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Fax machines necessitated a standard keyboard format, so the QWERTY layout — which is still used in modern computers — was pioneered in Technology Timeline, Figure 2: Marie Curie, one of the revolutionaries who paved the way for modern technologies. Curie was the first female Nobel laureate and the first person to win a Nobel prize in both physics and chemistry in recognition of her contributions to nuclear physics. On the 4th of July, , Curie died of aplastic anemia, a blood disease caused by exposure to nuclear radiation.

Edison pioneered phonographs in , but his most significant contributions were in the field of electricity. Other modern technologies, such as X rays for biological imaging and basic, fundamental space rocketry theories, had also been born at the end of the 19th century Technology Timeline, The 20th century brought an even greater array of inventions. In , chemist Gilbert Lewis formulated the chemistry used in rechargeable lithium batteries.

It took just ten years to go from the first monochrome television in the s to the first color television in the s. Source: Wikimedia Commons 18 from one side of the planet to the other was conceptualized. The development of space technology and other modern technologies enabled even more discoveries and innovation. And the development of transistors allowed engineers to build vast, sophisticated circuitry onto small boards, which was a significant step toward modern microprocessors and integrated circuits.

Memex, the first digital storage device which was developed by a US engineer called Vannevar Bush, was also a forerunner of modern computer storage devices. Technology Timeline, It must be noted that these countries do not lack the capacity and determination to catch up with their more developed peers; rather, they have faced and continue to face challenges such as political instability, poverty, and other developmental challenges.

For example, The Democratic Republic of Congo DRC has rich mineral deposits, but its growth is crippled by political instability and a decrepit government Cackler et al. Therefore, a crucial step to closing the technological gap is enhancing access to education and ensuring more children go to school. Most least-developed and developing countries were not even proper nations until the mids when their colonization and occupation by European powers ended. In contrast, the United States is years old, and most of the Western European nations are far older even than that Developing and least-developed countries have only started taking steps towards industrialization relatively recently.

Although they capitalized on earlier developments, it still takes years for the development culture and an appropriately-skilled workforce to develop. This results in most developing and least-developed countries needing technology they do not develop. Most devices such as cars, consumer electronics, technology-based services, and even industrial equipment are imported from developed nations. This phenomenon is known as technology transfer. If done correctly, this transfer can empower states to build their capacity for growth and sustainability.

However, even with the import of technology, developing and leastdeveloped countries often lack a sufficiently skilled workforce. In , Africa had an average of 7 scientific and technical journal articles per million people, FALL Infrastructure constraints also pose a significant challenge to developing and using technology in developing and least-developed countries.

For example, some of these countries lack reliable connectivity to the world through internet infrastructure, and most of them lack universal connectivity. Figure 4: Young African soldiers in Burundi. Burundi and multiple other least-developed countries have been plagued by civil wars and instability, which is a hindrance to their development.

In , Africa had an average of 7 scientific Native Development and Use of and technical journal Technology in Developing Countries articles per million Technology has and will continue to be people, compared to instrumental in the industrial and economic in developed progress of developing countries. Recent polls nations. Entrepreneurs and developers in developing and least-developed countries have capitalized on this extensive use of mobile phones to create innovative technology and services that use mobile phones as portals to multiple industries.

However, one of the biggest challenges for such development is the lack of capital. In recognition of the immense potential that such initiatives have in creating a positive impact and returning a profit, several programs have emerged to source funding. One such program is Kiva, an online platform that allows people worldwide to sign up and pool money to microfinance high-impact technology and Figure 5: An M-Pesa sign at a restaurant that allows payment through the financial service.

M-Pesa allows isolated populations to access financial services that would otherwise be more difficult to access. The service allows people to send and receive payments straight through their phones without the need to access the internet.

Some of the most successful ideas in developing and least-developed countries utilize mobile phones as gateways to industries and products that are not physically available in specific areas. These services can range from banking, health, information services, and even e-commerce. For example, phones have been used to access banking services, health information, weather information, online markets for goods, and many other virtual spaces.

The success of past technological applications in developing and least-developed countries also motivates new technological innovations to solve new problems Cackler et al. Perhaps the most successful mobile service in developing and least-developed countries is mobile money.

Mobile money is an SMS-based money transfer and monetary storage tool that was first developed in Kenya but has been adopted in many developing and developed countries worldwide. The Kenyan pioneer program called M-Pesa was rolled out in to widespread success.

M-Pesa appealed to people in rural areas, a demographic of people previously underserved in financial and banking services. With M-Pesa, clients do not have to travel long distances to get banking services such as sending money or receiving money — they merely have to visit an M-Pesa agent in the local town where they can deposit money into an account linked to their phone number, or they can withdraw money from their account.

Due to this simplicity, many people, especially rural farmers and entrepreneurs who needed to frequently send and receive money, preferred it over traditional banking services Conocimiento, This integration has dramatically improved the efficiency and ease of banking, one of the reasons M-Pesa in Kenya and similar services in other countries have been widely adopted.

The health sectors in developing and least-developed countries have also seen tremendous growth due to technological developments. Most developing countries have a hard time developing advanced medical equipment and building hospitals for their entire populations Casarez, The use of key technologies has immensely helped bridge the gap in access to healthcare. Similar services in Tanzania and Rwanda have also experienced much success. Agriculture is one of the critical industries in developing and especially least-developed countries where most of the population participates in subsistence farming.

In recent years, climate change and a deteriorating natural resource base have contributed to a decline in productivity, especially in Africa and South Asia. Aviation improvements have also improved export trade. For example, Kenya is one of the biggest exporters of horticultural products to the European Union despite being thousands of miles away. Horticultural products are timesensitive, but trade is possible because of modern fast transport speeds.

Figure 7: A motorcycle taxi operating in a rural township in Kenya. Due to unequal distribution of resources and infrastructure, rural areas in developing countries tend to be left behind as urban areas develop. Source: Wikimedia Commons Future Trends and Caveats crops and production systems, raise yields, and improve product quality. Notably, technology is already offering multiple benefits to agriculture in developing and least-developed countries as international administrations such as The United Nations and The World Bank push for more widespread technology adoption.

For example, the introduction of genetically-modified crops that are resistant or adapted to changing climate patterns has not only enabled developing and least-developed countries to cope with climate change, but has also increased production in these countries Cackler et al.

Transgenic crops such as herbicide-tolerant soybeans could potentially benefit developing economies. Some countries have also made traditional applications of technology to improve agriculture. Technology has also greatly improved the transport sectors in developing and least-developed countries.

A good case in point is the implementation of a light railway system in Addis Ababa, the Ethiopian capital, in This railway system has dramatically improved mobility and therefore eased business in the city. This improvement has enhanced import and export trade in the city and encouraged more trade FALL Despite all the advantages offered by technology in the developing world, it is imperative to remain aware of trends and risks around developing and adopting technology in these countries.

It is a challenge to ensure the fair distribution of technology in rural and urban areas. Urban areas often end up advancing faster while rural areas remain isolated and behind. This phenomenon tends to create a social divide between rural and urban communities. Adopting new technologies also requires a skilled workforce, meaning citizens in these countries often need to learn new skills and foreign languages to operate imported machinery.

Horticultural products are timesensitive, but trade is possible because of modern fast transport A majority of the companies and businesses in speeds. But as companies do adopt automation technologies, the people employed to provide manual work can be quickly rendered jobless. This fact creates a hostile attitude toward technology and makes society opposed to the adoption of specific technologies.

On the other hand, companies still using manual models face industry pressure to keep up with their competitors who have adopted faster and more efficient technology processes. When such companies do not adopt new technology, they fall behind, and monopolies tend to arise, potentially hindering further Figure 8: AI is dreaded by many as an existential threat to human existence, akin to an imaginary game of chess between human intelligence and artificial intelligence.

However, artificial intelligence could be the path to a prosperous and more inclusive future. Even as companies use technology to empower communities, it is equally essential that a balance of the competitive landscape is maintained. Over the past decade, the startup scene in developing countries has greatly improved. Jackson points out that this has led to new innovative ideas that utilize technology to offer cutting-edge solutions for common problems.

One area that has seen significant innovation is the finance and banking industries. With the rapid growth of fintech the use of computer programs and the internet to support banking and other financial services , many startups have emerged. Because they have access to the full power of the internet, such startups can offer way more advantages than those offered by USSD-based and SMS-based services such as MPesa.

For example, Chipper Cash, an African cross-border startup, runs a Peer-to-Peer P2P service that allows users to send and receive money over the internet for free. Chipper Cash also offers access to forex trading and even bitcoin trading. Perhaps a strong indicator of the potential interest that Fintech has in developing countries, Chipper Cash was able to raise 30 million USD during a funding initiative held in October , which even attracted the backing of Amazon founder Jeff Bezos Bright, Conclusion Another trend in the developing world is the rise of artificial intelligence AI.

This has attracted key global players in technology and AI into these regions. For example, Google opened an AI lab in Ghana in Technology has the potential to immensely boost the growth of developing and leastdeveloped countries if utilized properly. This has been evident in recent years as a more widespread use of technology has immensely boosted growth in these countries. The use of technology also enables these countries to invent new solutions to decades-old problems.

Key global players such as Microsoft, Google, and Amazon are starting to recognize that technology is a significant driver for growth in developing nations and are starting to set up a more dominant presence in developing and least-developed countries. Additionally, the startup sector is an important agent pushing the adoption of technology.

It is therefore important for developing countries to invest in their startup sectors and cultivate an innovative culture in their citizens by promoting access to education and making it easier for technology entrepreneurs to access funding. References Advocates for International Development. Bright, J. World Bank. Mobile technologies for third world development.

Fernflores, F. Stanford Encyclopedia of Philosophy. The future is intelligent: Harnessing the potential of artificial intelligence in Africa. United Nations. Disrupt Africa. Mobile phones are key to economic development. Are women missing out? World Economic Forum. Science History Institute.

Explain That Stuff. Center For Global Development. Payment instruments, finance and development. Source: Wikimedia Commons 24 Introduction Every year, researchers make hundreds of new discoveries that add significantly to the existing body of scientific literature.

Often, advancements made by researchers go hand in hand with advancements made to preexisting technologies. Imaging is particularly critical for cellular and molecular biologists, who need microscopy techniques in order to visualize cells, cellular components, and macromolecules. One popular type of microscopy is fluorescence microscopy, which, due to recent advances, has emerged as an essential technique for researchers in the field.

The goal of fluorescence microscopy is to study the anatomy of the living cell. Fluorescence microscopy techniques allow researchers to visualize the physiology of cells at a subcellular and systems level, giving insight into cellular organization, function, and kinetics Combs, Herschel, a British-German astronomer, noted that despite quinine solutions being clear, when illuminated by the sun, the solutions would appear blue. Throughout the second half of the nineteenth century, other researchers described fluorescence in great detail and worked to understand how fluorescence lighting gave researchers more clarity when studying specimens Renz, Throughout the rest of the century and up to the modern day, researchers have worked to improve fluorescence microscopy techniques.

The microscopes themselves are faster and allow for extremely good resolution, making them useful for a variety of scientific disciplines; additionally, multi-photon imaging described later in this article has become a widely popular technique to study deep tissue.

Tagging, which is the process of labeling different molecules often proteins or antibodies for detection in fluorescence microscopy, has also improved appreciably due to an increase in the number of fluorophores — the chemical labels used for tagging — and the introduction of fluorescent proteins to imaging techniques Combs, With several types of fluorescence imaging available, it can be difficult for less experienced researchers to choose the correct microscope and technique for their particular project.

This paper aims to review the physical explanations for fluorescence and give an overview of the mechanics involved in fluorescence microscopy. It also discusses several types of fluorescence microscopy with applications in cellular and molecular biology research; however, fluorescence microscopy also has integral uses in several other applications, including biochemistry, biophysics, environmental studies, and pharmacy see Figure 2.

This paper will primarily focus on production of fluorescence in fluorophores, as these are the compounds most commonly used in fluorescence microscopy. However, as mentioned above, fluorescence can also occur in other molecules, including proteins. Fluorescence is based on the excitation of electrons. Fluorescence occurs in a three-step process: photoexcitation of an electron, relaxation of the excited electron, and light emission Parang et al.

The photons are provided by an external source of light, which could be the sun, a lamp, or a laser. Once absorbed by the fluorophore, if the photon has enough energy to excite electrons photon hvEX , it puts the electrons in an excited electronic singlet state a state in which the spins of the excited electrons are still paired with the ground electron state ThermoFisher Scientific, n.

In total, the excited state lasts anywhere between one and ten nanoseconds. In the second step, electrons relax; as the electrons relax, the fluorophore undergoes conformational changes and interacts with its molecular environment, resulting in energy dissipation.

Note, however, that not every molecule excited in the first step enters S1. In order to understand how many fluorophores emitted light, scientists created a fluorescence quantum yield, which is defined as the ratio of the number fluorescence photons emitted to the number of photons originally absorbed ThermoFisher Scientific, n. Figure 1: Pictured is Sir Frederick William Herschel, the man credited with first discovering and scientifically detailing fluorescence. Because energy is dissipated in 25 Figure 2: Ecology is another field where fluorescence microscopy has led to several advances.

Pictured here is fluorescence imaging of a fungal colony. Studies using fluorescence microscopy can help researchers better understand the cellular interactions of organisms like fungi with the environment. One fluorophore can generate thousands of photons ThermoFisher Scientific, n. Fluorophores can theoretically go through this process infinitely.

These can all damage cells; they generally morph the redox states of mitochondria and can also oxidize DNA, proteins, and unsaturated fatty acids. DNA oxidation can result in mutations, while protein and unsaturated fatty acid oxidation renders them both useless. The combination of the change in redox state to the overall cell and degradation of DNA, proteins, and unsaturated fatty acids is referred to as photobleaching and can destroy the fluorophore Icha et al. Then, the microscope uses a high energy light source, like a Xenon or Mercury arc-discharge lamp, to illuminate the fluorophores through a lens.

Generally, the microscopes used in fluorescence microscopy are similar in some ways to conventional microscopes. Conventional microscopes traditionally use light to illuminate and magnify a sample. The light used in fluorescence microscopes is much more intense than the light used in conventional microscopes; this light, rather than illuminating the sample itself, excites a fluorescent species within the sample, which in turn produces light and creates the magnified image of the sample Rice, n.

In most cases, fluorophores are used to label the sample of interest one common example is attaching fluorophores to antibodies. Then, the microscope uses a high energy light source, like a Xenon or Mercury arc-discharge lamp, to illuminate the fluorophores through a lens; this lens is equipped with several filters that allow only specific wavelengths of light through these wavelengths are the wavelengths of light that can cause fluorophores to produce light.

The fluorophores in the sample absorb the light and emit photons with lower energy and wavelength. The light emitted from the fluorophores is subsequently filtered through a series of filters so that researchers can view only the light that is coming from fluorescence Rice, n. There are three basic variables to keep in mind when conducting experiments involving fluorescence microscopy.

The first is optimization of competing properties of image resolution Combs, Image resolution is typically defined as the smallest distance between two points on some sample that, when viewed, can still be distinguished from each other.

In fluorescence microscopy, the competing properties lie in the different dimensions, as fluorescence microscopy creates 3D images. Researchers want the optimum resolution between the lateral XY plane and the axial Z dimension; while they could get a very clear image from just focusing on one plane, they would be losing depth. Thus, striking a balance of where to focus the light is of utmost importance Combs, The second is the runtime of the experiment.

Generally, researchers want to optimize the speed of the acquisition of their image from the microscope without compromising the image resolution. Thus, investment into good equipment is critical. A barrier to speed is both size of sample and laboratory funding Combs, The third is the amount of fluorescence collected from fluorophores in the sample.

As aforementioned, fluorophores could theoretically fluoresce forever. Despite this, there are immediate issues with loss of light and energy as not every fluorophore fluoresces every time light is directed at the sample. More critically, however, are the issues of photobleaching and phototoxicity Combs, Though the two are similar, they are not the same please refer above for an explanation of photobleaching. It is a complex process that involves several different photophysical mechanisms that create highly reactive products, as well as produce high amounts of heat and damage DNA often through photobleaching.

Factors in the amount of phototoxicity present include excitation wavelength, intensity of excitation light and light produced by fluorescence, exposure time, and concentration and location of fluorophores. Fluorescent Tagging Techniques There are several different targets that researchers may want to track and image and therefore several different targets for tagging with fluorophores.

The most common target is proteins. When working with proteins, the first step that researchers must take is deciding which of three types of fluorescent protein to use. The first is intrinsically fluorescent proteins, which do not require the addition of an external fluorophore; rather, they become fluorescent after folding the process in which a protein acquires its functional, 3D shape. These are arguably the easiest to use, as researchers just have to make sure that they will fold in the environment they are placed in.

However, because they are not being externally manipulated, they lack the flexibility that researchers often need when studying dynamic cellular environments. The second type is extrinsically fluorescent proteins that bind directly to biomolecules like fluorophores. Often, these are as easy to use as intrinsically fluorescent proteins if the fluorophore is present in the cellular environment being targeted.

Typically, this is the case, but sometimes researchers need to supplement the fluorophore externally. The third and final type is extrinsically fluorescent proteins that need to bind to ligands in order to connect to fluorophores. These require the use of synthetic molecules, and while they are more difficult to use, they allow for a high amount of flexibility in fluorescence as the fluorescent tags are usually separate from the molecules that bind to the proteins themselves and are therefore easily interchangeable for other types of fluorophores Thorn, FALL If the researcher decides on an extrinsically fluorescent protein, they will generally rely on one of three tagging techniques.

The first technique involves the use of self-labeling enzymes. These are fusion tags that can catalyze the auto-attachment of organic fluorophores preexisting in the cellular environment that the proteins are in. Once the proteins come in contact with these enzymes, they are able to connect to fluorophores. While this method is advantageous in that researchers do not have to exogenously introduce fluorophores to the sample, it depends on the expression of the fusion tag, which results in variability of the amount of fluorescence produced.

The second technique is use of enzymes that catalyze attachment of fluorophores to some target sequence on the protein. This technique involves use of short peptide sequences that are rare in the native cellular environment. Enzymes, when exposed to the sequences, catalyze the binding of the protein to some fluorophore.

This technique can involve introduction of external fluorophores and also has some variability. In the third technique, researchers can use dyes that fluoresce instead of using enzymes to catalyze reactions between proteins and fluorophores. Different Types and Applications of Fluorescence Microscopy A baseline fluorescence technique applicable for several situations is the dark-field system. Dark-field microscopy refers to any kind of microscopy that excludes unscattered beams of excitation light from the final image produced, thus creating a darker field around the specimen being viewed and allowing for better visualization of the sample Weigel et al.

In fluorescence microscopy, creating a dark-field system gives several advantages to the researcher. The biggest impact is that the use of a dark-field system provides a black background to the image produced, allowing for the formation of an image with high contrast; this allows the researcher to see the details of the image more clearly. Additionally, the focal length of the system is relatively short, resulting in a concentration of energy in a smaller area, which minimizes energy loss Young, A major decision a researcher must make is use of 27 Figure 3: This image represents the ideal room setup for fluorescence microscopy experiments.

The room should be kept as dark as possible, with the only external light coming from any critical monitors and the excitation light. By cutting out as much light pollution as possible, the final image will come out with the highest possible resolution. This allows for a much higher resolution image but also comes with barriers of longer acquisition times and higher photobleaching and phototoxicity.

This method minimizes photobleaching and phototoxicity while having relatively fast acquisition of the image. However, as a result of the speed and low-intensity excitation photons, the images created tend to be lower-resolution, as information is collected not just from the areas of interest but areas outside of the bounds that researchers want to examine as well. Optical sectioning microscopy only collects information from one specific image plane that is in focus.

There are several different kinds of optical sectioning microscopy. Multiphoton imaging is typically used to collect deep-tissue information. Often, researchers use two-photon microscopy. In this technique, two-photons of relatively long wavelength are absorbed by the fluorophore at the same point in time, which minimizes the amount of stray light involved in the analysis and therefore reduces photobleaching and phototoxicity.

Because of this, the imaging can 28 be run for a long time. The main downside of multiphoton imagery is that researchers penetrate deeper into the tissue and image resolution goes down Larson, Lightsheet microscopy is another common optical sectioning technique. This technique is often used to study cellular kinetics and dynamics, which are both critical for understanding tissue formation Albert-Smet et al.

Issues come with building the microscopes themselves. Because they are so specific to the samples created, light-sheet microscopes often need to be custom built and require many extra parts. Thus, this technique is much more expensive than other fluorescence microscopy techniques Albert-Smet et al.

The basic goal of super-resolution imaging is to get the absolute highest possible resolution possible. The first is the Abbe criterion. The way to minimize the spots of diffraction is to decrease excitation wavelength and use samples with higher refractive indexes.

The second critical principle is the Rayleigh criterion, which puts a limit on angular resolution. Thus, the Rayleigh criterion defines the limit of resolution in terms of point object diffraction. In reference to fluorescence microscopy, these principles come into play when considering collection of fluoresced light from fluorophores. Despite these limits, researchers have been working steadily to break the resolution limit through super-resolution imaging techniques.

Conclusions There are several options available for researchers who are trying to employ fluorescence microscopy techniques for their work. As the tagging and imaging techniques become more specific, the results can have higher resolution and more specificity to what the researcher is studying.

However, one must take caution when choosing what technique to use, as different methods have different pitfalls and may not be suitable for all projects. As fluorescence microscopy continues to advance, there will undoubtedly be new microscopes, add-ons, and techniques that further refine imaging in cellular and molecular biology fields, FALL which leaves the possibilities for future research nearly endless.

These advances will come with a greater amount of difficulty in employing fluorescence microscopy techniques and a much steeper initial learning curve. As such, it is important to write up to date reviews on the state of microscopy to help guide researchers in their work.

References Achan, J. Quinine, an old anti-malarial drug in a modern world: Role in the treatment of malaria. Malaria Journal, 10 1 , Applications of Light-Sheet Microscopy in Microdevices. Frontiers in Neuroanatomy, 13, 1. Current Protocols in Neuroscience, 50 1. Imaging proteins inside cells with fluorescent tags. Trends in Biotechnology, 30 1 , 8— Genetics, 1 , 15— Icha, J.

Phototoxicity in live fluorescence microscopy, and how to avoid it. BioEssays, 39 8 , Assessing phototoxicity in live fluorescence imaging. Nature Methods, 14 7 , — Multiphoton microscopy. Nature Photonics, 5 1 , 1—1. Parang, Z. Scientia Iranica, 19 3 , — Fluorescence microscopy-A historical and technical perspective: Fluorescence Microscopy.

Cytometry 29 Part A, 83 9 , — Rice, G. Fluorescent Microscopy. Montana State University. Microbial Life - Educational Resources. ThermoFisher Scientific. Fluorescence Fundamentals. Genetically encoded fluorescent tags. Molecular Biology of the Cell, 28 7 , — ACS Photonics, 1 9 , — Faster, sharper, and deeper: Structured illumination microscopy for biological imaging. Nature Methods, 15 12 , — Chemistry LibreTexts. Principles and Technique of Fluorescence Microscopy.

Quarterly Journal of Microscopical Science, s 60 , MMPs like MMP play important biological roles in the regulation of reproduction and tissue repair, but their overexpression has been linked to the development of tumors and osteoarthritis Source: Wikimedia Commons Introduction In the human body, there are estimated to be at least 20, different types of proteins encoded by the genome Ponomarenko et al.

In fact, proteases are the enzymes crucial for the production of free amino acids needed to synthesize the entire proteome, and they play a crucial role in the functions of all life. One particular class of these proteases, the matrix metalloproteases MMPs , have significant roles in the regulation and function of the human body.

MMPs are primarily responsible for the degradation of the extracellular matrix, which is composed of various fibers, proteoglycans, glycoproteins and polysaccharides responsible for regulating cell growth and development Laronha and Caldeira, First discovered 32 in through the degradation of collagen in tadpoles, MMPs have been found to have roles in a variety of areas including angiogenesis, embryo implementation, and cell death Rodriguez et al.

MMPs are also secreted in a number of pathological processes, including arthritis, vascular disease and several types of cancer. As a result, MMP inhibitors have been studied as potential treatments for several diseases associated with overexpression of certain MMPs. Although many of these inhibitors showed promising results initially, the broad spectrum MMP inhibitors first investigated in the s led to off-target inhibition of beneficial MMPs, resulting in many patients experiencing musculoskeletal and gastrointestinal disorders Fields, Classified as members of the matrixin subfamily, these enzymes have four main components: a pro-domain associated with the inactive enzyme, a catalytic domain with a zinc ion, a linker peptide, and a hemopexin-like terminal domain Nagase et al.

When MMPs are first synthesized, a cysteine residue in the pro-domain is responsible for blocking enzymatic activity by coordinating to the catalytic zinc ion to form a tetrahedral sphere — preventing binding by a substrate Laronha and Calderia, These groups are typically activated by cleaving from other MMPs; however, they can also be activated by mercury reagents or strong oxidants such as HOCl. These strong oxidants are often associated with inflammatory conditions, possibly explaining MMP activity in patients with these conditions Nagase et al.

The active site, composed of approximately amino acids, contains a zinc ion that often has up to three calcium ions associated with it. It is believed that these calcium ions are responsible for helping to maintain the 3D folding structure of the polypeptide Nagase et al. This region is subsequently connected to the hemopexin domain via a proline-rich linker that lessens enzyme rigidity.

This domain is likely responsible for cleaving collagen, with the catalytic domain being sufficient for the cleavage of non-collagen substrates Laronha and Caldeira, Initial investigations by Kester and Matthews suggested that the interaction of a peptide substrate with a water molecule and the zinc ion is crucial for the process of catalysis.

The zinc ion was FALL proposed to be coordinated to the carbonyl carbon of the peptide bond and responsible for depolarizing the peptide bond, making it easier to break Kester and Matthews, Later investigations by M. Browner suggested a similar nucleophilic role for water in the enzymatic mechanism for human matrilysin, with a glutamate residue acting as the proton donor needed to cleave the peptide bond Browner et al.

However, more recent work from Manzetti et al. Instead, the group proposed that the zinc ion polarizes a glutamic acid residue to attack the peptide carbonyl to form a tetrahedral intermediate, with subsequent elimination of the amino group. They also proposed that a water molecule would subsequently attack the carbonyl group in the glutamic acid residue to free the enzyme for further catalysis Manzetti et al.

Their normal biological function, as well as their role in selected disease states, will be explored below. The collagenases, among the first MMP classes to be discovered, are responsible for the cleavage of fibrillar collagen — one of the most abundant protein classes of the extracellular matrix.

Secreted by a wide variety of cells such as fibroblasts and endothelial cells, the cleavage products of collagenases produce gelatin Laronha and Caldeira, It has been suggested they may a play role in the in vivo healing of injuries through the stimulation of keratinocytes Riley and Herman, However, elevated collagenase activity has been implicated in the development of abdominal aortic aneurysms and aortic occlusive disease.

Among MMPs, there are five main classes: collagenases, gelatinases, stromelysins, matrilysins, and membrane-bound MMPs. Gelatinases play a significant role in the digestion of gelatin, type IV collagen, and laminin. The addition of three fibronectin type II domains enables the enzyme to effectively bind gelatin for further processing into smaller peptides and free amino acids Laronha and Caldeira, Gelatinases are often associated with normal physiological states such as embryonic growth and development and angiogenesis but may also play a role in the pathogenesis of some bacteria.

For example, Thurlow et al. While arranged with a similar domain arrangement to that of the collagenases, stromelysins instead participate in cleaving other parts of the extracellular matrix such as elastin, fibronectin, and aggrecan Cui et al. Stromelysins play a regulatory role in the expression of connective tissue growth factor and may also be involved in normal cell apoptosis Cui et al.

However, stromelysin upregulation is associated with inflammatory conditions such as post-traumatic osteoarthiritis. Ding et al. This upregulation was responsible for damaging cartilage and producing catalytic fibronectin fragments, creating a positive feedback loop of further cartilage destruction Ding et al.

Unique among the MMPs, matrilysins lack the hemopexin and hinge region associated with most other MMPs, thus rendering them incapable of effectively binding to most types of collagen Laronha and Caldeira, Their primary purpose is cleavage of plasminogen to produce angiostatin fragments which are capable of inhibiting angiogenesis.

They are also capable of processing some cell surface molecules to either induce or inhibit apoptosis and tissue remodeling Cui et al. This class of MMPs has been implicated in the development of chronic tonsilitis. Acioglu et al. The group suggested that the degraded protein fragments generated by 34 elevated levels of matrilysin may be responsible for the inflammation associated with tonsilitis Acioglu et al.

Finally, the membrane-type MMPs are the only class of MMPs that are activated intracellularly and bound to the cell surface. In order to remain bound to cell surfaces, these enzymes have membrane anchoring domains, with a domain similar to that of the peptide furin present in the pro-enzyme Nagase et al.

Some of these MMPs have also been associated with neural functioning; for example, MMP24 is necessary for the development of neuroplasticity and pain recognition Cui et al. However, members of this MMP class also play a role in facilitating undesirable cell migration and proliferation through the degradation of the extracellular matrix; for instance, MMP upregulation led to cell migration that limited the effects of cardiac cell regeneration Liu et al.

MMPs and Cancer - A Deeper Investigation While an imbalance in various classes of MMPs has been implicated in a number of inflammatory conditions, most research into the biological activity of MMPs has been directed into its role in the development and spread of a wide variety of cancers. Studies have suggested that a lack of MMP expression can inhibit cancer spread. For example, Itoh et al. Conversely, the overexpression of MMPs has been suggested as a possible factor for increased cancer malignancy.

For example, Shima et al. Similarly, Johansson et al. Unlike many other types of enzymes, MMPs are capable of cleaving several different substrates in the extracellular matrix. Most MMPs are secreted by cells. Source: Wikimedia Commons and aggressive squamous cell carcinomas Johannson et al.

However, while MMPs have been implicated in the spread of cancer through angiogenesis enhancement, other studies have found that MMPs can limit tumor vascularization. Overall, MMPs play a complicated role in the spread and inhibition of cancer; this dual-faceted role suggests that simply limiting MMPs generally is not enough to stop cancer.

Early efforts at synthetic drug design focused on the introduction of a functional group capable of chelating the zinc ion to deactivate the enzyme Fields, Among the most promising of these substrates were the succinate-derived hydroxamic acids, in particular those with larger macrocyclic rings which could increase compound potency Steinman et al.

These hydroxamic acidbased products were derived from the natural structure of collagen but replaced the terminal amide group with a hydroxamate group FALL Whittaker et al. Other initial research efforts investigated carboxylic acids, thiols, phosphorus-based compounds, and various natural products. However, these groups were generally believed to be less effective at successfully chelating the zinc cation of MMPs. For instance, Babine and Bender suggested that carboxylic acid-derived inhibitors are generally fold less potent than their hydroxamate counterparts; they suggested this was due to the need of carboxyl groups to bind a proton after coordinating to zinc.

Similarly, the group reported that thiol-based compounds were fold less potent due to binding in a monodentate matter that is less stable than the bidentate binding of hydroxamates Babine and Bender, Because of these factors, the hydroxamic acid derivatives were the first to reach clinical trials, with drugs such as Marimastat intended to treat metastatic breast cancer through the inhibition of several different MMPs and Batimastat intended to treat inflammation through broad inhibition of several MMPs being among the first to be tested Gialeli et al.

However, clinical tests revealed a lack of efficacy for many of these drugs. For instance, the poor solubility of Batimastat led to its low bioavailability; it was subsequently replaced by the more soluble Marimastat Zucker et al. Similarly, clinical trials of the MMP inhibitor BAY for advanced small cell lung cancer revealed shorter survival rates than the placebo, while Ro was found to be ineffective in the treatment of rheumatoid arthritis Zucker et al.

More worrisome yet was the revelation of dose-limiting side effects associated with MMP inhibitors. Treatment of Marimastat in patients with advanced lung cancer was found to induce a severe polyarthritis for up to eight weeks after discontinuation of the drug Wojtowicz-Praga et al. Attempts to investigate the clinical failure of this first generation of MMP inhibitors suggested that off-target interactions and metabolic instability were possible culprits.

It has been proposed that the complicated proteolytic web of enzymes may be responsible for inducing some of the reported side effects, as hydroxamic acid inhibitors were found to inhibit several different MMPs and some of the related adamlysins Peterson, Additional research into hydroxamic acid groups has revealed that there may be poor selectivity for zinc over other transition metals, thus allowing these inhibitors to chelate other transition metals from other enzymes e.

Metabolic instability of hydroxamic acidbased inhibitors may have also contributed to the lack of drug efficacy. Hydroxamic acids can be easily hydrolyzed to carboxylic acids or reduced to amides by esterases, consequently reducing their effectiveness in chelating to zinc. It has been suggested that differences in blood plasma between mice and humans also explain why these inhibitors were more effective in animal models as opposed to clinical trials Fields, More Recent Improvements While the initial failure of MMP inhibitors discouraged further research into the subject, more recent improvements have improved their efficacy and selectivity.

Rather than chelating to the zinc ion, this inhibitor targets a side chain specific to MMP Source: Wikimedia Commons under investigation and have shown some signs of promise. Some of these new developments will be explored below.

Researchers have developed new functional groups that more effectively bind zinc than the initial class of inhibitors. One particular class of compounds that has shown great promise is phosphorus-based inhibitors. Biasone et al. Similar studies have been applied for carbamoyl phosphonates, which chelate in a manner similar to hydroxamic acids but target MMP-2 and MMP-9 with high specificity and no toxic side effects. Groups such as amides and heterocycles have also demonstrated incredible selectivity and potency for certain MMPs.

For example, pyrimidinetrione-based inhibitors were capable of achieving fold potency for MMP over MMP, and the introduction of oxazole terminal groups gave IC50 values ranging from 1. Additionally, while much effort has gone into improving zinc binding MMP-inhibitors, some studies have demonstrated potential efficacy of groups that lack a zinc binding group. These classes of molecules demonstrate higher selectivity for certain MMPs as they target MMP-specific features besides zinc.

High-throughput screening, a technique of evaluating millions of potential compounds in assays through robotics, has helped to determine which compounds may work best at specific inhibition Macarron et al. Similarly, through high-throughput screening and computer aided drug design, Li et al.

Finally, more recent attempts to generate specificity have focused on the identification and testing of antibody-based inhibitors. Unlike synthetic inhibitors, inhibitors based on monoclonal antibodies are capable of limiting certain functions of MMPs while allowing others to continue — especially for the membrane bound type MMPs. For instance, Ingvarsen et al. However, it had only minimal impacts on the collagenolytic functions of the enzyme Ingvarsen et al. Similarly, Sela-passwell et al.

Though their role in the proteolytic web is complex, MMPs have been demonstrated to have significant roles in the propagation and severity of a wide variety of diseases. Furthermore, although the initial class of MMP inhibitors failed due to their lack of specificity, new developments in synthetic and natural inhibitors represent a promising new front for effectively treating inflammatory diseases and cancers. Gialeli, C. Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting.

The role of matrix metalloproteinases in recurrent tonsillitis. International Journal of Pediatric Otorhinolaryngology, 74 5 , — Biology of metalloproteinases. Babine, R. Chemical Reviews, 97 5 , — Crystal structures of matrilysin-inhibitor complexes. Biochemistry, 34 20 , — Biochemical and Biological Attributes of Matrix Metalloproteinases.

Progress in Molecular Biology and Translational Science, , 1— Collagenase and surgical disease. Hernia, 10 6 , — Cells, 8 9. MMPs as therapeutic targets--still a viable option? Journal of Medicinal Chemistry, 51 5 , — The Journal of Biological Chemistry, 15 , — Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Research, 58 5 , — Johansson, N. Expression of collagenase-3 matrix metalloproteinase in squamous cell carcinomas of the head and neck.

The American Journal of Pathology, 2 , — Journal of Biological Chemistry, 38 , — M Kester, W. Crystallographic study of the binding of dipeptide inhibitors to thermolysin: implications for the mechanism of catalysis. Biochemistry, 16 11 , — Development of musculoskeletal toxicity without clear benefit after administration of PG, a matrix metalloproteinase inhibitor, to patients with knee osteoarthritis: a randomized, month, double-blind, placebo-controlled study.

Structure and Function of Human Matrix Metalloproteinases. Cells, 9 5. Omnibus approval is given by Audit Committee for the transactions which are foreseen and are repetitive in nature. A statement of all Related Party Transactions is presented before the Audit Committee and the Board on a quarterly basis, specifying the nature, value and terms and conditions of the transactions.

The said transactions are approved by the Audit Committee as well as by the Board. The Company has a Vigil Mechanism for Directors and Employees to report their concerns about unethical behavior, actual or suspected fraud or violation of the Company''s Code of Conduct. The mechanism provides for adequate safeguards against victimization of Director s and Employee s who avail of the mechanism. The employees of the Company are made aware of the said policy at the time of joining the Company.

As per second proviso to Section 2 of the Companies Act, ''the Act'' , a transition period of three years from the commencement of the Act is provided to appoint a new auditor when the existing auditor''s firm has completed two terms of five consecutive years. For the purpose of appointment of new Auditors, the Audit Committee along with the Management invited proposals from the reputed firms of Chartered Accountants and had detailed discussion with representatives of those firms. They have also confirmed that they are not disqualified to be appointed as statutory auditor in terms of the provisions of the proviso to Section 1 , Section 2 and Section 3 of the Act and the provisions of the Companies Audit and Auditors Rules, The firm provides audit, tax and advisory services through its 42 partners with staff from its offices in 11 cities, namely New Delhi, Mumbai, Bengaluru, Chandigarh, Chennai, Gurgaon, Hyderabad, Kolkata, Kochi, Noida and Pune.

Further, the report of the Statutory Auditors along with the notes is enclosed with the financial statements. The observations made in the Auditors'' Report are self-explanatory and does not contain any qualification. Therefore, it does not call for any further comments. Also the Auditors of the Company have not reported any fraud as specified under Section 12 of the Companies Act, The report of the Secretarial Auditors is annexed as Annexure 4 to this report.

The report is self-explanatory and does not contain any qualification. For this, the key success enabler and most vital resource is world-class talent. Mastek Group continually undertakes measures to attract and retain such high quality talent. As on March 31, Mastek Group had a total Head count of The Directors wish to place on record their appreciation for the contributions made by employees to the Company during the year under review at all levels.

The disclosure required under Section 12 of the Companies Act, read with the Rule 5 of the Companies Appointment and Remuneration of Managerial Personnel Rules, as amended from time to time is annexed as Annexure 5 and forms part of this report. The required disclosures in this regard are annexed as Annexure 6. The risks are identified and discussed at regular intervals. In respect of individual directors including the nonexecutive chairman and the managing director, their personal performance was carried out using a peer review process, facilitated by an outside subject matter expert with confidential processing of inputs, interpretation of findings followed by one-on-one meeting of the individual Directors, and concluding with an aggregate presentation to the entire board.

Board and Committee functioning was reviewed and evaluated on the basis of responses from directors, Committee Members, Managing Director and the CEO to structured questionnaires, covering various aspects of the composition and functioning of the Board and its Committees. In a separate meeting of the Independent Directors, performance of non-independent directors, performance of the Board as a whole and performance of the Chairman were also evaluated, taking into account the views of executive directors and nonexecutive directors.

The Directors were asked to provide their valuable feedback and suggestions about the overall functioning of the Board and its committees and its areas of improvement for a higher degree of engagement with the Management. The Board expressed its satisfaction with the Evaluation results, which reflects the high degree of engagement of the Board and its committees with the Company and its Management.

Based on the outcome of the evaluation and assessment cum feedback of the Directors, the Board and the Management have also agreed on various points which will be implemented over an agreed timeframe.

Induction and familiarization programme for Directors The details of the induction and familiarization program for the Directors are given in the Corporate Governance Report. Independent Directors Mr. Sandilya, Ms. Priti Rao, Mr. Atul Kanagat and Mr. Priti Rao and Mr.

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The hour Chainlink price analysis accentuates this sentiment and also issues a sell signal, with 15 indicators suggesting a downward movement against only one indicator suggesting an upward movement. The analysis shows the bearish dominance across the mid-term charts while showing little buying pressure for the asset across the same timeframe.

Meanwhile, ten indicators remain neutral and do not issue any signals at press time. What to expect from Chainlink price analysis? Traders should expect LINK to continue to move downwards as the bears take over the markets. The suggestion is reinforced by the 4 and the hour technical analyses. Bilal Ahmed is a blockchain enthusiast and an avid reader who loves writing about ramifications of blockchain and cryptocurrencies.

He believes in doing due diligence with facts before transmitting. Additionally, the currency calculator shows the closing rate of the previous day as well as the highest and lowest rates of the conversion Bitcoin - United States dollar. The results are displayed in a clearly arranged table. In addition to the Bitcoin - United States dollar rate, the Markets Insider currency calculator also offers other exchange rates for about international currencies. Bitcoin - United States dollar Currency Calculator You have currently selected the base currency Bitcoin and the target currency United States dollar with an amount of 1 Bitcoin.

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Playing safe in cryptocurrencies is also one game you can play, and it can only be done by investing your money in digital tokens like bitcoin. There are many available, but going with bitcoin will provide you with any certainty that you will make money. Moreover, bitcoin is considered the safest digital token around, which is why investing is not going to be a hectic task. It is readily available, and apart from that, it will also present you with more opportunities of selling investments and make money.

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Last words The above gives a few of the implementable methods of cryptocurrency moneymaking. However, if you are not very well aware of the message, perhaps keeping yourself away from them is for your good. Regardless of the complexity and easiness you will find in any of the details, if you are not prepared and practised, adopting anyone is not a good idea.

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In the menu, you can select the desired exchange rates of about international currencies from the two lists. Additionally, the currency calculator allows you to calculate historical exchange rates in addition to the current rate. The results are displayed in a table with the closing rate of the previous day, the opening rate as well as the lowest and highest rates of the respective date.

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How to Use a Bitcoin ATM to Buy or Send Bitcoin (More than $1000) - Step by Step Guide

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