with unique Kushite characteristics. By comparison, Egyptian pyramids of similar height generally had foundation footprints that were at least five times larger and were inclined at angles between 40–50°.  The tombs inside the pyramids of Nubia were plundered in ancient times. Wall reliefs preserved in the tomb chapels reveal that their royal occupants were mummified, covered with jewellery and laid to rest in wooden mummy cases. At the time of their exploration by archaeologists in the 19th and 20th centuries, some pyramids were found to contain the remains of bows, quivers of arrows, archers' thumb rings, horse harnesses, wooden boxes, furniture, pottery, colored glass, metal vessels, and many other artefacts attesting to extensive Meroitic trade with Egypt and the Hellenistic world.  A pyramid excavated at Meroë included hundreds of heavy items such as large blocks decorated with rock art and 390 stones that comprised the pyramid. A cow buried complete with eye ointment was also unearthed in the area to be flooded by the Meroë Dam, as were ringing rocks that were tapped to create a melodic sound.  In the 1830s Giuseppe Ferlini came to Meroe seeking treasure and raided and demolished a number of pyramids which had been found “in good conditions” by Frédéric Cailliaud just a few years earlier. At Wad ban Naqa, he leveled the pyramid N6 of the "kandake" Amanishakheto starting from the top, and finally found her treasure composed of dozens of gold and silver jewelry pieces. Overall, he is considered responsible for the destruction of over 40 pyramids.<br>  Having found the treasure he was looking for, in 1836 Ferlini returned home. A year later he wrote a report of his expedition containing a catalog of his findings, which was translated in French and republished in 1838. He tried to sell the treasure, but at this time nobody believed that such high quality jewellery could be made in Black Africa. His finds were finally sold in Germany: part of these were purchased by king Ludwig I of Bavaria and are now in the State Museum of Egyptian Art of Munich, while the remaining – under suggestions of Karl Richard Lepsius and of Christian Charles Josias von Bunsen – was bought by the Egyptian Museum of Berlin where it still is.  George Reisner, a Harvard archaeologist, investigated the pyramids at Nuri and mapped more than 80 royal Kushite burials in 1916-1919. Reisner started to explore burial chambers but he found they were flooded caused by rising water table. He abandoned further excavation because he thought it was too dangerous, probably because a collapse of a staircase had killed five of his workers. Some of his findings were published in 1955.  National Geographic funded explorations from 2015-2019 using underwater scuba diving equipment and remote controlled robots.

Nubian pyramids are pyramids that were built by the rulers of the ancient Kushite kingdoms. The area of the Nile valley known as Nubia, which lies within the north of present day Sudan, was home to three Kushite kingdoms during antiquity. The first had its capital at Kerma (2500–1500 BC). The second was centered on Napata (1000–300 BC). Finally, the last kingdom was centered on Meroë (300 BC–AD 300). They are built of granite and sandstone. The pyramids were partially demolished by Italian treasure hunter Giuseppe Ferlini in the 1830s.

努比亚金字塔是北非库施王国及古埃及王国统治者所建造的金字塔,埃及尼罗河第一瀑布阿斯旺与苏丹第四瀑布库赖迈之间的地区被称为努比亚。库施将首都从科尔玛(Kerma)迁移到纳帕塔(Napata)及麦罗埃(Meroë)后,文化受到古埃及的影响,于是统治者开始建造金字塔。大约有220座金字塔位于努比亚地区,努利地区的金字塔建造时代较晚。


Etymology.

According to a legend, many babul trees (known locally as velan trees) surrounded this region, which led to the name "Vellore".  Vellore is also known as the Second Madras because of its importance and location relative to Chennai (Madras).

History.

The recorded history of Vellore dates back to the ninth century, as seen from a Chola inscription in the Annamalaiyar Temple in Tiruvannamalai.  Vellore is strategically located and well-connected by rail and bus routes to major towns in the neighbouring states of Andhra Pradesh, Karnataka and Kerala. Many dynasties and rulers dominated Vellore throughout its history, including the Pallava dynasty, Medieval Cholas, Later Cholas, Vijayanagar, the Rashtrakuta dynasty, the Sambuvaraya chieftains, the Nawabs of the Carnatic, and the administration of the British. In the 18th century, Vellore was involved in the Carnatic Wars between Britain and France. It was situated close to several decisive battles, including those at Ambur (1749), Arcot (1751), and Vandavasi (1760).  Vellore Fort is important to Vellore's history. Due to a lack of historical records, it is not known exactly when the fort was constructed, but estimates based on stone inscriptions suggests that the fort was most likely built during the rule of Chinna Bommi Nayak between 1526 and 1595. The fort is a good example of Tamil Nadu military architecture, while the Jalakandeswarar Temple within the fort represents Vijayanagara architecture.  Christian Medical College & Hospital, founded in 1900 by the American medical missionary Dr. Ida S. Scudder, is another Vellore landmark. The hospital has grown into a medical institution of international repute.  The central prison in Vellore, established in 1830, had imprisoned notable figures like C. Rajagopalachari and Ramaswamy Venkataraman. Other landmarks include the Aruganthampoodi mausoleums, located close to the section of National Highway 48 between Vellore and Arcot, where the family members of Tipu Sultan were buried; and the Muthu Mandapam, a memorial on the banks of Palar River built by the Tamil Nadu Government to honor Sri Vikrama Rajasinha, the last ruler of the Kingdom of Kandy in Sri Lanka, who ruled from 1798 to 1815 and was imprisoned in Vellore Fort for 17 years until his death.

Vellore Fort.

The fort of Vellore was built around 1566 CE by the chieftains of Sadashiv Raya of the Vijayanagara Empire. In the mid-17th century the fort was owned by various parties. The Aravidus, the last dynasty that ruled Vijayanagara lost Vellore to the Bijapur Sultan before being captured by the Marathas after a siege that lasted four and a half months in 1676. The fort came under the charge of Dost Ali, the Nawab of Carnatic, before passing on to the British in 1760. Vellore Fort withstood Hyder Ali's siege from 1780–82, and would later become the base for Lord Cornwallis’ march on Bangalore to defeat Tipu Sultan.  When Tipu Sultan was killed at Sringapatam during the Fourth Anglo-Mysore War (1798-79 CE), his kingdom was handed back to the Hindu Wodeyar kings of Mysore and the British exiled Tipu's surviving sons, daughters, their families, and their entire entourage to Vellore Fort. They stayed in the palaces in the fort and participated in the Mutiny of 1806.

Vellore mutiny.

In 1805, the new Commander-in-Chief of the Madras Army of the British East Indian Company, General Sir John Cradock, began an ambitious reform of the army's disciplinary system. New, standardized regulations were approved for the Madras Army, which dictated how sepoys should wear their uniforms and appear on duty. Under these regulations, Hindus were prohibited from wearing religious marks on their foreheads while on duty, and Muslims were required to shave their beards and trim their moustaches. One change that was especially problematic was a new headdress associated with Indian converts to Christianity, which included a leather cockade. This caused an uproar, as leather was a cultural taboo for the upper caste sepoys of the Madras Army. As a result, many sepoys believed that their British officers were conspiring to convert them to Christianity.  In May 1806, a few soldiers protested against these changes and were sent to Fort St. George in Chennai, where they were publicly lashed and discharged from the army. With the levels of resentment towards the British already high, the sons of the deceased Tipu Sultan exacerbated the conflict by assisting the mutineers who revolted on 10 July. Under the pretense of attending the wedding of one of Tipu Sultan's daughters, mutineers gathered in Vellore Fort where the wedding was held and revolted. Raising the flag of the Kingdom of Mysore, they declared Tipu Sultan's son Fateh Hyder king. The mutineers caused about 200 British casualties before their revolt was put down by British reinforcements under Sir Rollo Gillespie, and many of the mutineers were either summarily shot, captured, court-martialed, and/or executed.  As a result of the uprising, the dress codes were retracted, and Cradock was dismissed. Although the mutiny took place before larger revolts in the 1850s, it was indicative of the simmering dissent in the Indian soldiery. The Vellore mutiny is considered to be the first large-scale Indian mutiny against the British, and a prelude to the much larger Sepoy Mutiny in 1857.

Economic, Social and Cultural Changes in Vellore in the 20th Century.

The economic condition of the district in the earlier stages was not sound with the absence of major industries. Industries like Bharat Heavy Electricals Ltd. Ranipet, Tamil Nadu Explosives Ltd., and Vellore Katpadi were established as the result of governmental police. There has been notable growth of small scale industries and tanneries in the district, which not only generated employment opportunities, but also contributed economic growth to farmers. Uzhavar Sandhai helped the rural poor improve the economy. Women-driven self help groups played an important role in building rural economy and teaching rural women to be self-reliant. Vellore also changed socially as time went by. Increased social awareness and upward social growth marked the successful foundation of its districts. Literacy improved in part of the Arivoli Movement.  During the first half of the 19th century, the town came under British rule.

Geography and climate.

Vellore is at, 220m above sea level. The city has a semi-arid climate. It is in the Vellore district of the South Indian state, Tamil Nadu, west of the state capital Chennai. Vellore lies in the Eastern Ghats region and Palar river basin. The topography is almost plain with slopes from west to east.  Vellore is in a tropical savanna climate (Köppen climate classification "Aw"). The temperature ranges from to. Like the rest of the state, April to June are the hottest months and December to January are the coldest. Vellore receives of rainfall every year. The southwestern monsoon from June to September brings 517.1 mm of rainfall, with September being the rainiest month. The northeastern monsoon which lasts from October to December brings 388.4mm of rainfall. The humidity ranges from 40%–63% during summer and 67%–86% during winter.

Demographics.

According to the 2011 census, the Vellore district had a population of 3,936,331 with a sex-ratio of 1,034 females for every 1,000 males, much above the national average of 929 to 1000. 19,898 were under the age of six, (10,093 males and 9,805 females). Scheduled Castes and Scheduled Tribes accounted for 14.16% and.18% of the population, respectively. The city's literacy rate was 77.15% compared to the national average of 72.99%.  The city had a total of 42,598 households, with 70,257 workers, including 297 cultivators, 395 main agricultural labourers, 4,387 in household industries, 59,281 other workers, 5,897 marginal workers, 59 marginal cultivators, 74 marginal agricultural labourers, 667 marginal workers in household industries, and 5,097 other marginal workers.  According to the religious census of 2011, Vellore's population was 80.09% Hindu, 14.28% Muslim, 4.79% Christian, 0.02% Sikh, 0.03% Buddhist, 0.51% Jain, with 0.26% following other religions, and 0.02% following no religion or not indicating any religious preference.  As of 2001, 69.88% of the city's land area was developed. Out of the developed area, 55.76% was used for residential purposes, 8.34% for commerce, 1.58% for industry, 3.3% for education, 16.46% for public and semi-public use, and 10.12% for transport and communication. Although population density varies between different areas, the average density of the city of Vellore is 241 persons per hectare.

Administration and politics.

Vellore is the municipal headquarters of Vellore district. The town was first recognized as a third-grade municipality in 1866, promoted to first-grade in 1947, to selection-grade in 1970, and to a municipal corporation on 1 August 2008. The functions of the Vellore Municipal Corporation are divided into six departments: General Administration/Personnel, Engineering, Revenue, Public Health, Planning, and Information Technology (IT). These departments are under the executive control of a municipal commissioner. Legislative powers are held by a body of 60 members, with each councilor being elected from one of the city's wards. The legislative body is headed by an elected mayor who is assisted by a deputy mayor.  Vellore is a part of the Vellore & Katpadi state assembly constituencies and elects 2 members to the Tamil Nadu Legislative Assembly once every five years. Since the 1977 elections, All India Anna Dravida Munnetra Kazhagam (AIADMK) won the assembly elections in 1977 and 2009, while Dravida Munnetra Kazhagam (DMK) won seats in 1980, 1984 and 1989. Elections were won twice by the Indian National Congress (INC), in 1991 and 2001, while the Tamil Maanila Congress (TMC) secured seats in 1996 and 2001. The current MLA of Vellore constituency is P.Karthikeyan of the DMK.  Vellore is a part of the Vellore & Arakkonam Lok Sabha constituencies. It consisted of the following six assembly constituencies before 2009: Katpadi, Gudiyatham, Pernampattu, Anaicut, Vellore, and Arni constituencies. After the 2009 reorganization, it is composed of Vellore, Anaicut, Kilvazhithunaiankuppam, Gudiyatham, Vaniyambadi, and Ambur constituencies.  Since 1951, the Vellore parliament seat was won by the Indian National Congress four times in the 1957, 1962, 1989 and 1991 elections; AIADMK twice during the 1984 and 2014 elections; CWL once during 1951 elections; independent once during the 1980 elections; Dravida Munnetra Kazhagam five times during the 1967, 1971, 1996, 2004 and 2009 elections; once each by NCO during the 1977 elections; and twice by Pattali Makkal Katchi (PMK) during the 1998 and 1999 elections. The current Member of Parliament from the constituency is Kathir Anand from the DMK party.  Law enforcement in Vellore is organized by the Vellore subdivision of the Tamil Nadu Police headed by a deputy superintendent. There are four police stations in the city, one of them being an all-women station. Different special task forces focus on prohibition enforcement, district crime, and social justice and human rights. Administrative duties are performed by a branch that operates at the district level and is headed by a superintendent.

Economy.

According to the Indian Census of 2001, the urban workforce employment rate of Vellore is 43.64%. Vellore, being the headquarters of the district, has registered growth in its tertiary sector activities with a corresponding decrease in the primary sector. Most employment is provided by the leather industry, agricultural trading, and industries in and around the city. Approximately 83.35% of the workforce is employed in tertiary sector comprising transport, services and commerce. The secondary sector activities like manufacturing and household industries employs 13.52% of the workforce. Male worker employment (43.64%) is higher than female work employment(24.39%).  Vellore is known as the leather hub of India. Hundreds of leather and tannery facilities are around Vellore and nearby towns, such as Ranipet, Ambur and Vaniyambadi. The Vellore district is the top exporter of finished leather goods in the country. Vellore leather accounts for more than 37% of the country's export of leather and leather-related products (such as finished leathers, shoes, garments and gloves). Bharat Heavy Electricals Limited (BHEL) is one of the nine major government owned enterprises in the nation. The Boiler Auxiliaries Plant of BHEL in Ranipet is the industrial hub of Vellore. Chemical plants in the Ranipet-SIPCOT economic zone are a major source of income to Vellore residents. EID Parry is a sanitary-ware manufacturing company with 38% of the world's market share in bathroom accessories. Tirumalai Chemicals and Greaves are among the international brands that have manufacturing units in the city. Automobile and mechanical companies of global Brands, including SAME Deutz-Fahr, TVS–Brakes India, Mitsubishi, Greaves Cotton and MRF have their manufacturing units in the area. Brakes India Sholingur's foundry division is located at Vellore-Sholingur and is a major employer in the area. Asia's biggest explosives manufacturing company, Tamil Nadu Explosives Limited (TEL), is in Vellore at Katpadi. This is India's only government explosives company with more than a thousand employees. The company is headed by a senior Indian Administrative Service officer. Kramski Stamping and Molding India Pvt Ltd, a German precision metal and plastic integrated-component manufacturing company with automotive, telecommunications, electronics and medical applications is located in Erayankadu, near Vellore. Major businesses in the city center are on Officer's Line, Town Hall Road, Long Bazaar and Bangalore, Scudder, Arni, Gandhi and Katpadi Roads. Many boarding and lodging houses are in and around Scudder and Gandhi Roads. Microsoft Corporation (India) Pvt. Ltd. announced the launch of 14 Microsoft Innovation Centers (MICs) in India. Trichy, Vellore, Coimbatore, Madurai and Salem in Tamil Nadu.  Christian Medical College & Hospital (CMCH), on Ida Scudder Road in the heart of the city, is Vellore's largest private employer and has a large floating population from other parts of India and abroad. Lodging, hospitals and allied businesses are among the major sources of income generated in the central part of the city. The Government Vellore Medical College and Hospital (VMCH) are located at Adukamparai in Vellore. With hospitals such as Apollo KH Hospital in Melvisharam and Sri Narayani Hospital & Research Centre in Sripuram, coupled with colleges such as CMC & VIT and other engineering and science colleges, the health care industry is growing rapidly.  Other rural industries than agriculture include weaving and beedi and matchstick rolling. The Indian Army has a number of recruits from the Vellore district (especially from Kammavanpet known as "the military village") and military spending is a major source of income.

Education.

Vellore is considered a prominent destination for medical and technological education in India. It has a state-government university, a private technological university, one government and one private medical school and several engineering and arts and science colleges.  The country's first stem-cell translational research centre was established in Vellore in December 2005. The central government's biotechnology department selected the Christian Medical College (CMC) as the first in a series of centers as it already had world-class clinical hematology and biochemistry departments. The college made a breakthrough which attracted the attention of the country's medical and scientific community: the Centre for Stem Cell Research at the Christian Medical College succeeded in reprogramming cells from adult mice to make them function like stem cells found in the human embryo. The agricultural research station at Virinjipuram is in the Northeastern Zone of Tamil Nadu. It is one of 32 research stations of Tamil Nadu Agricultural University (TNAU). The Government of India-sponsored National Watershed Development Project for Rainfed Areas (NWDPRA) scheme has been in operation since October 1997, and it makes conservation measures conducted in water and soil of 18 watersheds in the Vellore and Tiruvannamalai districts.  Thiruvalluvar University was split off from the University of Madras and is located near Vallimalai, Vellore. Most government-run arts and science colleges in Vellore, Tiruvannamalai, Villupuram and Cuddalore districts are affiliated with Thiruvalluvar University. Thanthai Periyar Government Institute of Technology is the only government engineering college in Vellore. The Vellore Institute of Technology (VIT) has been ranked best private engineering university in India by the magazine "India Today". Christian Medical College & Hospital (CMCH), one of the largest hospitals in India and Asia, is based out of Vellore. It is a major health care provider for the surrounding districts.  Auxilium Women's College (founded in 1954) is the first women's college in Vellore district; Other arts and sciences colleges in the city are the Dhanabakyam Krishnaswamy Mudhaliar Women's College (DKM) near Sainathapuram and the Muthurangam Government Arts College (MGAC) in Otteri, near Bagayam. Voorhees College (founded 1898) is the oldest college in the district and known as the institution where S. Radhakrishnan (former president of India) studied; a commemorative stamp for the centenary of the college was issued by the government of India. C. Abdul Hakeem College is in Melvisharam. Arignar Anna Arts College for Women (AAA) is located in Walajapet.  The Government Law College was established in 2008. It offers a three-year Bachelor of Laws (BL) degree with an annual intake of 80 students. The college is in Katpadi, Vellore. There are several Arabic colleges in Vellore such as the Madrasa Al-Baqiyathus Salihath (popularly known as "Baaqiyaath"), founded by Shah Abdul Wahab and is the second oldest Arabic college in India after Darul Uloom Deoband in Uttar Pradesh.  Schieffelin Institute of Health – Research and Leprosy Centre (SIH-R & LC) is located near Vellore and was established in 1955 to care for leprosy patients.

Tourism.

Vellore Fort is the most prominent landmark in the city. During British rule, Tipu Sultan's family and the last king of Sri Lanka, Vikrama Rajasinha, were held as royal prisoners in the fort. The fort houses a church, a mosque and a Hindu temple, the latter known for its carvings. The first rebellion against British rule erupted at this fort in 1806, and it witnessed the massacre of the Vijayanagara royal family of Emperor Sriranga Raya. The fortifications consist of a main rampart, broken at irregular intervals by round towers and rectangular projections. The main walls are built of massive granite stones, surrounded by a broad moat fed with water by subterranean pipes from the Suryagunta reservoir.  Within the fort is the similarly aged Jalakanteswara Temple. The fort houses the Tipu Mahal where Tipu Sultan is believed to have stayed with his family during the war with the British; the graves of Tipu's sons are found at Vellore. It is managed by the Archaeological Survey of India. Vellore Fort has been declared a Monument of National Importance and is a famous tourist attraction. The State Government Museum is inside the fort and opened to the public in 1985. It consists of art, archaeology, prehistory, weapons, sculptures, bronzes, wood carvings, handicrafts, numismatics, philately, botany, geology, and zoology exhibits. Historical monuments of the North Arcot District are contained in the gallery. Special exhibits include a double bronze sword from Vellore Taluk dating to 400 BC, stone sculptures from the late Pallava to Vijayanagar periods, ivory chess boards and coins used by the last Kandian King of Sri Lanka, Vikrama Raja Singha. Educational activities at the museum include an art camp for school students and the study of inscriptions and iconography for college students.

Transport.

Road.

The Vellore municipal corporation maintains of roads. It has of concrete road, of kutcha road and of bituminous road. The National Highways passing through or terminating at Vellore as per new numbering are:  Vellore is connected with major cities in the states of Tamil Nadu, Andhra Pradesh and Karnataka. Bus service is available to Chennai, Coimbatore, Bangalore, Thiruvananthapuram, Tirupathi, Kadapa, Anantapur, Salem, Chittoor, Kuppam, Kolar, Kolar Gold Fields, Madanapalle, Vijayawada, Hyderabad, Mangalore, Karur, Kumbakonam, Aranthangi, Mannargudi, Nagapattinam, Hosur, Marthandam, Thoothukudi, Thiruchendur, Sengottai, Cuddalore, Kurnool, Trichy, Thuraiyur, Thammampatti, Thiruvannamalai, Tindivanam, Pondicherry, Kallakkurichi, Tirupattur, Viluppuram, Kanyakumari, Arani, Madurai, Tirunelveli, Kanchipuram, Tiruttani, Kalpakkam, Pallikonda, Ponnai, Gudiyatham, Dharmapuri, Erode, Tirupur, Palakkad, Krishnagiri, mumbai Gingee and other major towns and cities in South India. Vellore is served by a city bus service, which connects the city, suburbs, and other places of interest. The bus service extends about 30 km from the city center. There are two bus terminals: the Town Bus Terminus (opposite the fort and near CMC Hospital) and the Central Bus Terminus (Near Green Circle). Other bus terminals are located at Chittor Bus Stand (near VIT Road), Bagayam and Katpadi (Junction bus stop). The bus stands are maintained by the Vellore Municipal Corporation. New Bus terminus will be constructed at a cost of ₹46.51 crore in a 9.25 acre area under the Smart City project by the Vellore City Municipal Corporation, is expected to be completed in 24 months and become operational by January 2022.

Rail.

Vellore has three main railway stations: Vellore Katpadi Junction, Vellore Cantonment and Vellore Town. The largest is Vellore Katpadi Junction (5 km north of CMC hospital). It is a major railway junction on the Chennai-Bangalore broad-gauge line running to Chennai, Bangalore, Tirupati, New Delhi, Howrah, Kanyakumari. There are direct rail links to Vijayawada Junction, Tirupati, Jhansi, Bhubaneswar, Nagpur, Bangalore, Coimbatore, Lucknow, Dehradun, Agartala, Ahmedabad, Ludhiana, Bhopal Junction, Mumbai, Mangalore, Tiruchchirappalli, Kumbakonam, BilaspurKorba, Patna, Ernakulam, Trivandrum, Kanniyakumari, Shirdi, Kanpur, Gaya, Dhanbad, Jammu Tawi, Madurai, Bhilai, Gwalior, Chennai Central, Howrah Station, New Delhi Railway Station, Coimbatore, Guwahati, Silchar, Howrah, Nagarcoil, Kozhikode, Kollam, Thrissur, Jaipur, Dibrugarh, Varanasi, Pune, Hyderabad, Vishakapatnam and other major cities. More than 150 trains cross the Vellore-Katpadi Junction daily. Nearly 250 to 265 trains halt this junction. This is the major and busiest junction in South India and 1st Important railway station in Vellore district.  Vellore Cantonment is in Suriyakulam on the Viluppuram-Tirupati broad gauge line, 8 km from Katpadi Junction. EMU and passenger trains to Tirupati, Chennai and Arakonnam depart from here. The 150-km broad gauge line was extended to Villupuram in January 2010. It connects Vellore and South Tamil Nadu; however, it is serviced by slow passenger trains. The line was opened for goods trains in June 2010. An EMU from Vellore Cantonment to Chennai Central was introduced on December 22, 2008. Vellore Town Station is in Konavattam on the line connecting Katpadi Junction with Viluppuram Junction via Tiruvannamalai.

Air.

The Vellore Airport was established in 1934 and is located in Abdullapuram, 11 km away from the city centre. It had been used to land trainer aircraft and helicopters. It was reactivated as a part of the Airports Authority of India idle airports activation programme in July 2006 to facilitate regular flying by trainee pilots of the Madras Flying Club whose operations were restricted with the increase in scheduled aircraft movement at Chennai Airport. Vellore airport is in the process of being revived under the Regional Connectivity Scheme (RCS). UDAN, runway and terminal building works are under progress, all the required infrastructure works scheduled to be ready by June 2019 for operations.

Utility services.

Electricity supply to Vellore is regulated and distributed by the Tamil Nadu Electricity Board (TNEB). The city and its suburbs form the Vellore Electricity Distribution Circle. A chief distribution engineer is stationed at the regional headquarters. The water supply is provided by the Vellore municipal corporation from the Palar river through Palar headworks and Karungamputhur headworks and distributed through ten overhead tanks. As of 2005, there are 16,371 connections to 33,772 households. In 2000–2001, a total of 7.4 million litres of water was supplied daily for households in the city. The other sources of water are Otteri Lake, Sathuvancheri town panchayat, Ponnai and street wells.  According to the municipal data for 2011, about 83 metric tonnes of solid waste are collected from Vellore every day by door-to-door collection. The source segregation and dumping are carried out by the sanitary department of the Vellore municipal corporation. The municipal corporation covered 16 wards for waste collection as of 2001. There is no underground drainage system and the sewage system for sullage disposal is through septic tanks, open drains and public conveniences. The municipal corporation maintained of storm water drains in 2011. As of 2011, 24 government and private hospitals and one veterinary hospital take care of the citizens' health care needs. As of 2011, the municipal corporation maintained 5,241 street lamps: 735 sodium lamps, 73 mercury vapour lamps, 4,432 tube lights and one high mast beam lamp. The municipal corporation operates the Netaji Daily Market that caters to the needs of the city and the rural areas around it.

Vellore is a city and the administrative headquarters of Vellore district in the Indian state of Tamil Nadu. It is located on the banks of the Palar River in the northeastern part of Tamil Nadu and is separated into four zones that are further subdivided into 60 wards, covering an area of 87.915 km and housing a population of 423,425 as reported by the 2001 census. It is located about west of Chennai, and about east of Bangalore. Vellore connects Mumbai - Chennai and Vellore connects most of the indian cities. Vellore is governed under a mayor and the Vellore Municipal Corporation. It is a part of both the Lok Sabha and state assembly constituencies of Vellore.

韦洛尔(泰米尔语:)是印度泰米尔纳德邦的一座城市,人口约39万,印度工程类前茅的韦洛尔科技大学和印度顶尖医学院CMC学院座落于此。(2001年)。