Price Rise/Rise in Prices which happen over a sustained time period is termed as Inflation. In layman’s term, it means that the value of money diminishes, in the sense that the purchasing power of money to buy good and services is significantly reduced.
Though, it is difficult, as per the combined study of economists and academics to pinpoint the root cause of inflation , since there are so many factors at play, the below mentioned factor contribute significantly to price rise :
1. Demand Pull Inflation: Where demand far exceed supply of a product. In economies experiencing rapid growth, this is a fairly common phenomenon. Have you felt that around the time of festivals the cost of essential item, food grains, vegetable and fruits shoot up? That is because of more and more consumption of such products in those seasons,
2. Cost Push Inflation: When a company’s cost of production increases due to any reason such as increased cost of raw materials, or increased cost of labour or increased rate of taxes levied on certain products, the result is felt in the escalated final price.
3. Monetary Inflation: If there is a surplus of money circulating in the market against the same quantity of goods and service, the purchasing power of a single rupee goes down and hence, the value of goods and service becomes more and prices shoot up.
4. Increase in the cost of fuel and Petrol: Even a slight increase in the cost of petrol or diesel is bound to create a massive ripple in the inflation rate. That is because, the fuel cost is added to the raw material cost, the transportation cost and overall the margin becomes wider.
5. External Factors: As the prices of goods and commodities rise in the global market, the same is reflected in the country, as they are imported. Such situations are largely outside the gambit of our national policy makers and difficult to check.
For a common man, inflation is a grave concern. He is constantly forced to make adjustments to his quality of life to keep pace with this disproportionate increase in price. However, with the growth in economy,ruling party justifies that inflation is a natural fallout. Yes, but as long as it is sustained by better growth and increments in salary, commensurate with the rise in prices, which sadly never happens.
Besides, for the people who draw fixed amount, for example pensioners and those who fend off savings in the form of interests from banks, inflation hit deep.
Moreover, recent years have witness an exponential hike in price, which impact adversely the lives of people already at subsistence level, many of whom are forced to commit suicides enmasse, not being able to ensure a decent life for their families.
Uncontrolled or badly managed price rise is detrimental to the well-being of society and hence, in order for a stable economy to function, it is important to have checks and controls in place to ensure proportional price rise.Sweeping reforms are needed to control hoarders from creating false panic in market and reform agriculture to ensure that the prices of essential commodities are least affected by disproportionate price rise.


Early this fall, I wrote a post about END7, a global advocacy campaign run by the Global Network to raise awareness of the seven most common Neglected Tropical Diseases (NTDs) and cultivate the resources necessary to eliminate them as public health threats by 2020.
I had honestly never heard of NTDs before even with all my international traveling. However, NTDs keep millions of children in the developing world out of school from preventable, treatable diseases further reinforcing the cycle of poverty and despair. Per END7, there are seven NTDs (Elephantiasis, river blindness, trachoma, snail fever, hookworm, whipworm and roundworm) that are responsible for 90% of the global burden of NTDs. NTDs are a huge problem: It is estimated that NTDs infect one in six people worldwide including one billion children.
END7 recently released a beautiful, touching video titled “Three Generations, One Hope for Health“. Shot in Coast Province, Kenya by Mo Scarpelli, a Brooklyn-based filmmaker and multimedia journalist, the video features the story of Fatuma, an eight year-old girl who emanates hope and perseverance despite the fact her little sister and grandma both suffer from NTDs.
Meet eight-year-old Fatuma, her younger sister Neema and their family who live in Burangi, a remote village in Kenya surrounded by water where neglected tropical diseases (NTDs) are endemic. Their village has no paved roads, no hospitals and is a hotbed for NTDs. Just five years old, Neema has already been sick with intestinal worms for four years. As Fatuma grows taller and stronger, her little sister has grown weaker and has been doing poor in school.
Meanwhile, their grandmother also suffers from worms and has elephantiasis, a painful swelling of the feet which are covered with open wounds. Both these diseases can be treated with medication for only $0.50 per year. More than half the population of Kenya live on less than $1 a day and is at risk for one or more NTDs.
Please take a moment to watch this touching five minute video, “Three Generations, One Hope for Health”, which aims to move people towards awareness of NTDs and offer hope that someday we will be able to overcome them by easy, effective and inexpensive treatment.
I was curious how END7 filmed such a beautiful, touching video as it isn’t an easy feat. Here is what END7 told me about the work behind “Three Generations, One Hope for Health”.
END7 decided to support a mass drug administration (MDA) – when entire communities are given NTD pills to treat and prevent multiple NTDs at once – in Malindi, a rural village in the Coast Province of Kenya, because people really weren’t receiving consistent treatment. This MDA occurred in June 2013.
A big part of END7’s work is communicating the human, emotional aspect of these diseases. So we sent Mo Scarpelli, a Brooklyn-based filmmaker and multimedia journalist who is captures characters and personal narratives, to film and photograph the MDA. Her website can be found here.
This MDA occurred during a week focused on health. Since community health care workers were already being trained on a variety of health issues, they also learned how to distribute NTD treatments. Then, they went around from home to home, distributing the pills and educating the community about what they were taking.
Mo witnessed this all. In Malindi for a week, she traveled around with the Ministry of Health staff and their partners, and the community health care workers. This is when she met the Kahindi family –Neema, Fatuma, their grandmother and mother – and learned all about their struggle and optimism. Mo encountered the family entirely organically – she’s all about finding stories rather than scripting them, and that’s how we prefer to work, too.
We can END7 by 2050. It is up to us to spread awareness. For more information, please check out END7 here.


Native to Australia, the bottlebrush shrub is an attractive, hardy addition to any sheltered, sunny garden or conservatory. They're known for their tough little leaves, textured bark and red, bottlebrush-like flowers. They can be maintained as a shrub, but more often than not, they're grown as a small tree with a graceful weeping habit. Prune your bottlebrush to keep it looking its best.
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Starting at the lower part of the shrub, cut several of the branches close to the trunk. When you've opened up the lower, inside part of the tree a bit, take a few steps back and examine the tree's form. If it looks a little lopsided, prune a few more branches for balance.
Cutting on the leaf nodes, prune a few more of the branches from the lower part of the tree. Make the cuts at different places, for a more natural, layered look. If the tree begins to look a little umbrella-like, with a bare lower trunk and a full canopy, stop pruning the lower branches. Bottlebrush plants look their best when they have a natural, flowing form.
Cut off any lower branches that fork. This will help encourage the branches to reach up and out, and give the bottlebrush an attractive, weeping look. Part of the appeal of weeping trees is their movement in the breeze, and the bottlebrush is no exception.
Continue to prune carefully as you move up the shrub, taking time to examine the shape of your plant. Prune the ends off higher, arching branches throughout the growing season, especially after the bottlebrush blooms are spent -- this will encourage more blooms. Continue to open up the inside of the shrub by pruning the inside branches. If the inside gets too dense, the sunlight isn't able to reach the branches and they may attract mould and pests.
Ease off the pruning as the growing season ends and winter begins. If you prune too late in the year, the resulting new growth may be susceptible to damage in a severe cold snap.
Tips and warnings
- For the first three years of the shrub's life, prune by cutting back one-third of the growth at the base of the shrub. The shrub will bounce back quickly and reward you with a rapidly growing, more sturdy plant.
- Old and tired bottlebrush plants often benefit from an occasional hard pruning down to the ground.
- You'll need to grow the bottlebrush under glass in most parts of the UK.
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Powers Of Attorney
A power of attorney is a document utilized in cases where one person (the agent) has to act on another’s (the principal) behalf to conduct the principal’s business or personal affairs.
It is very important to have a power of attorney in place in the event that a person becomes incapacitated either mentally or physically and is incapable of carrying out personal and business affairs.
In the event of alleged mental incapacity, there has to be a legal proceeding and hearing in order to adjudge the person as incompetent. The court in its sound discretion appoints someone to represent and make legal decisions for the incapacitated person.
Traditionally, powers of attorney only addressed financial issues. However, good practices should include among other matters the right to consent to medical treatment, the right to have access to and receive medical reports and records, and the right to obtain information that would otherwise be precluded by financial privacy laws. Consideration should also be given to name a successor person to have the power to act in the event the initially named agent cannot act.
A properly drawn power of attorney can avoid this type of proceeding.
Also to be considered are living wills and/or medical directives which relate to health and medical treatment (HIPAA) issues that might arise.


What is Forskolin?
Forskolin is an active compound found in the roots of the Indian coleus (Coleus forskohlii), a tropical plant related to mint. For centuries, this plant has been used in traditional herbal medicine to treat various conditions and diseases.
Modern scientific research has now shown that some of these health benefits may be true, or at least plausible. As a weight-loss supplement, forskolin gained popularity in the US after being featured on the Dr. Oz Show in January 2014.
Forskolin (coleus forskohlii) is a naturally-occurring chemical compound whose highly-regarded association with being a potential weight loss catalyst and muscle building accelerator has exploded with popularity…but why sudden internet interest now?
Natural, pure forskolin is an exotically-acclaimed extract and multipurpose aromatic herbal ingredient (bioactive labdane diterpene) derived from the roots of the Plectranthus Barbatus/Lamiaceae plant. It is and has been an important cultural and medicinal plant throughout the world, especially in traditional Indian Ayurvedic medicine for many years expressing beneficial anti-microbial and anti-inflammatory properties along with diverse pharmacological benefits.
Forskolin's deeply-rooted origins come from the mint family and is commonly found in eastern hemisphere locations; Thailand, India and Burma as well as Brazil and parts of Africa. The storied indigenous history of the Indian coleus perennial plant species (makandi/coleonol) has long been linked as an ancient herbal tonic medicine to help treat varying:
gastrointestinal / digestive disorders
cardiovascular / circulation conditions
respiratory disorders / cough
central nervous systems
skin problems / infections / boils / eczema
body stiffness & rheumatism
Why does it have Scientists, Doctors and Celebrities Buzzing?
The most talked about natural weight loss is finally here! A plant of the mint family that grows in Southeast Asia and India, Forskolin is a revolutionary breakthrough that has the Media in a frenzy!
Forskolin Identifed as Cyclic Adenosine Monophosphate, which is extracted from the root of the plant is Mother Nature's Answer to Weight Loss!
How does Forskolin work?
Increases Intracellular Levels of CAMP - Simply put, forskolin releases fatty acids from adipose tissue, allowing them to be burned for energy, leading to the melting effect of the the belly fat.
Dissolves Fat Cells - This thermogenesis effect is the result of a chain reaction initiated by the chemicals in forskolin. It increases an enzyme in the human body called adenylate cyclase. This enzyme increases levels of another enzyme called cAMP (cyclic AMP) which is found in fat. Then a third enzyme, lipase, will be stimulated, resulting in fat burning.
Nutrition Forskolin works by blocking these enzymes and preventing the formation of these fatty deposits. In essence it not only burns fat we have stored, but also prevents more fat from forming!
The best part about Nutrition Forskolin is it can work on its own! No more time wasted shopping for expensive diet products and no more hours wasted at the gym!
Forskolin has been clinically proven to:
Increase the speed of metabolism by 70%
Increase HCA levels and production of leptins by 150%
Help the body burn fat as energy instead of storing it
Rich in antioxidants and serotonin, boosting energy levels
Reduce levels of Cortisol (the stress hormone) to improve mental health
Help Eliminate Bad Toxins & Extra Fat Tissue Cells That Have Been Built Up Over the Years
Disclaimer: This website is for information purposes only. By providing the information contained herein we are not diagnosing, treating, curing, mitigating, or preventing any type of disease or medical condition. Before beginning any type of natural, integrative or conventional treatment regime, it is advisible to seek the advice of a licensed healthcare professional.


Using magnetic resonance imaging (MRI), a new study has identified several areas of the brain that frequently faltered, literally shut down for a few seconds at a time, in sleepy subjects, but not in those who had enough rest.
Some people seem able to function after pulling all-nighters, but a new study shows that they’re probably not 100-percent “there.” Researcher David Dinges of the University of Pennsylvania School of Medicine followed 24 adults after normal rest, and then again after they missed a night of sleep. He found that the brain literally shuts down for a few seconds as a result of sleep deprivation. Okay one minute — shut down the next. Using magnetic resonance imaging (MRI), Dinges identified several areas of the brain that “frequently faltered” in the sleepy subjects, but not in those who had enough rest.
“Imagine you are sitting in a room watching a movie with the lights on,” he said. “In a stable brain, the lights stay on all the time. In a sleepy brain, the lights suddenly go off.” Dinges noted that the sleepy person switches back and forth between complete wakefulness and sudden brain shutdown.
You’ve probably experienced this phenomenon if you’ve ever been in a conversation with someone who seemed perfectly coherent until he nodded off mid-sentence, only to fade back in a few seconds later and pick up where he left off. Or, perhaps you’ve found yourself nodding off at the wheel of your car when just seconds earlier you felt alert. And that’s the issue that has the researchers concerned — the fact that brain fade-outs can compromise safety. In fact, the report, published in The Journal of Neuroscience, specifically expressed concern about people who drive when exhausted, noting that a four-second brain lapse could spell disaster.
Certainly, it is scary to consider that those commuters zooming past you on the highway might be sleep-deprived. But it’s equally scary to realize that some of the professionals whom you entrust with your well-being — doctors and nurses, for example — routinely pull all-nighters.
It’s hardly news that medical residents work long hours. A 2005 study by Brown University and the University of Michigan found that doctors on “heavy duty,” with an average of only 3.5 hours of sleep, functioned at the same level as if they had consumed three to four vodka cocktails. Earlier concerns about impaired functioning in sleepy residents led the Accreditation Council for Graduate Medical Education to set a new policy limiting residents to an 80-hour work week — which, as we just learned from the latest study, won’t help much.
It’s incredible to think that an 80-hour cap on hours worked per week represents a big cutback. And even with the new regulations, the fine print leaves plenty of room for trouble. The 80-hour limit can be averaged out over four weeks, so residents might have a 100-hour shift one week, and a mere 60-hours the next. Plus, the new standards prohibit working more than 30 hours non-stop in one shift — but a 30 hour shift, by definition, requires an all-nighter, and that means your doctor might be performing medical procedures while in a drunken-like stupor, fading in and out of consciousness. Not comforting, is it?
And the long hours put in by doctors are just the tip of the iceberg in the medical community. According to the International Council of Nurses, “In a large number of hospitals nurses report the existence of a documented policy that imposes mandatory overtime.” A study by the University of Pennsylvania Medical School found that 81 percent of nurses aren’t able to leave work at the scheduled time. Because of the nursing shortage, twelve-hour shifts are becoming the norm, and many nurses routinely work double shifts.
This spells trouble for both nurse and patient safety. A study last year published in Medical News Today found that about 67 percent of the nurses reported at least one episode of drowsy driving after working overtime. This same study found a strong link between working long hours and making medical errors such as delivering the wrong medication or writing wrong information in a patient chart.
At least in some places, nurses are getting fed up. A few weeks ago, the nursing staff at a Veteran’s Administration facility in Illinois staged a protest in response to a contractual requirement that they work overtime. Certainly, the long hours put patients at risk. As the executive director of the Illinois area nurse’s union, Henry Bayer, said, “An exhausted worker is a safety hazard waiting to happen. A lot of the accidents that happen are when they are on overtime.”
No wonder so many patients go into the hospital only mildly ill and never come out. No wonder the statistics are off the charts for prescribing errors. The upshot is that you’d be well advised to get plenty of sleep yourself in order to keep yourself healthy and out of the hospital, where dozy nurses and drowsy doctors abound, with their brains flickering on and off…like the lights in a prison during an execution by electric chair.


Mearnwhile, in a desperate attempt to find someone harmed by global warming, the NY Times blames us for problems on the other side of the world:
Climate scientists have concluded that widespread burning of fossil fuels is releasing heat-trapping gases that are warming the planet. While this will produce a host of effects, the most worrisome may be the melting of much of the earth’s ice, which is likely to raise sea levels and flood coastal regions.This is backwards thinking. Bangladesh is a dysfunctional country. Even the name sounds like some sort of wasteland, instead of a real nation. They have too many people, and they cannot even take care of themselves.
Such a rise will be uneven because of gravitational effects and human intervention, so predicting its outcome in any one place is difficult. But island nations like the Maldives, Kiribati and Fiji may lose much of their land area, and millions of Bangladeshis will be displaced.
“There are a lot of places in the world at risk from rising sea levels, but Bangladesh is at the top of everybody’s list,” said Rafael Reuveny, a professor in the School of Public and Environmental Affairs at Indiana University at Bloomington. “And the world is not ready to cope with the problems.” ...
At a climate conference in Warsaw in November, there was an emotional outpouring from countries that face existential threats, among them Bangladesh, which produces just 0.3 percent of the emissions driving climate change. Some leaders have demanded that rich countries compensate poor countries for polluting the atmosphere. A few have even said that developed countries should open their borders to climate migrants.
“It’s a matter of global justice,” said Atiq Rahman, executive director of the Bangladesh Center for Advanced Studies and the nation’s leading climate scientist.
Though Bangladesh has contributed little to industrial air pollution, other kinds of environmental degradation have left it especially vulnerable.The West has helped them overpopulate too much already. The world is a changing place, and so is human population. Maybe it would be a good thing if more of Bangladesh were under water. I certainly do not think that we should stop using carbon so those people can make a bigger mess of their country.
Bangladesh relies almost entirely on groundwater for drinking supplies because the rivers are so polluted. The resultant pumping causes the land to settle. So as sea levels are rising, Bangladesh’s cities are sinking, increasing the risks of flooding. Poorly constructed sea walls compound the problem. ...
In an analysis of decades of tidal records published in October, Dr. Pethick found that high tides in Bangladesh were rising 10 times faster than the global average. He predicted that seas in Bangladesh could rise as much as 13 feet by 2100, four times the global average. In an area where land is often a thin brown line between sky and river — nearly a quarter of Bangladesh is less than seven feet above sea level — such an increase would have dire consequences, Dr. Pethick said.
It is silly to think that some people should be compensated because they might have to move over the next century. A lot of people move every 5 years, and it is no big deal. These Third World countries are very much better off for Western industrialization. They certainly did not object, or propose to do it any differently. They benefit from better food and other goods. They should appreciate it. Industrialization was not a mistake, and there is no need to apologize for it.


Professor Tim Elliott and his team are trying to identify characteristics of cancer cells that make them more likely to respond to a certain type of immunotherapy. They hope that pinpointing these attributes can make it easier to identify the patients that will respond well to the therapy.
Only around a quarter of patients respond well to a type of immunotherapy called checkpoint blockade. Unfortunately, oncologists are currently unable to predict which patients will benefit. Professor Tim Elliott and his team are trying to change this by uncovering what it is that sets tumours that respond apart from those that don’t.
“I grew up in the industrial North of England and was the first person in my family to go to University. I studied Biochemistry at the University of Oxford, where we spent a year placement in one of the research labs. I found myself in the MRC Immunochemistry Unit run by Nobel Laureate Rod Porter and fell in love with lab-life immediately.
"I started to teach myself how to cook at Uni which turned out to be a lot like working in the lab and have cooked pretty much every day since then! I even had a phase of entering cooking competitions in the early 1990's!"
Checkpoint blockade works by boosting - or reactivating - certain cells of the immune system that localise near the tumour. These inactive cells may have become exhausted from overstimulation or have been neutralised by the tumour.
Professor Tim Elliott and his team have been studying these immune cells in mice. When given checkpoint blockade treatment, around 50% of mice are cured. This provides an ideal tool to study what these mice have in common and what sets them apart from the mice that don’t respond to the treatment. In this way Professor Elliott hopes to identify characteristics of the natural immune response to cancer that make it more likely for patients to respond to checkpoint blockade immunotherapies, opening up exciting possibilities for personalised cancer treatment.
I hope that in the future, cancer will be amenable to earlier detection, that there will be more widely effective immunotherapies and that these will have fewer side-effects so that it becomes another manageable chronic condition of old-age.Professor Tim Elliott
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Copy number variants (CNVs) overlap over 7000 genes, many of which are pivotal in biological pathways. The implications of this are profound, with consequences for evolutionary studies, population genetics, gene function and human phenotype, including elucidation of genetic susceptibility to major common diseases, the heritability of which has thus far defied full explanation. Even though this research is still in its infancy, CNVs have already been associated with a number of monogenic, syndromic and complex diseases: the development of high throughput and high resolution techniques for CNV screening is likely to bring further new insights into the contribution of copy number variation to common diseases. Amongst genes overlapped by CNVs, significant enrichments for certain gene ontology categories have been identified, including those related to immune responses and interactions with the environment. Genes in both of these categories are thought to be important in evolutionary adaptation and to be particular targets of natural selection. Thus, a full appreciation of copy number variation may be important for our understanding of human evolution.
The recent appreciation of copy number variation as a frequent and widespread feature of human genomes has the potential to revolutionise our understanding of clinical and population genetics and genetic epidemiology. Changes in copy number are important for all types of human disease: genomic disorders, monogenic diseases, infections, autoimmunity, cancer and other complex disorders, and should now be considered in study design for all aspects of human genetic analysis.
Until recently it was assumed that healthy individuals carry two copies of every autosomal gene, with one copy inherited on the maternally-inherited chromosome, and the other inherited paternally. Any deviation from this was assumed to be phenotypically harmful: it was initially predicted that any two ‘normal’ individuals are approximately 99.9% similar genetically, with single nucleotide polymorphisms (SNPs) providing the main source of human genetic variation (Altshuler et al., 2000). This view has been completely overturned in the last few years, since the overcoming of two major problems which previously delayed or prevented detection of common CNVs. The most critical was the resolution gap between microscopy-based and molecular biological technologies – resolved by the advent of microarray-based comparative genome hybridisation (array CGH) in 1998 (Pinkel et al., 1998). The second issue was that there has historically been much greater research effort directed toward analysis of disease than to in-depth analyses of ‘normal’ genomes; this may have led to a selection bias such that aberrations with detrimental phenotypic effects were sought, whereas relatively benign ones were not looked for and, therefore, not found. Recent technological advances, however, have revealed this copy number variation to be much more common than previously suspected, with apparently healthy individuals varying from each other in a large number of genomic regions.
Large chromosomal aberrations, containing many genes, have long been known to cause developmental abnormalities and, on a smaller scale, genomic disorders can be caused by microdeletions or duplications (<10 Mb). In some cases, the copy number change of only a single gene is thought to underlie such diseases, as exemplified by the duplication of PMP22 in Charcot-Marie-Tooth disease type 1A (CMT1A) (Roa et al., 1991) and the deletion of RAI1 in Smith-Magenis syndrome (SMS) (Slager et al., 2003), both of which came to light only after extensive investigation of affected individuals. Before 2004, however, only a handful of genes were known to vary in copy number in apparently healthy individuals. For example, both deletions and duplications in the HLA class III genes encoding the complement components C2 and C4 are relatively common in healthy individuals (reviewed in Campbell et al., 1986), although they have also been known to associate with systemic lupus erythematosus (SLE) for many years (Agnello et al., 1972; Hauptmann et al., 1974). Other gene clusters such as the betadefensin antimicrobial cluster (Hollox et al., 2003) and olfactory receptor genes (Trask et al., 1998) were also known to vary in copy number, but such phenomena were thought to be anomalies.
Some genes varying in copy number are associated with phenotypic effects in combination with particular environmental exposures. The GSTM1 gene, for example, is found in only half of the Caucasian population, with the other half carrying homozygous deletions that are thought to increase susceptibility to some cancers, possibly due to a reduction in metabolism of certain carcinogenic compounds in the environment (reviewed in Rebbeck, 1997). Conversely, individuals carrying three copies of the gene have ‘ultra rapid’ GSTM1 activity (McLellan et al., 1997), which may confer protection against certain cancers by increasing the breakdown of harmful environmental toxins.
Several genes encoding drug-metabolising enzymes were also known to be variable in copy number, which, in some cases, could lead to different responses to certain drugs. The cytochrome P450 gene CYP2D6 metabolises up to 20% of all drugs in clinical use, and the rate of metabolism varies depending on the levels of expression of this enzyme in the liver (reviewed in Schaeffeler et al., 2003). As there are extensive polymorphisms of this gene, including whole gene deletions (Sachse et al., 1997), these expression levels are highly variable (Zanger et al., 2001), resulting in some people being ultra-rapid metabolisers, and others, particularly those with deletions, being poor metabolisers who are at higher risk of adverse effects after drug therapy. A similar effect is seen with other cytochrome P450 genes: people who smoke are more likely than non-smokers to carry a duplicated version of CYP2A6, the product of which metabolises nicotine to the inactive cotinine. Individuals with higher enzyme activity have less nicotine in their blood for the same number of cigarettes smoked, encouraging them to smoke more (Rao et al., 2000).
Despite these specific examples, it was not generally appreciated that a wide range of genes could be affected by CNVs, without obvious phenotypic effect. This was partly a result of our initial ignorance of how widespread and frequent such variation was. Following two seminal publications (Iafrate et al., 2004; Sebat et al., 2004), a number of studies have been published, revealing a wealth of CNV loci in the genome, overlapping many genes (Tuzun et al., 2005; Conrad et al., 2006; Hinds et al., 2006; McCarroll et al., 2006; Mills et al., 2006; Redon et al., 2006; de Smith et al., 2007; Korbel et al., 2007; Wong et al., 2007). In our investigation alone, a 2-stage custom array CGH analysis of just 50 unrelated healthy French Caucasian males revealed over 2500 genes overlapped by CNVs – 1284 of these genes were previously unknown to vary in copy number (de Smith et al., 2007). This illustrates that a substantial proportion of copy number variation remains to be discovered, and that CNVs are abundant in apparently healthy individuals. Such high-resolution CGH studies will continue to be useful in refining mapping of known CNVs and also in identification of smaller CNVs: it is clear that many more variant regions remain to be identified and characterised.
Published CNV data are documented on the TCAG Database of Genomic Variants (http://projects.tcag.ca/variation), and by November 2008 this contained 6225 CNV loci, covering an estimated 28.8% of the genome. These loci consist of 19,792 separate CNVs, of which almost half overlap genes (Table (Table1).1). Considering the extent of this recently discovered genomic variation, and the fact that many biologically important and potentially disease-causing genes are indeed involved, there are likely to be significant phenotypic consequences for long-term health.
The mechanisms through which CNVs are formed have, as yet, been only partially elucidated. It is apparent that there are different subgroups of CNV in the genome, some with stable regions flanked by consistent boundaries, others with more complex, overlapping copy number variant regions (CNVRs), and these different variant types may arise through different processes or combinations of processes. For example, a proportion of variants have been associated with regions of segmental duplication (Sharp et al., 2005; Redon et al., 2006), and these low copy repeats are thought to propagate CNVs in the genome through a process known as non-allelic homologous recombination (NAHR). Only ~50% of reported variant sequences have been found to overlap segmental duplications (Cooper et al., 2007), and, therefore, other non-homology-based mechanisms, such as non-homologous end joining (NHEJ), have been implicated in the formation of some CNVs (Korbel et al., 2007; Perry et al., 2008). Another process, initiated by errors in DNA replication rather than in recombination, has recently been proposed to play a role in the formation of some copy number changes. Fork stalling and template switching (‘FoSTeS’) has been suggested to explain tandem duplications and other complex rearrangements of the PLP1 gene leading to Pelizaeus-Merzbacher disease (PMD) (Lee et al., 2007); such mechanisms might also account for the formation of CNV duplications, and possibly deletions, especially in complex regions where CNV generation is not readily explained by NAHR or NHEJ.
In a recent investigation into the origins of common deletion variants, we suggested a mechanism of CNV formation involving Alurepeats that has not been described previously. These elements are significantly enriched at the breakpoints of this class of deletion, and for nine out of 40 deletion breakpoints, the Alupoly-A tail ends precisely at the breakpoint junction (de Smith et al., 2008). This suggests the Alupoly-A sequence may be involved in the formation of some CNVs, possibly due to these sequences being prone to single or double-strand breakage, initiating the process of NHEJ. Alusare thought to correlate with gene-rich and GC-rich regions of the genome (International Human Genome Sequencing Consortium, 2001), and it may be possible that these repeats play a greater role in the formation of gene CNVs than non-gene variants. This is consistent with the fact that the CNVs found to have an enrichment of Alusat their breakpoints were initially discovered using a custom CGH array biased towards genes (de Smith et al., 2007).
Different types of genes may, therefore, be more or less prone to copy number variation depending on the type and number of nearby repeat elements (e.g. Alusand segmental duplications). In turn, this could have an effect on the underlying mechanisms of formation that are involved. The structure of a gene could also affect the type of CNV they overlap, for example some very repetitive genes may be more likely to contain complex CNVRs, whereas others may be less repetitive and only contain ancient stable CNVs – a large number of CNVs may have arisen many generations in the past and persisted stably in the population since then. For instance, on the basis of sequencing data, linkage disequilibrium and imputation of extended haplotypes, it was deduced that each of 20 deletion CNVs found in multiple unrelated individuals had a single unique historical origin, and had been stably inherited over many generations (de Smith et al., 2008).
It is clear from family studies that de novo copy number changes may occur during meiotic processes. However, copy number differences have recently been reported between monozygotic twins (Bruder et al., 2008) and there are also early reports of CNVs occurring between different tissues in the same individual (Piotrowski et al., 2008). Thus it is clear that genomic rearrangements leading to CNVs do not occur solely during meiosis. The relative importance of the various mechanisms which might give rise to CNVs, either in meiotic or somatic tissues, is completely unknown; nor is there any indication of the extent of somatic CNV mosaicism or of the rate of accumulation of such de novoCNVs during a person's lifetime. These issues may be very important for particular phenotypes, particularly with respect to cancers and diseases of ageing.
The distribution of CNVs in the genome is thought to be non-random, and several ‘hot’ spots of variation have been identified: for example, 250 regions of 1 Mb DNA sequence have been found in which >50% bases are within variants (Cooper et al., 2007). In particular, CNVs occur more frequently towards centromeres and telomeres (Nguyen et al., 2006), perhaps because of the repetitive nature of these genomic regions. Equally, the relationship between the size of chromosomes and the number of variants contained within them is not straightforward, with some chromosomes having a relatively high proportion of copy number variation and others having a low proportion relative to their size. Chromosome 18, for instance, has only ~19.8% copy number variant sequence, while chromosomes 16, 17, 19, and 22 each have >41% copy number variant sequence (http://projects.tcag.ca/variation). This may reflect interchromosomal differences in genomic structure, for example chromosome 19 is rich in segmental duplications and tandemly clustered gene families (Grimwood et al., 2004), which may make it more prone to copy number variation. Alternatively, variations in selective pressures may lead to more or less variable chromosomes, for example the Y chromosome, which is thought to be subject to relaxed selection (reviewed in Charlesworth and Charlesworth, 2000), has a particularly high proportion of copy number variant sequence (~41.8%).
A significant relationship has also been reported between genes and CNV regions, with gene-rich genomic regions enriched with CNVs, and vice versa. Cooper et al. (2007) found an enrichment of CNVs in the most gene-rich regions of the genome (>30% cf. 21% genome-wide average), and an enrichment of exon density in the most CNV-rich genomic regions (>2.7% cf. 2.1% genome average). Analysis of CNVs in the rat genome also revealed that CNVs overlapped more genes than expected based on random distribution, suggesting this phenomenon is not limited to the human genome (Guryev et al., 2008). Data from other workers, however, suggest that there is a bias against structural variants overlapping genes (Redon et al., 2006; Korbel et al., 2007). Some of these discrepancies may reflect differences in the technological approaches used to find CNVs, for example some arrays may contain probes biased towards genes. Future studies using higher resolution technologies and approaches with reduced bias for particular genomic features, such as whole genome sequencing, should resolve this controversy.
If indeed there is a bias against CNVs overlapping genes, this could be due to selective constraints acting against these variants. Alternatively, there may be selection against genomic deletions rather than CNVs as a whole, as the genome is thought to be more tolerant of duplications than deletions (Brewer et al., 1999). Conrad et al. (2006) reported that CNV deletions were biased away from genes, and also found a strong under-representation of SNPs within genes in regions of deletions compared with the genome-wide average. Consistent with this, a lower proportion of CNV deletions compared with duplications were found to overlap OMIM genes (Redon et al., 2006). Purifying selection may, therefore, be acting against CNVs in genes generally or more specifically against gene deletions.
In addition to the apparent non-random distribution of CNVs, there also appear to be certain patterns in the types of genes overlapped by variants. Gene ontology (GO) analyses from various studies have revealed genes variant for copy number to be enriched for a number of categories, including immune responses and responses to external biotic stimuli (Feuk et al., 2006). Other genes involved in interactions with the environment, such as sensory perceptions of smell and chemical stimuli, as well as genes connected to taste and sight, have also been associated with CNVs (Redon et al., 2006; de Smith et al., 2007; Wong et al., 2007). In higher resolution studies, enrichment of genes involved in neurophysiological processes and in brain development has also been noted (de Smith et al., 2007). The protocadherin gene cluster on chromosome 5, for example, is particularly rich in CNVs. These genes are thought to play a role in the generation of combinatorial complexity in brain synaptic connections (Cooper et al., 2007), which hints at an impact of CNVs on the genetics of brain function and intelligence. These variant environment-response and neurodevelopmental genes may be acted upon by natural selection, thus playing a role in adaptability and fitness in response to external pressures (Feuk et al., 2006).
As well as enrichments for certain gene groups, CNVs seem to be biased away from other types of genes. For example, an impoverishment of genes encoding nucleic acid binding proteins or involved in nucleic acid metabolism was found in deletion regions (Conrad et al., 2006). Similarly, genes involved in cell signalling and cell proliferation were also reported to be underrepresented in CNVs (Redon et al., 2006). Such underrepresentation presumably reflects the effects of strong selective pressure, due to the crucial role of these genes in transcriptional regulation and development.
Copy number variation can affect genes in a variety of ways, and this, in turn, may be reflected in their effects on phenotype. Where whole genes vary in copy number, a simple consequence would be variation in gene expression through dosage effects, whereby gains or losses in copy number would increase or decrease expression levels respectively. It has been estimated that CNVs account for at least 17.7% heritable variation in gene expression (Stranger et al., 2007), and for dosage-sensitive genes, both gain- and loss-of-function events could be phenotypically harmful or beneficial, depending on the gene. Variation in expression due to CNVs may also vary from gene to gene, for example in three commonly deleted genes, GSTT1, GSTM1 and UGT2B17, gene dosage variation was found to explain 88, 75 and 26% of the observed variation in expression levels respectively (McCarroll et al., 2006). Similarly, for the α-synuclein gene (SNCA) an almost perfect correlation was found between gene dosage, mRNA and protein levels (Miller et al., 2004). However, not all gene CNVs result in corresponding changes in expression levels, for example in individuals carrying varying copy numbers of α-defensin genes, no relationship was found between total mRNA levels and gene copy number (Aldred et al., 2005). Indeed, Stranger et al. (2007) found that in the significant CNV expression associations, 5–15% of these were representative of negative correlations between copy number and gene expression. The majority of associations were, however, due to the correlation of increased expression with increased gene copy number.
Gene dosage effects are not the only consequences of copy number variation that can affect gene expression. Stranger et al. (2007) found that around half of the effects of CNVs on expression levels were due to disruption of gene coding sequences, such as removal of exons, or by affecting regulatory elements and other functional regions. CNVs that involve part of a gene could lead to the formation of variant proteins through processes of exon shuffling or generation of splice variants. Novel fusion genes may even be produced: for example, Korbel et al. (2007) identified a new gene resulting from the fusion between the coding regions of two olfactory receptor (OR) genes, OR51A4 and OR51A2. The potentially damaging phenotypic effects of such genomic events is shown by a recent study, which identified a gene fusion between PRSS1 and PRSS2 that is thought to be the underlying cause of disease in a French family with hereditary pancreatitis (Masson et al., 2008a).
Deletions or duplications lying outside coding sequences may also affect gene expression by changing the location or efficiency of important regulatory elements, including through position effects. There is also evidence that CNVs can affect long-range gene regulation, as Stranger et al. (2007) detected several significant associations >2 Mb away from genes. Deletion of a gene repressor element could lead to increased transcriptional levels of that gene, whereas duplication of sequences downstream from a promoter could lower expression levels due to the altered position of the promoter relative to the gene (Rodriguez-Revenga et al., 2007). For example, a small duplication downstream of the proteolipid protein gene (PLP1) silences expression of the gene and has been shown to result in a spastic paraplegia type 2 phenotype similar to that seen with null mutations of the same gene (Lee et al., 2006). Another potential effect of intergenic CNVs could be phenotypic mosaicism due to position effect variegation (Muller, 1930; Schultz, 1936), whereby a gene may be brought into closer proximity with regions of heterochromatin, which can spread into the euchromatin region resulting in the silencing of that gene (reviewed in Kleinjan and van Heyningen, 1998). The spreading of heterochromatin is variable between cells, so that mosaicism in gene silencing results from the gene being expressed in some cells but not in others. Tissue-specific effects could also arise through copy number changes of specific regulatory elements or isoform-specific exons, leading to expression changes only in particular isoforms of the gene product.
The effect of CNVs on gene expression, and their potentially disruptive effects on gene structure and function, suggests that they are likely to make a considerable contribution to human diseases. Due to the relatively recent discovery of CNVs, however, and current limitations in high throughput techniques, the full extent of CNV disease associations is not yet clear. Nevertheless, from the growing number of instances where such associations have been demonstrated, it is likely that they make a substantial contribution to human disease.
Given the large number of genes which are overlapped by CNVs (Table (Table1),1), a significant proportion of biomedically relevant genes are likely to be affected. In our CNV discovery study, for example, almost half the genes intersecting variants were represented in the OMIM database, including genes associated with Mendelian diseases, genomic disorders and common diseases (de Smith et al., 2007). Indeed, many gene copy number changes contribute directly to monogenic diseases. In recessive diseases, hemizygosity due to deletion of a gene, or part of a gene, could unmask a mutation on the other gene copy. Conversely, duplication of a healthy gene copy on one chromosome could theoretically mask the effects of a disease-causing mutation in the gene on the other chromosome, thus rescuing the phenotype. Indeed, it has been predicted that a proportion of the variable penetrance shown by many dominant genetic disorders could be explained by CNVs (Beckmann et al., 2007).
Autosomal dominant early-onset Alzheimer's disease (ADEOAD) is known to be caused by missense mutations in APP genes on chromosome 21, but duplication of the APP locus has also been found in patients with this disorder (Rovelet-Lecrux et al., 2006). This copy number gain is thought to lead to an abundance of amyloid deposits in the brain. Similarly, triplication of the SNCA gene, which leads to a profusion of Lewy bodies, has been associated in patients with autosomal dominant Parkinson disease (Singleton et al., 2003). Neither of these genes are known to be overlapped by variants in healthy individuals, and these copy number gains are, therefore, thought to underlie disease: such features are termed copy number mutations (CNMs). Loss or gain of exonic material could also result in missense mutations or frameshifts: indeed Duchenne muscular dystrophy (DMD) is usually caused by de novo deletions and duplications resulting in frameshifts. If these were discovered for the first time today, they would be known as CNMs. Importantly, most sequencing strategies for identification of mutations causing monogenic disease would miss such variants, which might therefore account for a significant proportion of ‘missing’ mutations, and complicate genetic counselling.
As well as monogenic diseases, variations in copy number of large genomic regions are the underlying cause of many genomic disorders, and such aberrations can affect the copy numbers of multiple genes. In some cases, the dosage changes of many genes are thought to contribute to phenotype, for instance with the ~1.6-Mb deletion at chromosome 7q11.23 that leads to Williams-Beuren syndrome (Peoples et al., 2000). In other disorders, such as CMT1A and SMS, dosage changes in only a single gene are thought to underlie disease (Roa et al., 1991; Slager et al., 2003). Interpretation of the data derived from clinical investigations into the underlying cause of suspected genomic disorders is frequently complicated by the presence of CNVs. We do not yet have a full appreciation of the normal spectrum of copy number variation, particularly in non-HapMap (The International HapMap Consortium, 2003) population groups, and so it may be very difficult to distinguish between benign CNVs and disease-causing variants. Further complications may be caused by CNVs that overlap larger aberrations, so that different combinations of variants mitigate or worsen phenotypes. This could help to explain, for example, the different manifestations of phenotypes seen in trisomy 21 patients: for example, ~40% patients have congenital heart defects (Freeman et al., 1998) and ~1% develop leukaemia (Zipursky et al., 1992).
The situation with regard to complex disease is even less straightforward. Recent advances in complex disease analysis, using genome-wide SNP association approaches, have highlighted new genes and potential pathogenic pathways (Frayling et al., 2007; Sladek et al., 2007), but the SNP markers found still do not account for the estimated heritability of these disorders. It is likely, therefore, that other genetic factors contribute to common complex disorders, including rare variants, epigenetic modifications and copy number variation. Although CNVs overlap many biologically important genes, several of which were already associated with disease, this is not of itself evidence that they play a role in disease. Therefore, studies are now underway to identify specific disease-associated CNVs. This has already led to reported disease associations with variants that are relatively common in apparently healthy populations. A substantial proportion of these associations has been found with genes involved in the immune system and in defence against disease. The first example of this was the discovery that low copy number of a frequent CNV including the FCGR3B gene is associated with glomerulonephritis in rats and humans (Aitman et al., 2006). This gene plays a key role in regulation of inflammatory and immune responses, especially in the tethering of neutrophils to immune complexes and the clearance of these complexes, and has since been associated with systemic lupus erythematosus (SLE) and other systemic autoimmune disorders, such as ANCA-associated vasculitis (Fanciulli et al., 2007).
As described earlier, variations in copy number of another gene, complement component C4, have long been associated with SLE. This gene also plays a role in the clearance of immune complexes, as well as in the activation of complement pathways that act against invading microbes, and in the reduction of the threshold for B lymphocyte activation. It has recently been confirmed that low copy numbers of C4 increase risk of SLE, while high copy numbers of this gene have a protective role against disease (Yang et al., 2007).
Another gene involved in defence against disease is CCL3L1, which is also incorporated within an extremely common and highly polymorphic CNV. This gene has been implicated in susceptibility to and disease progression in HIV, since CCL3L1 is the most effective ligand for CC chemokine receptor 5 (CCR5), which is the major HIV co-receptor, thus it is an important HIV-suppressive chemokine (Menten et al., 2002). Possession of low CCL3L1 copy number is a major risk factor for HIV, associated with higher viral loads and increased subsequent loss of T-cells (Gonzalez et al., 2005).
Possibly the most intriguing example of a disease-associated CNV that overlaps genes related to the immune system is that of the beta defensin genes, which are candidates for variation in susceptibility to autoimmune and inflammatory disorders, due to their anti-microbial and pro-inflammatory roles. These genes vary greatly in copy number both in humans (Armour et al., 2007) and also macaques, suggesting this is an ancient hotspot for copy number variation (Lee et al., 2008). A large repeat unit at chromosome 8p23.1, including DEFB4, SPAG11, DEFB103, DEFB104 and DEFB105 amongst others, is highly variable in copy number, with individuals carrying between 2 and 12 copies per diploid genome. High copy numbers of this unit increase susceptibility to the common inflammatory skin disease psoriasis, consistent with an exaggerated immune response leading to an inflammatory disease (Hollox et al., 2008). Conversely, low copy numbers of the DEFB4 gene have been associated with colonic Crohn's disease, which is thought to be due to a weakening of the antibacterial barrier in the colonic mucosa due to relative deficiency of beta-defensins (Fellermann et al., 2006). This is the first example of a common CNV that in low copy numbers can lead to one disease, and in high copy numbers may lead to another phenotypically distinct disease.
Variants have also been shown to overlap cancer-relevant genes, for example a 630-kb deletion region on chromosome 3p21.3 deleted in lung cancer, incorporating three tumour suppressor genes TUSC2, TUSC4 and NAT6, was found to overlap a relatively common deletion CNV in an ostensibly healthy population (Wong et al., 2007). Many other oncogenes and tumour-suppressors are affected by copy number variation, including LPP, MLLT3, MEN1, APC, VAV2, TNFRSF25, BCAS1 and HIC2 (Conrad et al., 2006; de Smith et al., 2007; Wong et al., 2007). Studies to determine their consequences for cancer susceptibility are underway, but we already have at least one example of a significant association. A UGT2B17 deletion variant, found in around 11–12% of healthy subjects, exhibits a significant association with risk of prostate cancer in Caucasians. Increased levels of serum testosterone and other androgens are a risk factor for prostate cancer, and it is thought that deletion of this gene, which is involved in androgen metabolism, may lead to increased serum androgen levels (Park et al., 2006). One interesting question, which has yet to be investigated, is whether there is any relationship between the inherited CNVs in cancer-relevant genomic regions and the incidence of the various genomic losses and gains that occur during cancer progression. Since these changes have considerable prognostic significance, such a relationship may have important consequences for early decisions on therapeutic management.
As described, genes involved in brain development are enriched in CNVs (de Smith et al., 2007), and a proportion of these variants may, therefore, contribute to susceptibility to neurological and psychiatric disorders, such as bipolar disorder (BD) and schizophrenia. Indeed, some of the most important BD and schizophrenia candidate genes, such as PDE4β, CHRNA7 and DISC1, are overlapped by known variants. In a cohort of BD patients, for example, a significant increase was found for the presence of a known CNV overlapping the GSK3βgene compared with healthy controls (Lachman et al., 2007). This is a credible candidate gene for BD as it is involved in neuronal cell development, and transgenic mice with GSK3βoverexpression have been shown to mimic acts of clinical mania, with increased locomotor activity and acoustic startle response (Prickaerts et al., 2006). The GSK3βvariant has only been documented in two healthy control samples thus far, so it could be described as a rare CNV. Some studies aimed at identification of variants associated with particular diseases, however, have uncovered gene copy number variants that are present only in patients with those diseases, and not in the general population. These variants should, therefore, properly be termed copy number mutations (CNMs), as they are not present at appreciable frequency (>1%) in the general population and may be the direct cause of disease, rather than acting as susceptibility loci.
In addition to common CNVs playing a role in neurological disorders, a number of de novo CNMs have also been associated with such diseases. Variants incorporating three brain-expressed genes involved in glutamate signalling, GLUR7, AKAP5 and CACNG2, were found only in patients with schizophrenia in one study (Wilson et al., 2006). It is speculated that these genes are differentially expressed during early human embryonic development, and that the development of a normal central nervous system depends on complex regulation of these genes (Wilson et al., 2006). A recent study also indicates that rare de novo variants with high penetrance may underlie schizophrenia in some cases. Xu et al. (2008) found a 10% frequency of novel variants in patients with sporadic schizophrenia, which was eight times higher than in controls. The number of genes overlapped by these variants was relatively small, but GO analysis showed the most enriched categories to be pathways associated with neuronal development (Xu et al., 2008). These results are mirrored by another recent report of an association with rare variants affecting neurodevelopmental genes in cases of schizophrenia (Walsh et al., 2008).
The findings of these studies of schizophrenia have parallels in recent investigations into the genetics of autism, as associations of de novo variants have also been determined with this neurodevelopmental disorder (Sebat et al., 2007; Marshall et al., 2008). Sebat et al. (2007), for example, found the frequency of spontaneous mutations to be 10% in sporadic cases of autism, compared with only 1% in unaffected controls, and a number of genes, including SHANK3, NLGN4 and NRXN1, have been implicated in the aetiology of autism through studies of copy number variation. Interpretation of these data is somewhat complicated, however, by the difficulties inherent in (a) proving that a particular copy number variation is actually de novo (most current methodologies suffer from high false negative, as well as false positive results) and (b) establishing the ‘normal’ rate of generation of de novo copy number changes.
The distinction between common gene copy number variants and rare CNMs is not always a clear one. A particular example of this are the common copy number gains and losses of the region on chromosome 7 that incorporates the PRSS1 and PRSS2 genes, missense mutations in which are known to cause hereditary pancreatitis. This is an autodigestive disease, whereby an activation cascade of pancreatic digestive enzymes is caused by the premature activation of trypsin (Le Marechal et al., 2006). CNVs overlapping the two genes have been found in healthy individuals, but a triplication of this region is associated with disease. It is thought that the increased dosage of the triplicated PRSS1 and PRSS2 genes may disrupt the balance between activation and inhibition of trypsin within the pancreas (Le Marechal et al., 2006), which suggests that a duplication of the same locus on both chromosomes could have the same effect. The triplicated region is, therefore, a copy number mutation that underlies disease, whereas a single copy gain on one chromosome (i.e. duplication CNV) could be described as a premutation CNV for the adverse phenotype. The situation is further complicated, however, by the recent identification of a duplication of this locus in four patients with hereditary pancreatitis, which was not found in controls (Masson et al., 2008b): it is possible, therefore, that duplication of this locus may, in some individuals, cause disease but in others act as a benign CNV.
The same disease has also recently been shown to result from another genetic mechanism altogether. As mentioned earlier, Masson et al. (2008a) identified a hybrid PRSS2/PRSS1 gene, which they describe as having a ‘double gain-of-function’ effect, with both qualitative and quantitative consequences, in a French family with hereditary pancreatitis. This fusion gene essentially consists of a duplication of half of each gene, thus acting as a ‘quantitative’ CNM, in addition to a ‘qualitative’ missense mutation, which has resulted in a highly penetrant phenotype in this family. This appears to be a novel genotype-phenotype relationship.
Very few investigations have so far been carried out to examine the dual effects of CNVs and SNPs. One example, however, is analysis of the complement factor H and membrane cofactor (CFH) gene, which contains an amino acid variant that predisposes to age-related macular degeneration (Klein et al., 2005). This gene is contained within a CNV region; thus it is possible that variations in copy number of this gene, or its surrounding genomic region, could modify the risk of disease. In support of this, a haplotype carrying deletions of the nearby CFHR1 and CFHR3 genes has been shown to be protective against the disease (Hughes et al., 2006). This example highlights the need to evaluate the contribution of both types of variant to complex phenotypes and disease, as cases like these may only be the tip of the iceberg (Masson et al., 2008a).
It is likely, therefore, that variations in gene copy number play an important role in human health, with some common gene CNVs increasing susceptibility to certain complex diseases, whereas so called CNMs are the direct cause of Mendelian-like diseases. Current estimates indicate that copy number variants overlap more of the human genome than SNPs (current estimates of ~29% bp cf. 0.4% (http://projects.tcag.ca/variation)); however, it remains to be proven whether CNVs are the main source of inter-individual differences in physiological phenotype, as well as overall fitness and disease susceptibility. The interaction between functionally-relevant SNPs and CNVs adds a further level of complexity to investigations.
In addition to the possible effects on phenotype, the potential for gene or domain duplication as a result of copy number variation suggests a possible role in human evolution; while conserved genomic sequences represent loci of central biological importance, regions of genomic variability may also be important in evolving species, as it is genetic variation upon which natural selection acts. Copy number variation in the form of gene duplication, for example, has long been known as a source of evolutionary change (Bridges, 1935; Muller, 1936), generating protein diversity, increases in gene dosage and evolution of new functions (Ohno et al., 1968), and is consequently thought to be one of the primary mechanisms in the proliferation of primate species (Dumas et al., 2007).
GO analysis of regions of the genome shown to be subject to recent selection has revealed several enriched categories, including chemosensory perception and olfaction, acquired and innate immunity, gametogenesis, spermatogenesis, fertilisation, and vitamin transport (Voight et al., 2006). As already discussed, many of these categories are also enriched for copy number variation, suggesting a relationship between evolution and CNVs. For example, genes involved in chemosensation and immune response are over-represented amongst those overlapped by CNVs: these genes are important in adaptation to novel environmental niches (Nguyen et al., 2006). An enrichment was also found for genes involved in fertility and reproduction (de Smith et al., 2007), which are thought to be subject to rapid adaptive evolution in primates due to sexual competition and defence against pathogens (Voight et al., 2006).
CNVs may, thus, provide a substantial proportion of the genetic variability which is the substrate for natural selection, increasing genetic plasticity so that organisms can evolve more quickly in response to novel external pressures, and thereby playing an important role in their evolutionary fitness and adaptability (discussed in Feuk et al., 2006). An investigation into copy number variation in the chimpanzee genome revealed many variants that overlap with human CNVs, and found similar enrichment for immunity and environmental response-related genes, which suggests these variants could be retained in the genomes of both species by natural selection (Perry et al., 2006). Alternatively, because they apparently lack immediate phenotypic impact, CNVs in these genes may accumulate to a greater extent than in critical genes, in which variants may have more adverse phenotypic effects. An additional possibility is that the same regions of human and chimpanzee genomes are vulnerable to the mechanisms which lead to CNV formation, so that CNVs tend to arise at similar locations.
There is evidence of positive selection acting on some CNV genes, in that there is overlap between genes identified in studies of positive selection and copy number variation. Indeed, a positive correlation was recently determined between copy numbers of the salivary amylase gene (AMY1) and protein expression levels, and mean gene copy numbers were found to be greater in ‘high-starch’ populations, compared to populations with ‘low-starch’ diets that consist mainly of meat, fruit, honey and milk (Perry et al., 2007). Given the relatively recent change to high-starch diets, it is suggested that positive selection has acted on pre-existing CNVs to increase AMY1 copy number in populations which have adopted a high-starch diet but that, in the absence of such selection, copy number has evolved neutrally.
Nevertheless, it is clear that, in many instances, CNVs have the potential to be deleterious. An important question, therefore, is why there is so much copy number variation in the genome when this has potentially adverse phenotypic effects. For instance, why is there so much variation in the copy number of DEFB4 when there are deleterious effects associated with both too few and too many copies of the gene? It seems most likely that CNVs are an unavoidable consequence of errors in genetic recombination and repair, which may particularly afflict regions containing many repetitive elements or in which there are tandem duplications of regions of the genome. Where CNVs affect important genes they are presumably subject to strongly negative (purifying) selection; however, phenotypically neutral CNVs may persist and accumulate, so that when a population is subsequently exposed to a change in the environment, some of this accumulated genetic variation may include CNVs that fortuitously impart a selective advantage, which thus becomes a substrate for natural selection.
Recent CNV studies have revealed a previously cryptic level of genetic variation at a much higher level than SNPs, and have also improved our knowledge of disease aetiology, which may ultimately contribute towards the treatment of certain diseases. The full extent of copy number variation in the human genome remains to be elucidated, but by using technologies with ever-increasing resolution, and studying a larger number of samples, including individuals of a wider range of ethnicities, this situation should be ameliorated in the near future. Improved mapping capacity has already demonstrated that the size of many CNVs in the TCAG database of genomic variants is inflated (de Smith et al., 2007; Kidd et al., 2008; Perry et al., 2008). Using high-resolution oligonucleotide arrays, Perry et al. (2008) reduced the likely amount of CNV sequence by >50% for 876 loci, and estimated that 88% (1020/1153) of loci they investigated were smaller than documented. The number of known small-sized variants, however, is likely to increase with the advent of whole genome sequencing studies.
The high level of copy number variation uncovered so far, and the large number of genes involved, suggests that these variants are likely to contribute not only to specific single-gene disorders but also to common complex diseases, such as obesity and type II diabetes, which are thought to be caused by interactions between multiple genetic loci and the environment. Copy number variants are also likely to play a role in susceptibility to certain cancers in at least two ways: inherited variants may decrease expression of tumour suppressor genes, or may increase expression of oncogenes to a level that may subsequently require only a single additional somatic mutation to lead to cancer. Additionally, germline and somatic variants may cause genomic fragility that could increase the likelihood of an individual developing further genomic rearrangements that may result in tumour development, or affect disease progression.
At the time of writing, however, only a handful of studies have associated specific CNVs with human diseases, and as yet there have been no intensive genome-wide surveys for variants associated with common diseases. CNVs may act in conjunction with single nucleotide mutations, and possibly SNPs, to produce an adverse phenotype so that future studies need to take an integrated approach, taking into account genetic variants at both the copy number and nucleotide level, along with environmental factors. This must now be a priority, and will require the development of high-throughput methodologies for replication of phase 1 genome-wide association data in large sample cohorts, rapidly establishing absolute copy number of particular CNVs in several thousands of individuals. It may be that some common variants initially appear benign, but in combination with other genetic and environmental factors, have deleterious effects resulting in disease.
Determination of CNV disease associations may also enable earlier diagnosis based on an individual's genetic constitution, or may contribute to elucidation of pathogenic pathways, allowing identification of disease sub-types amenable to particular therapeutic approaches. Similarly, by testing for disease susceptibility loci, individuals may be able to determine their individual risk for certain diseases, enabling them to alter their lifestyle based on this information. Any CNV that affects clinical phenotype, disease prognosis or response to particular therapies will be of particular interest in our movement towards the era of personalised medicine.
Higher Education Funding Council for England (HEFCE), UK


Fitness for Life: Middle School provides a foundation for students to be physically active and fit throughout their whole lives. This middle school version of the award-winning high school text Fitness for Life meets the new NASPE National Physical Education Standards and state standards, and it is an ideal companion to the FITNESSGRAM/ACTIVITYGRAM assessment program. This book includes everything that made the original Fitness for Life one of the most widely used and respected high school texts. In addition, Fitness for Life: Middle School follows the IDEA formula:
I = Integrates with other academic areas (e.g., math, science, language arts)
D = Developmentally appropriate for middle school students
E = Educationally and pedagogically sound
A = Articulates with the high school level Fitness for Life
In Fitness for Life: Middle School, students follow the recommendations of the Physical Activity Pyramid to perform the correct amounts and kinds of activities. They also learn these skills:
• Assess their own fitness levels and develop plans for improvement using short- and long-term goals
• Develop skills to help them build self-esteem, communicate effectively, deal with peer pressure, and handle other social concerns
• Understand how their bodies work so they can move more effectively and efficiently
Fitness for Life: Middle School is coauthored by Charles Corbin, a world-renowned expert in teaching lifetime fitness; Guy Le Masurier, who was an editor for Fitness for Life, Fifth Edition, and who coauthored the Children’s Physical Activity Guidelines for NASPE; and Dolly Lambdin, a nationally recognized leader in the field.
The text includes 18 lessons organized into 9 chapters. The lessons guide students in developing the skills they need in order to enjoy physical activity and explore the topics of body composition and nutrition, aerobics, sports, recreation, flexibility, and muscle fitness. The final chapter focuses on how to develop a healthful, active living. Each chapter includes the following elements:
• Two lessons designed for the classroom portion of the class
• A “Moving Together” feature that uses physical activity scenarios to address social issues of importance to middle-schoolers
• A “Biomechanical Principles” feature that analyzes components of human movement
• A “Take It Home” feature that guides students in independent projects that reinforce classroom lessons and encourage community interaction
• A chapter review
There are other features throughout the book:
• “Fit Facts” that offer interesting facts about health and fitness
• Lesson vocabulary listing the key terms in each lesson
• Web addresses that direct students to the FitnessforLife.org Web site for more content
• Review questions for each lesson
Fitness for Life: Middle School not only sets the stage for high school by exposing middle-schoolers to a variety of developmentally appropriate and fun physical activities, but it also helps prepare them for a lifetime of health and fitness.
Visit www.FitnessforLife.org for more information and sample materials.
Unit I Fitness and Activity for All Chapter 1. Introduction to Physical Activity and Fitness Chapter 2. Learning Skills for Enjoying Physical Activity Chapter 3. Lifestyle Physical Activity
Unit II Aerobics, Sports, Recreation, and Flexibility Exercises Chapter 4. Active Aerobics Chapter 5. Active Sports and Recreation Chapter 6. Flexibility Exercises
Unit III Muscle Fitness, Body Composition, and Planning Chapter 7. Muscle Fitness Exercises Chapter 8. Body Composition, Physical Activity, and Nutrition Chapter 9. Planning for Physical Activity
Student text for middle school physical education classes.
Charles B. Corbin, PhD, is a professor emeritus in the department of exercise and wellness at Arizona State University. He has published more than 200 journal articles and has authored or contributed to more than 70 books, including Fitness for Life, an award-winning book now in its fifth edition. An internationally recognized expert in physical activity, health and wellness, and youth physical fitness, he has keynoted more than 35 state AHPERD (Alliance for Health, Physical Education, Recreation and Dance) conventions and made major addresses and prestigious lectures in more than 15 countries. He is past president and fellow of the American Academy of Kinesiology and Physical Education, a fellow of the American College of Sports Medicine (ACSM), and a lifetime member of the American Alliance for Health, Physical Education, Recreation and Dance (AAHPERD). Among his awards are a Healthy American Fitness Leaders Award, an AAHPERD Honor Award, a Physical Fitness Council Honor Award, a Council on Physical Education for Children (COPEC) Hanson Award, and the Distinguished Service Award from the President's Council on Physical Fitness and Sports (PCPFS). Dr. Corbin was named an AAHPERD Alliance Scholar and a National Association for Kinesiology and Physical Education in Higher Education (NAKPEHE) Distinguished Scholar and was recently inducted into the National Association for Sport and Physical Education (NASPE) Hall of Fame.
Guy C. Le Masurier, PhD, is a professor of physical education at Malaspina University College, British Columbia, Canada. He has published numerous articles related to youth physical activity and physical education and coauthored the National Association for Sport and Physical Education (NASPE) Physical Activity Guidelines for Children. Dr. Le Masurier has given more than 30 research and professional presentations at national and regional meetings. He reviews research for numerous professional journals and has contributed to Fitness for Life, Fifth Edition, and the Physical Best Activity Guide. Dr. Le Masurier is a member of AAHPERD (American Alliance for Health, Physical Education, Recreation and Dance), NASPE, ACSM (American College of Sports Medicine), and Canadian AHPERD.
Dolly D. Lambdin, EdD, is a senior lecturer in the department of kinesiology and health education at the University of Texas at Austin. She has 16 years of experience in public and private schools and 30 years in teacher preparation at the university level, much of it simultaneous. This required her to teach curriculum theory and teaching methods and actually teach hundreds of 5- to 14-year-olds. She has supervised more than 100 student teachers, visiting thousands of public school classes and learning from scores of fabulous cooperating teachers. Dr. Lambdin served as National Association for Sport and Physical Education (NASPE) president (2004-05), on the NASPE Board of Directors (2000-2006), and on the writing teams for the Texas Physical Education Essential Knowledge and Skills, the NASPE Beginning Teacher Standards, the Texas Beginning Teacher Standards, NASPE Online PE Guidelines, and the NASPE Appropriate Practices Revision. She has been an invited keynote speaker at state and national conferences. Dr. Lambdin has been honored as the Outstanding College and University Physical Educator of the Year by the Texas Alliance for Health, Physical Education, Recreation and Dance, and she has been recognized for distinguished leadership by the Council for School Leadership for Physical Education (CSLPE).
Supplementary Instructional Materials
Fitness for Life: Middle School Teacher’s Guide
2007 • Paperback with CD-ROM • 260 pp
ISBN 978-0-7360-6828-4 • Free to course adopters
Includes bound-in CD-ROM. Provides five lesson plans for each chapter: two lesson plans for the classroom sessions and three activity plans that supplement and reinforce the classroom content. Most plans are presented in four steps:
1. Gathering Information (for classroom lessons), or Instant Activity (for activity lessons)
2. Lesson Launcher
3. Lesson Focus
4. Reflection and Summary
The lesson plans feature these elements:
• Performance outcomes related to NASPE standards
• Activity resources
• Student worksheets for use in class or as take-home assignments
• Review quizzes and answer keys
• Assessment rubrics
• Other reproducibles
FREE to course adopters. Call for details
Fitness for Life: Middle School Web site
ISBN 978-0-7360-6778-2 • Free to course adopters
Includes test package for teachers, additional activities, and links to resources that support the learning. The middle school text’s companion Web site also provides a wealth of additional student content:
• Lesson vocabulary in English and Spanish
• Extended discussion of selected topics from the student textbook
• Links to other sites and interactive features, such as calorie counters and BMI calculators
• Two educational computer presentation programs developed exclusively for Fitness for Life: Middle School in which students answer questions and participate in teacher-directed activities
The Web site will be kept up to date with accurate and student-friendly content links and new content and research. The Web site is a valuable resource that supports Fitness for Life: Middle School by offering the accessible and valid information teachers want in a format middle-schoolers love. A bonus feature on the Web site is the “Ask the Author” section, where students can e-mail in their questions and have them answered by author Chuck Corbin.


Usable design makes documents easier to use and lends credibility to the document creators. A few simple tips, such as following Gestalt principles and using plain language, can improve document usability. Workshop attendees will apply knowledge learned through interactive document redesign activities.
Turner, J. & Schomberg, J. (2017, March 2). Inclusivity Through Documentation: Using Gestalt Principles and Plain Language to Create Effective Documents. Presented at The Collective 2017, Knoxville, TN.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License


News & Announcements
To Build Healthy Communities For Native Kids, Involve Them
Posted: December 07, 2017
In the heart of the Crow Reservation in southeastern Montana, the 450-person town of Valley of the Chiefs has faced mounting difficulties over the past several decades. In the last two generations, the Crow Nation has lost 80% of its population and 73% of its land. Economic dispossession has rattled Valley of the Chiefs, as members of the community have turned to substance abuse and violence. For youth, who make up around 43% of the population, the town is especially harsh.
Valley of the Chiefs is one of six communities selected this year to participate in Raising Places, a new initiative developed by the Chicago-based design firm Greater Good Studio and funded by the Robert Wood Johnson Foundation to initiate ground-up local projects that will support a healthier environment for children–and by extension, everyone around them. “The research has shown for a long time that where you grow up matters,” says Sara Aye, executive director of the Greater Good Studio. “It matters for your health, it matters for your broader success in life. We can’t create a culture of health in America if we don’t have healthy places for kids to live and grow.”
Raising Places partnered with local groups in each of the communities, which range from a street in Minneapolis to a town in upstate New York, to begin the process of designing and implementing child-centric projects that will bolster overall community health. While a number of projects have originated with children’s health in mind (like the nonprofit KaBOOM!’s initiative to fund innovative play spaces across the U.S.), Raising Places is taking it a step further by actually bringing children and teens into the brainstorming and design processes.
“It was really important to us to develop a diverse and engaged design team in each of the communities,” Aye says. And by “design team,” she adds, she means a cohort of local leaders–artists, organizers, planning department experts, school and youth group administrators, and youth themselves. “They’re not designers, but we’re training them to think as designers,” Aye says. With the help of the Raising Places program staff, these teams will be the ones who will come up with, test, and ultimately carry through the projects.
In Valley of the Chiefs, one of the ideas the team is working with is the concept of a culinary school, Aye says. “In their research, they really saw a focus on food, and the traditions around eating communally and Native food,” she adds. “There’s also a dire need for healthy food and jobs for young people–jobs that can lead to careers.” While the culinary school could act as an avenue to employment, the team is also looking into addressing that need through an idea to build out, from scratch, a real main street in the town, where local entrepreneurs could open businesses to sell goods. The main street, the team imagines, could also be supplemented by an online platform to expand their sales market, and the business owners could act as mentors to the town’s young people, who could also work at the businesses.
Across the country in the Downstreet neighborhood of Hudson, New York, the design team there is focusing on addressing a very different set of concerns. “One of the ideas there is around police and community interaction, particularly how police and youth interact,” Aye says. Hudson is a heavily policed town, and one that’s often plagued by violence; children and young people there, Aye says, often express a sense of trauma around dealing with police. “One of the insights they had is that police are often working to fix symptoms, but they don’t deal with root causes,” Aye says. Out of that observation came an idea for a civilian review board that would include youth, and focus on helping the police force become more self-aware and sensitive to the effect they have on young people.
Read more on FastCompany.com.


The circulatory system includes the heart, blood vessels, and blood, is vital to fight diseases and maintain homeostasis (adequate temperature and pH balance). The main function of the system is to transport blood, nutrients, gases, and hormones to and from the cells throughout the body.
Circulatory system facts
The circulatory system is extremely long.
If I had to place all the arteries, capillaries and veins in an adult, from end to end, they would extend around 60,000 miles (100,000 kilometers). Moreover, the capillaries, which are the smallest blood vessels, would make up approximately 80 percent of this length.
In comparison, the circumference of the Earth is approximately 25,000 miles (40,000 km). That means that a person’s blood vessels could surround the planet approximately 2.5 times!
Red blood cells must pass through blood vessels
The capillaries are small, with an average of approximately 8 microns (1/3000 inch) in diameter, or approximately one-tenth the diameter of a human hair. The red blood cells are approximately the same size as the capillaries through which they travel, so these cells must move in single file lines.
However, some capillaries have a slightly smaller diameter than blood cells, forcing cells to distort their ways to pass through.
Large bodies have a slower heart rate
Throughout the animal kingdom, the heart rate is inversely related to body size: in general, the larger the animal, the slower the resting heart rate. An adult human has an average resting heart rate of approximately 75 beats per minute, the same speed as an adult sheep.
But the heart of a blue whale is about the size of a compact car, and only beats five times per minute. A shrew, on the other hand, has a heart rate of approximately 1,000 beats per minute.
The heart does not need a body
In a particularly memorable scene in the 1984 film, “Indiana Jones and the Temple of Doom,” a man tears the still-beating heart of another man. While easily removing a person’s heart with a bare hand is a science fiction thing, the heart can still beat after being removed from the body.
This mysterious pulsation occurs because the heart generates its own electrical impulses, which make it beat. As long as the heart continues to receive oxygen, it will continue to function, even if it is separated from the rest of the body.
Red blood cells are special
Unlike most other cells in the body, red blood cells have no nuclei. Lacking this large internal structure, each red blood cell has more space to transport the oxygen that the body needs. But without a nucleus, cells cannot divide or synthesize new cellular components.
After circulating inside the body for approximately 120 days, a red blood cell will die from aging or damage. But don’t worry, your bone marrow constantly makes new red blood cells to replace those that perish.
The stress can really “break your heart”
A condition called stress cardiomyopathy involves a sudden and temporary weakening of the heart muscle (the myocardium). This results in symptoms similar to those of a heart attack, such as chest pain, shortness of breath and pain in the arms.
The disorder is also basically known as “broken heart syndrome” because it can be caused by an emotionally stressful event, such as the death of a loved one or a divorce, rupture or physical separation of a loved one.
Human blood comes in different colors, but not in blue.
The oxygen-rich blood that flows through the arteries and capillaries is bright red. After delivering your oxygen to your body tissues, your blood turns a dark red color as it runs back to your heart through your veins.
Although veins sometimes look blue through your skin, it is not because your blood is blue. The deceptive color of your veins is due to the way in which different wavelengths of light penetrate your skin, are absorbed and reflected in your eyes, that is, only high energy light (blue) can reach the veins and back.
But that does not mean that the blood is never blue. The blood of many mollusks and few arthropods lacks the hemoglobin that gives human blood its redness, and instead contains the hemocyanin protein. This causes the blood of these animals to turn dark blue when it is oxygenated.
Living in space affects the circulatory system.
Here on Earth, a person’s blood tends to accumulate in the legs due to gravity (the veins in the legs have valves that help maintain blood flow from the legs to the heart).
Things are different in space. Instead, blood builds up in the chest and head (a phenomenon called fluid change), which causes astronauts to have a congested nose, headaches and swollen faces. This change in the fluid also causes the heart to enlarge so that it can handle the increased blood flow in the area surrounding the organ.
Even though the body has the same amount of fluid as before, the brain and other body systems interpret the fluid change as a sudden increase in the general fluid. In response, the body uses several different processes to get rid of excess fluid, resulting in a general reduction in the volume of circulating blood.


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Learn here how to create a this bird using a few techniques in Corel Draw. Successful completion of this tutorial requires an intermediate knowledge of Corel Draw. We think it's easy as there is no need for Art school sketches that are usually needed in the first step. Let’s get started!
Final Image Preview
Below is the final image we will be working towards. Want access to the full Vector Source files and downloadable copies of every tutorial, including this one? Join Vector Plus for just 9$ a month.
Create new document, whatever size. A4 is fine. Draw the shape of the bird's body using the Free Hand Tool and make it nice with the Shape Tool. This part requires a bit of creativity :)
Color the shape blue. Then Copy the shape and paste in the same place. Now using the Up Arrow key, move the second shape 4 pixels up. And then change the color of the second shape to a lighter blue. For better a effect use the Radial Gradient Fill Tool with a lighter to darker blue. Still the first shape should be darker to get that dark line at the bottom.
Copy the shape and place it in the white area. Copy it again and paste it. Then make it a bit larger and put it over the smaller one (green on pink example). Using the Back Minus Front option Cut the shape off. Then change it to blue (or use the gradient that we did in last step). And place it on our main shape.
Do the same again but cut a smaller, thiner part. Those steps are needed to add some light effects, which make it more 3D.
This step uses only one simple option: Intersect (marked by red box, shown below). Just as in the steps above, select two object and Intersect. You will get the shape that both object share.
This technique is an easy way to get shapes that you want in many other situations. In the picture below, notice that we used circles on the main shape, then the eye, then the eyeball, etc. Be sure to apply a radial fill to the eye as shown above.
Do the same thing again. This time create the bottom part of the bird (that's the way birds are built, a white patch makes the bird look more real).
Coming back to using the Back Minus Front option. Cut off the shape of the first eyelash. Than copy, paste, resize, and rotate to put them together. Now copy the whole thing and paste in place, change to a darker blue, rotate a bit, and move it to the back. Lastly, group it and place it on the bird.
To draw the legs and nose you need to use the Free Hand Tool and make it nice with the Shape Tool. In this step, we want to show you how using the same color, but in different brightness, adds more depth and dimensionality.
This must be the easiest step because you do do not have to be exact. Just draw away and create some jagged shapes for the eye. The more uneven the better.
Now let's make the wings. In the image below, you can see again how we cut the shape out of the circle using different circles. Then we rounded the corners a bit using the Shape Tool. Also, we added some light effect, just like in Step 4.
Place the wing on the bird. Also, Copy and Paste In Place the same wing, but change color to gray, move to the back, and move to the left a bit. That gives the effect of the second wing on the other side of the bird (you can see tiny gray part near the legs).
We're almost done. The hat is a simple thing drawn using the Freehand Tool to create the shapes shown below. They each were given different brightness, fills, and a radial gradients was placed on the white stripe to add 3D.
Place the hat on the bird. Add a dark blue ellipse under the hat (some kind of shadow of the hat). And our Quirky looking twitter bird in vectors is done!
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Electronic parts are inside every device bought today, and they’re what makes the device do what it does. If a company builds its own hardware, odds are high that they will need to design and build their own electronics. An electrical engineer knows how the pcb assembly process works, but this guide is meant for the uninitiated. Read on to learn the basics of PCB manufacturing.
The Production Process
A PCB is also referred to as a printed circuit board. It’s a flat fiberglass piece containing traces that connect electrical components, as well as pads that allow the components to connect to the board itself. PCBs consist of fiberglass, epoxy, conductive copper and a mask to keep solder in its intended position. They’re made using automated processes, usually by outside companies.
Application of Solder Paste
The first step in PCB assembly is to apply solder paste to the fiberglass board. The paste consists of tiny metal balls and flux; it must be applied precisely. In manufacturing environments, this is accomplished with a stencil, a fixture and a paste applicator. When stencils are removed, solder is in the right positions.
Pick & Place
After solder paste application, the boards go to pick & place machines. These robotic instruments position parts correctly, and ready them for soldering. Components are soldered to the board’s surface, and these machines can run day and night. Compare that to the high potential for error when humans place these components, and it’s easy to see why robotics are taking over the industry.
Once components are placed, the PCBs go to a reflow oven. The oven heats the boards until solder melts and joins the parts securely. Parts move on a conveyor belt past heaters that gradually warm the boards to the correct temperature, and they cool at controlled rates.
Quality Assurance and Inspection
After reflow, PCBs enter the testing phase. Mistakes during manufacturing result in non-functional components, short circuits and other errors. Visual inspections, optical inspections and x-rays can point out such errors; if flaws are detected the board will be reworked or scrapped. The sooner errors are found, the sooner they may be fixed—at substantial savings for the company.


The Build a Temple game is similar to the Hangman game, except it is positive and thus appropriate for a church class. I think, and this is just my personal opinion, that Hangman is too negative for church classes. Remind the students that they are working together as a team and are not competing against each other.
Play the game as follows.
- Think of a word that pertains to the lesson, and write several dashes on the chalk-board, where each dash represents a letter in the word.
- Ask the students to guess a letter. If their letter is in the word, draw a rectangle on the board, and write that letter above the appropriate dash. For correct letters, draw the rectangles as successively shorter rectangles, and place each new rectangle on top of the existing rectangles. If their letter is not in the word, remove a rectangle from the board. If a rectangle can not be removed because there are no rectangles on the board, just ignore their incorrect letter.
- Have the students continue guessing letters, and draw or remove rectangles appropriately until the word has all of its letters correctly written above the dashes. When the word has been correctly spelled, the students should have several rectangles on top of each other, with the rectangle-length reducing such that the finished stack of rectangles represents a temple.
Hint: Tell the students that every word in the English language has at least one vowel. This is a hint that the students should first guess vowels. It is likely that once the vowels have been identified, the word will be recognized by the students, and the students will correctly guess the consonants in the word.
Example: The final results for the word Smith (with no mistakes made) would look like the following.
Variation: of this game is to add rectangles to the board but not remove rectangles.