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You can't take the rush out of a gold rush town and get it to stroll or sit down. The rush is its nervous system fueled by large and singular events. Johannesburg likes to think of itself more as drag strip racing than random family outings in sensible cars. So the 2010 World Cup is the turbo kicking into Johannesburg's already accelerated history.
The Heisenberg Principal of Uncertainty – more as metaphor than scientific fact – argues that speed and position cannot be measured simultaneously. Or in a nuanced understanding, the more precisely you know one, the less you know the other. It's a question of concentration and degree, a question in which the observer is implicated.
Right now Johannesburg is concentrated on the Big Event accelerating it into another "World Class" future. It's laying down fast infrastructure to prove it, from the Gautrain to the BRT, and like Haussmann's Paris, it will be hard to ignore the spokes of World Class in 2010. It's an undeniably exciting time for Johannesburg and South Africa.
But what remains of the city, or of cities generally, or of the societies and architectures that compose them, after the Big Event has rushed on to another part of the world? Do cities have other times to return to, or do they just get busy on the bid for the next World Class race meet?
In the uncertainty dilemma, Johannesburg favors speed. It's a young city. Position is more of an afterthought, the grabbing of styles or the deployment of staging techniques. Or in that secluded moment, buckled up in an airline seat thumbing through the duty-free magazine and feeling compelled to want something, position is just a listless pause before takeoff.
Positions-making-and-having-their-own-times do not often occur in urban thinking in South Africa. It's why Johannesburg has a problem understanding that immigration - as seepage more than tourism or business trips - is forming more complex urban situations, a cosmopolitan awakening that is continental. Johannesburg could become a unique city to live in, rather than an estate agent's brochure to read, or a "World Class African City" to visit.
But lurking in Johannesburg there is always a yearning for the fast Las Vegas gambling town– a city where no one is born or dies, but everyone visits for at most two weeks: to make a fortune or lose one, to get married or get divorced, to get laid or hold forth with bourbon. Speed comes at a cost. At high speed, position is a post-modern desert on the way to a craps game - a dumping ground for retreads, sign posts and this week's failed lottery tickets.
The Heisenberg dilemma of speed and position is not unique to Johannesburg as a city. The dilemma has occurred in all cities growing quickly from provincial origins into metropolitan futures, as more and more people demanded to live in them for whatever reason.
When the dilemma presented itself towards the end of the 19th Century, Chicago conveniently burned to the ground and infrastructure gave rise to the 20th Century version. Sentiment was a non-starter in Chicago's new beginning. But other cities grappled with measuring the new slang of urban expansion against their outdated design and social dictionaries. In the case of 19th Century London or Paris, it was a repressive classical dictionary where tidiness, beauty and infrastructure were successfully deployed against the "social anarchy" of new urban societies demanding and making new urban forms.
Nowadays property values do the excluding work of classicism in World Class Cities and "New Urbanism" has become the solution for also-ran cities. Prepackage and fence-in, the pocket bourgeoisie add instant property value to World Class Satellites. A few extra bucks for a cappuccino is a small price to pay for hefty guards at the gates ensuring the pockets remain uncontaminated and free to believe they're in that arcade in Milan.
In cities like Lagos or Sao Paulo, the slang is overwhelming and the dictionaries can't cope. The organism is too large to put under current design macroscopes, despite heroic efforts by architect-visionaries like Rem Koolhaas, with unfortunately too little time to turn their full attention to Africa, South America or other exotica.
Philosophically, we no longer live in a Newtonian universe where space and time are neatly separated and can be discussed mechanically. To discuss position or speed now is to discuss each with the adjunct of the other, and acknowledge the observer in prejudices. It is relative, yes, but more it is a paradox that demands continual shifts in viewpoint and thinking.
Simply put, position accrues time(s) as depth. Positions are stained by social force and habit, cultural bric-a-brac, topography and climate, each coming laden with ideas and demands. They resist speed and suggest that other times be recognized and built upon. Position is not a nostalgic desire to stand still, but more like having dinner in a motor home speeding down the highway, the concentrated and existential time-within-Time we occasionally call living-for-life or savoring-the-moment.
Speed, on the other hand, is more often than not taken as a singular metaphor that becomes a mechanical solution or a psychosomatic internal combustion engine, a physical or mental force urging us all into a future that necessarily remains just out of reach.
Flying is still an unlikely miracle to most human beings. The unlikely miracle gave rise to the Uber-Bourgeoisie, a World Class that inverted immigration from a movement of the very poor to a movement of the very rich. To the Uber-Bourgeoisie, architecture and cities are an interactive string of spectacles and events designed in fast time. The Uber-Bourgeoisie hit the pause button when they need a moment to dwell in extruded apartments where the kitchen is in New York and the bedroom in Shanghai. World Class Architects are the designers and event managers of this new immigration, the iconic Moses accelerating the Uber Bourgeois into the promised stratosphere of spaces mimicking the space-time continuum and making reluctant concessions to local gravities to prevent champagne glasses falling off tables.
Glancing for a moment out of the aircraft window to look at a stretch of the Sahara that still takes weeks to cross on foot, then returning to read the Economist, it is justifiable to think that humanity now lives in irreconcilable times, and that the humanist, if mechanical proposition in Newtonian thought where space and time seemed predictable and cohesive and could form part of a social solution, is now impossible.
But then suddenly, as happens in the stratosphere, whether financial or architectural, the Uber-Bourgeois Shuttle hit an airless pocket and dropped thousands of meters. The ground and its footsloggers seem not only worthy of thought, but imminent.
Thomas Jefferson envisioned a productive agrarian state in which he hoped cities would play a minor role. His cohort, Ben Franklin, made terse, dismissive edits to Jefferson's meandering texts, probably because Franklin was impatient to get back to Paris, a city he loved to live in. Philadelphia he reserved for homilies. In the yin-yang of two thinkers carving a Humanist United States out of a soon to be indigenous-free stretch of land some 3,000 miles long, Franklin retained his emotional attachment to the continental European city as an interesting, enjoyable and elaborately social place. Jefferson, on the other hand, foresaw that in the New World, the city would become a mechanical wealth-making device where the rich exploited the poor - the translation of Newtonian mechanics into urban purpose.
Implicit in the 19th Century Industrial Revolution was the growing idea of the city as a functional device. 20th Century Modernism made this explicit and fine-tuned the parts - Corbusian houses as machines-to-live-in – to fit the idea of the city as a productive machine. Lately, with the functional device established, the post-Modern city can now be marketed worldwide as a consumable object or service.
In Heisenberg terms, the continental European city, by and large, through agglomerations of position established by long histories of occupation, resisted the singular idea of the city as speed-turned- device-turned-service. Cities in the New World were less able to resist this; they still fill and empty like a factory floor in economies measured by housing start-ups and foreclosures, as if dwelling were beside the point in contexts based on movement.
Johannesburg is a 20th Century city whose reason for being was the mining and processing of gold. It was born of industrial purpose and would have few references other than speed had it not occurred in Africa, the only continent, other than Asia, where viable indigenous populations had position enough to survive colonialism, then gain independence. So Johannesburg, if it emptied as a factory floor like Pittsburgh or Detroit, would always be guaranteed further occupation. It would lose one value, only to quickly gain another.
There should have been something reassuring in this, that Johannesburg was not weakly positioned in a desolate middle-class landscape like the Mid-West, where immigrant nuclear families were connected like vacuum cleaners sucking wealth from a fluctuating New World grid. Johannesburg might have understood its position more like Rome - a rock on the edge of an ocean, corroded and added to by consistent social tides.
But in the Heisenberg dilemma Johannesburg continues to ignore position and insist on speed. This is because Johannesburg understands itself as a New World City, rather than an Old World City, or Another World City.
Uniquely in sub-Saharan Africa, Johannesburg was founded by settlers neither as an administrative capital, nor a commodity-based city or port. From the outset Johannesburg was an industrial city. So it embraced the paradigm of American cities like Pittsburgh and subscribed to the wealth-making ideas of New World cities, more or less as middle-class processing plants. The wave of post-World War II wannabe-middle-class European immigrants into South Africa certainly reinforced this idea.
But in populated Africa the paradigm was far from convincing. In the New World Continents of North America and Australia, indigenous populations were quickly decimated and an inversion was possible - immigrants became permanent and middle-class and the already marginalized locals stayed marginalized. These were continents that could fully embrace speed and create more or less convincing fictions of position on the blank pages of uninhabited landscapes.
It is almost as if, in realizing its mistake, Johannesburg was forced into denial and developed an obsessive-compulsive need to prove that is was not only part of the New World machine, but could develop it in alarming new ways.
In forcing the necessary immigrant-local inversion during the golden era of the New World City after 1945, Johannesburg and other South African cities began to conceive themselves as countries-within-countries with quality checks to control influx - plants that could then choose raw material from local populations to process into urban middle class. After the International Socialist rhetoric of pre-war South Africa gave way to a National Socialist government after the war, their constituents, the 80% rural Afrikaans population, were first in line to benefit. By the early 60's, 80% had been urbanized.
Johannesburg was a highly efficient machine, often bemused by bad international reception of its resounding success. In obsessive compulsiveness, it not only kept up with New World infrastructure, but in things like plumbing surpassed the wildest expectations of Modernism, managing to keep the shit of 6 distinct groups of human beings separate and create spaghetti-like facades on factories - an unprecedented addition to Modernist design vocabulary.
The choice of speed and its translation into urbanism as a wealth transferring process, still lingers in post-94 Johannesburg's thinking and behavior. Johannesburg's World Class criminal efficiency can be seen as part of this habit, a consequence of propagating the city more as process than position.
But strangely enough, in the singular lead-up to the World Cup and the frenetic construction of mega-public transport systems, the city is showing interesting signs of establishing position, socially, politically and mythically.
The taxi drivers, a growing constituency since the waning years of apartheid, have worked South African cities into a web and lexicon of flexible connectivity, and relish the iconic value of their popular limousines in a city infatuated by smart cars. In the lead-up to the World Cup they are throwing a spanner in the public works, claiming not only their economic and functional role, but also their position as part of the city's new mythology.
Other than the Russian Constructivist exuberance just after 1916, Modernism with its terse functional and protestant attitude to the human condition, had little to offer that was celebratory. On New Year's Day in Durban, the taxi drivers eschew the merely functional role of getting people to work. Hundreds gather on the beach front, laden with passengers taking a holiday and setting up barbeques – a busman's holiday of sorts. To an outsider this might be confused with large family outings, but in the sense of Heisenberg, it is the depthening of position as the 16 person taxi has developed a distinct urban sociability and along with this a political resistance to the one-machine idea endemic to both apartheid and post-apartheid political thinking in South African.
The mark of a city is how it deals with both celebration and tragedy. Whether it is tied to singular events like the Nuremburg Rally or other nation building tactics to gain a sense of social connection and belonging, or whether it develops these from the organic give-and-take and frictions of daily urban life. In South Africa's continuing social insecurity there are still far too many National Holidays. It's alarming in a country with a notorious history of collusion between capitalism and the national socialist state that being South African, being sociable and feeling worthwhile as a human being should still be considered the exclusive patronage of the central government or of the marketing ploys of capitalism galvanizing a nation into wanting what it cannot afford.
In the lead-up and aftermath to World Cup 2010, it would be good to remember the street traders and the World Summit on Sustainable Development in Johannesburg in 2002. By 2002 street traders had staked their claims, like early gold prospectors, across the horizontal plane of inner city Johannesburg. In the interests of putting on a smart face for international visitors, traders were removed from many city streets for 2 weeks. 2 weeks is a short time in the speedy history of the world, but street traders could not suspend trading for longer than 4 days. So ironically a World Summit on Sustainability put an end to the fragile sustainability of many street traders.
2010 is a much different time from 2002. South Africa's situation is now reflected globally in the crash of international capitalism and the reappearance of the ground. It seems a better time to concentrate on the experimental possibilities and implications for design and architecture in Johannesburg and other South African cities, than cling to maligned speculations on what is or what is not a World Class City.
By Rodney Place
Place is a Johannesburg artist. He has spent a few years in Eastern Europe.
Place is a Johannesburg artist. He has spent a few years in Eastern Europe.


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(08-24-2014, 07:23 PM)joshb_18 Wrote: Better than my first body haha but that s14 is really dope
(08-25-2014, 12:29 AM)silwek Wrote: Looking good :)
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Six Nations 2013: Ryan Jones pleased with manner of Wales win
Last updated on .From the section Rugby Union
Wales captain Ryan Jones said he was satisfied with his side's victory in Italy and the manner in which they built their 26-9 win in Rome.
"We have come into the game, with the weather atrocious, and Italy are a very tough team to break down," said Jones.
"They are big and physical and they were at home with a great record here, and it is a tough place to come.
"We knew what the challenge was and games like that are all about the arm wrestle and not breaking first."
Tries by centre Jonathan Davies and wing Alex Cuthbert, and points from the reliable boot of Leigh Halfpenny, secured the win at Stadio Olimpico.
Wales, who won the Grand Slam in 2012, have now won two of their three games so far in this season's championship, with a 30-22 defeat by Ireland and a 16-6 win over France preceding the victory in Italy.
Italy recorded the shock victory of the tournament with a 23-18 win at the same venue over France, but they then suffered a 34-10 defeat by Scotland in Murrayfield.
This was Wales' sixth consecutive win over the Azzurri and a fourth successive away victory for Wales in the Championship - a feat they last achieved in 1979.
"It was about territory, putting the ball in the right areas and making sure the points count," added Jones.
"You have to build a win in places like this - it's a three-six-nine point game.
"The early points in the second half settled us down and we defended superbly and we managed to pull away in the end."
Wales now travel to face Scotland at Murrayfield in two weeks, knowing a win would see them host England in the final round of the tournament at the Millennium Stadium with a possible Six Nations title to play for.
Jones, who extended his record to 31-times as captain against the Azzurri, paid tribute to Wales' dominant scrum, the one area of the game that Italy traditionally seek to dominate.
Wales' front row of tight-head prop Adam Jones, hooker Richard Hibbard and loose-head prop Gethin Jenkins completely outmuscled their Italian opposite numbers at the scrum.
"Robin McBride [Wales forwards coach] is happy and there are six front rowers with big cheesy similes in [the dressing room] and they will be looking forward to the plaudits," said Jones.
"It's the second game in a row and it hasn't been pretty, but we have managed the win, with wonderful endeavour."


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Can you be more specific?What/where is laggy?
Maybe because in the main theme of OXCE there was no announcement of the update from January 15, 2019? Personally, I just found out that the download links have changed, but I haven't found the update history for this version, although I reviewed the topic.P.S. Since I play on Android, the exe that is attached to the mode has to be discarded, and OXCE is updated via apk.
I was asking if someone can tell me what in the new OXCE is laggy.
I'm not sure if laggy is the right description, but I noted right away on the battlescape that units appear to move a bit slower (almost like smoother?).
- the global pop-ups are emerging with 1 -1,5 sec animation, versus the 0,2 sec animation previously;
Looks like you have turned on the slow-mode... hotkey F8.PS: also please attach your options.cfg file, so we can see your settings
Two more sprites.
What if you could train robots in the empty hangar? Just the suggestion.
Yes, they should just use 1.0, 2.0, 3.0, 4.0, etc.
Just a heads up: Openxcom_xfiles_0.9.8e.zip does not seem to have OpenXcomExPlus.exe inside while the X-Com_Files_readme.txt in the archive mentions it. One of those two things should likely be fixed.
Ther's OpenXcomEx.exe, just like the previous releases. OXCE and OXCE+ were merged a long time ago.
Yup, which is why I point out that OpenXcomExPlus.exe is still mentioned in readme and probably something should be corrected here.
Fantastic work, Nord.I'm taking the Megaworm on the spot. I'd take the Muckstar too, but do you have a live version?
Out of my pc now, but i've posted live and inventory pics some time ago. 8-10 pages up.


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Countries websites
Thematic websites
Thursday 20 October 2016 – A team from Egis* has won the "Grand Prix" award in the French National Engineering Awards 20161 for their design of the Citadelle Bridge in Strasbourg. The prize giving ceremony this year took place at the French Ministry for the Environment, Energy and Marine Affairs. This prestigious distinction is another acknowledgement of the ingeniousness and high added value of Egis in the field of the design of urban structures.
Built under the project ownership of the Compagnie des transports strasbourgeois (CTS), the Citadelle Bridge is part of the plan to extend the Strasbourg LRT line D to the German border town of Kehl. It was designed to enable trams to cross the Vauban docks, without affecting the waterway gauge, and ultimately arrive in the town of Kehl. It was built by the GTM Hallé/Eiffage Construction Métallique business grouping.
Delivered at the end of the summer and due for commissioning in April 2017, the Citadelle Bridge will allow the tram and soft transport modes (pedestrians and cycles) to gain access to the future Deux Rives development park to be built on the former site of the Strasbourg port and which is currently in planning stage.
19 October 2016
The structure is a metallic bridge with a through-arch supporting a curved suspended deck measuring 163 metres between abutment centres. While the blueprint adopted for the arch was a specific architectural intention, its shape is also a technical response to the exertions to which it is subjected.
"The innovation in the bridge essentially lies in finding the perfect geometry from a perspective of balancing thrusts," explains Jean-Bernard Nappi, an architect at Egis, in charge of the architectural design of the structure.
Due to the urban restrictions on both banks, the route curves considerably as it passes over the Vauban docks. The placement of the arch, the width of the deck and the pattern of suspension cables offer sufficient gauge to allow the tramway and pavements to be created. They also result in a perfect balance of arch and deck thrusts.
"The structure is the result of highly integrated design between the architect and the engineers," adds Claude Le Quéré, Bridge Engineer at Egis, responsible for designing the Citadelle Bridge. "All our work around designing the shape combined technical requirements with the aesthetic vision, with a desire for simplicity and the aim of making the bridge elegant, in keeping with the project for the future development of the area."
The Engineering Structures and Railway teams at Egis pooled their skills to manage all the interfaces with the LRT line: the selection of a compatible alignment, the selection of a track-laying method, consideration of deformability criteria at each end of the bridge, and the integration of railway facilities and equipment.
The Citadelle Bridge is now part of the Strasbourg cityscape and fulfils the ambition of the Eurométropole to build an emblematic bridge, capable of acting as an anchor for the rehabilitation and urban development of part of the Strasbourg port zone.
* The innovation in the bridge essentially lies in finding the perfect geometry from a perspective of balancing thrusts," explains Jean-Bernard Nappi, an architect at Egis, in charge of the architectural design of the structure.
** The Egis team comprises Jean-Bernard NAPPI, architect, Claude LE QUÉRÉ, Alexandros GIANNOPOULOS, Bridge Engineers, Nabil YAZBECK and Frédéric MENUEL, Bridge specialist at Egis.


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50+ events in August 2017 about fracking and onshore oil and gas in the UK, including: Court of Appeal hearing on planning permission for Cuadrilla's Preston New Road site, plus rallies, council decisions, consultation deadlines, survey results, exhibitions, walks, talks, meetings and film screenings. Please let us know here if you'd like us to add your events or if any details are wrong. This post will be updated throughout the month with new information.
With thanks to DrillorDropREAD DIARY


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A demonstration from Val, a bartender at the recently closed PKNY Tiki bar in New York City. He has a somewhat unusual method regarding the shaking and the ice, although what he's doing makes sense. I tend to prefer a little less lime juice in mine — 3/4 ounce — but I'm not as big a fan of tartness as some people.*
*Is "tartness" a word?


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Metabolism is influenced by age, food intake, and conditions such as diabetes and obesity. How do physiological or pathological metabolic changes influence stem cells, which are crucial for tissue homeostasis? This Commentary reviews recent evidence that stem cells have different metabolic demands than differentiated cells, and that the molecular mechanisms that control stem cell self-renewal and differentiation are functionally connected to the metabolic state of the cell and the surrounding stem cell niche. Furthermore, we present how energy-sensing signaling molecules and metabolism regulators are implicated in the regulation of stem cell self-renewal and differentiation. Finally, we discuss the emerging literature on the metabolism of induced pluripotent stem cells and how manipulating metabolic pathways might aid cellular reprogramming. Determining how energy metabolism regulates stem cell fate should shed light on the decline in tissue regeneration that occurs during aging and facilitate the development of therapies for degenerative or metabolic diseases.
Stem cells serve as the origin for all tissues during embryonic and postnatal development, and contribute to tissue homeostasis and repair throughout adult life. Stem cells hold great promise for replacement therapies for degenerative diseases and age-related disorders. Embryonic, postnatal and adult stem cells share two crucial characteristics: the ability to produce at least one daughter stem cell upon division (self-renewal) and the ability to generate differentiated cells (potency). Stem cell potency varies depending on the type of stem cell. For example, embryonic stem cells (ESCs) are pluripotent and can generate all three germ layers (endoderm, ectoderm and mesoderm) (Thomson et al., 1998). Stem cells that are present in adult tissues can be either multipotent or unipotent (i.e. giving rise to multiple differentiated cell types, or only one cell type, respectively) (Nakada et al., 2011). Interestingly, induced pluripotent stem cells (iPSCs) can be generated from either embryonic or adult differentiated cells upon expression of specific combinations of transcription factors (Takahashi and Yamanaka, 2006) (Box 1). As iPSCs can be generated from a specific patient, the use of these cells avoids potential medical or ethical issues when considering their application in regenerative medicine.
Emerging evidence suggests that pluripotent stem cells and certain adult stem cells are metabolically distinct from their differentiated counterparts and that these metabolic properties are important for stem cell identity. Furthermore, molecular regulators of energy metabolism have essential roles in stem cell fate, in particular, the decision to self-renew or differentiate. Finally, stem cells respond to fluctuations in organismal energy states in vivo. This Commentary will discuss the connections between stem cells and energy metabolism, focusing on human and mouse stem cells. The influence of metabolism on stem cells in other species has been described elsewhere (Jasper and Jones, 2010). The main stem cell types that will be discussed are ESCs and iPSCs as examples of pluripotent stem cells, and neural stem cells (NSCs) and hematopoietic stem cells (HSCs) as examples of adult tissue-specific stem cells.
Metabolic properties of stem cells
Stem cells appear to depend mostly on glycolysis for production of ATP
In contrast to differentiated cells, many stem cells appear to rely to a greater extent on glycolysis than on oxidative phosphorylation to generate adenosine-5′-triphosphate (ATP). Bioenergetics studies have revealed that human ESCs (Zhang et al., 2011b; Zhou et al., 2012) depend, in a large part, on glycolysis for ATP production (Fig. 1). Consistently, mitochondria are less complex and fewer in number in human ESCs than in their differentiated progeny (Cho et al., 2006; Facucho-Oliveira et al., 2007; St John et al., 2005; Varum et al., 2011; Zhang et al., 2011b). Furthermore, studies analyzing mitochondrial respiration, glycolytic flux or proteomic profiles of purified adult HSCs have shown that these adult stem cells rely primarily on glycolysis to generate ATP (Miharada et al., 2011; Simsek et al., 2010; Unwin et al., 2006). The dependency of stem cells on glycolysis for ATP generation is reminiscent of that of cancer cells (Hsu and Sabatini, 2008; Warburg, 1956). Unlike oxidative phosphorylation, glycolysis can proceed anaerobically, raising the possibility that the dependency of a stem cell on glycolysis is an adaptation to the low oxygen levels that are present in vivo during development and in an adult stem cell microenvironment or 'niche' (see below) (Fig. 1).
Interestingly, metabolic differences between stem cells and differentiated cells might even promote the 'stemness' state. A glycolytic engagement is a crucial step in the conversion of terminally differentiated cells into iPSCs (Folmes et al., 2011; Panopoulos et al., 2012; Suhr et al., 2010; Varum et al., 2011). But do metabolic shifts precede pluripotency acquisition or does a stem cell state promote changes in metabolism? Evidence exists for both possibilities. Chemically inhibiting mitochondrial activity in human ESCs promotes the expression of pluripotency markers (Varum et al., 2009). However, the reprogramming factor OCT4 (also known as POU5F1) and the related factor OCT1 (also known as POU2F1) have many metabolic transcriptional targets, and loss of OCT1 leads to a shift away from glycolysis (Kang et al., 2009; Shakya et al., 2009), suggesting that transcriptional regulators of pluripotency and self-renewal coordinate the metabolism of stem cells. It is possible that during reprogramming a positive feedback loop is initiated, in which transcription factors first elicit a metabolic shift that is then necessary to induce additional endogenous pluripotency factors to complete the reprogramming into a stem cell state. The shift toward glycolysis might also minimize the production of reactive oxidative species (ROS), which could indirectly affect stem cell function, as described by Kobayashi and Suda (Kobayashi and Suda, 2012).
However, stem cell metabolism is likely to be more complex than a simple reliance on glycolysis. For example, one study reported that human ESCs generate the majority of ATP from oxidative phosphorylation, not from glycolysis (Birket et al., 2011). Such a difference to other studies is not completely understood yet, but could arise from the sensitivity of the detection technology used, or the fact that there might be slightly different stages of pluripotency – and thus metabolism – among ESCs (Zhou et al., 2012). Mouse ESCs also depend on the amino acid threonine as a crucial source of energy, whereby the citric acid cycle metabolite acetyl-coenzyme A is generated through the action of threonine dehydrogenase (Shyh-Chang et al., 2013; Wang et al., 2011; Wang et al., 2009). Interestingly, lipid metabolism is also emerging as a key regulator of stem cell maintenance and differentiation (Ito et al., 2012; Knobloch et al., 2013). A more in-depth analysis of the metabolism of stem cells is needed to clarify the circumstances under which the different components of respiration are utilized (Box 2).
It is worth noting that metabolic information obtained from cultured stem cells might not reflect the metabolism of stem cells in their natural niche for two main reasons (Joseph and Morrison, 2005). First, culture systems can differ quite dramatically from stem cell niches in terms of nutrient availability, cell–cell and cell–extracellular matrix contacts, and oxygen availability (Mohyeldin et al., 2010). These differences might be particularly significant for cells that are normally relatively quiescent, but are triggered to divide rapidly once they are exposed to growth factors in vitro, such as adult NSCs (Morshead et al., 1994). Second, stem cell cultures are often a heterogeneous mixture of stem cells, progenitors and differentiating cells. Future metabolic studies performed on small numbers of cells immediately after their isolation from tissue will aid our understanding of the metabolic profile of stem cells in vivo (Box 2).
Regardless of technical limitations, it is becoming increasingly clear that stem cells harbor different energy metabolism requirements compared with differentiating progeny. The unique metabolic properties of stem cells could be harnessed to facilitate the development of stem-cell-targeted therapies, in which stem cells are selectively directed to self-renew or differentiate by manipulating their metabolic state.
Oxygen availability directs metabolic and stem cell states
The dependency of stem cells on anaerobic glycolysis for energy production might be an adaptation to the low levels of oxygen that are present where these cells reside in vivo. For example, the uterus of rodents has particularly low levels of oxygen (3.5–5%) during the period of late blastocyst development and implantation (Fischer and Bavister, 1993), a period of intense stem cell proliferation. Adult HSCs and NSCs are also thought to reside in niches that are characterized by low oxygen levels (<1–6%) (Eliasson and Jönsson, 2010; Silver and Erecińska, 1998), and it is likely that most stem cell niches experience low oxygen although further investigation of other stem cell compartments is needed.
Accumulating evidence supports the idea that the fates of embryonic and adult stem cells are controlled by oxygen signaling (Mannello et al., 2011; Mohyeldin et al., 2010; Rafalski and Brunet, 2011; Suda et al., 2011). For example, lower levels of oxygen (3–5% compared with 20% atmospheric O2) promote human ESC self-renewal in vitro by preventing premature differentiation (Ezashi et al., 2005). Low oxygen concentrations (5%) also help the reprogramming of fibroblasts into iPSCs (Ezashi et al., 2005; Yoshida et al., 2009). In a similar manner, NSCs that are isolated from embryonic rodent or neonatal human brains show enhanced proliferation and reduced levels of cell death when cultured in low oxygen (Chen et al., 2007; Pistollato et al., 2007; Studer et al., 2000). Oxygen gradients in the niche might even help to direct stem cells to differentiate into specific cell lineages. Indeed, low oxygen (3–5%) can specify the fate of differentiating NSCs, promoting the production of dopaminergic neurons and oligodendrocytes (Pistollato et al., 2007; Studer et al., 2000).
The hypoxia-inducible transcription factors (HIF), which are stabilized and activated under low oxygen (<9% O2), are crucial for relaying the effect that oxygen has on stem cell fate. For example, HIF2α (also known as EPAS1) is necessary for mouse ESC self-renewal and the upregulation of pluripotency genes, such as Oct4 (Covello et al., 2006; Mathieu et al., 2011). Mice lacking HIF1α have substantial reductions in the number of HSCs in bone marrow transplantation assays and during normal aging (Takubo et al., 2010). The expression of Hif1α in HSCs is, in part, controlled by MEIS1, a transcription factor that is expressed in HSCs and downregulated during differentiation (Simsek et al., 2010), suggesting that HSCs are programmed to thrive under low oxygen. In a similar manner, HIF1 signaling is also important for normal mouse brain development (Tomita et al., 2003), and gene expression analyses comparing adult NSCs with differentiated neural cells indicate that adult NSCs have higher expression levels of Hif1a, emphasizing the importance of hypoxia signaling for NSCs (Bonnert et al., 2006; Ramalho-Santos et al., 2002).
Collectively, these studies suggest that low oxygen concentrations trigger alterations in HIF signaling, which, in turn, affects the metabolic and the 'stemness' networks of the cell, both of which might be linked by reciprocal amplification loops. Dissecting the interactions and feedback loops in this 'metabolic–stemness' network and understanding how it responds to external oxygen availability will be crucial in order to develop better methods to maintain stemness and enhance reprogramming.
Nutrient-sensing pathways coordinate energy metabolism with stem cell function
Nutrient-sensing signaling pathways orchestrate cellular and organismal metabolism in response to dietary changes. Accordingly, a number of these signaling pathways and molecules, including the insulin-forkhead box O factors (FOXO) pathway, mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and Sirtuins, have been implicated in the regulation of lifespan and healthspan (Greer and Brunet, 2008). This section reviews how nutrient-sensing pathways affect stem cell fate, thereby connecting energy metabolism with tissue regeneration and homeostasis.
The insulin–FOXO and mTOR pathways in stem cell quiescence and oxidative stress resistance
The insulin–FOXO pathway
The insulin–FOXO pathway regulates aging in a conserved manner from worms to mammals (Kenyon, 2010). Insulin and insulin growth factor 1 (IGF1) signaling leads to the phosphorylation of FOXO transcription factors (FOXOs) by the protein kinase AKT and serum-glucocorticoid regulated kinase (SGK) and the subsequent inactivation of these transcription factors by sequestration in the cytoplasm (Greer and Brunet, 2005). Conversely, FOXOs translocate to the nucleus when insulin and IGF1 signaling is reduced, that is, under conditions that lead to longevity. There are four FOXO family members in mammals (FOXO1, FOXO3, FOXO4, FOXO6). The isoform FOXO3 has been linked to exceptional longevity in several independent studies (Anselmi et al., 2009; Flachsbart et al., 2009; Pawlikowska et al., 2009; Willcox et al., 2008).
FOXOs have recently been shown to be essential for both adult and embryonic stem cells (Table 1). FOXO1, FOXO3 and FOXO4 are important for the long-term homeostasis of HSCs and NSCs in adult mice, as deletion of FOXO family members leads to the premature depletion of these adult stem cells (Miyamoto et al., 2007; Paik et al., 2009; Renault et al., 2009; Tothova et al., 2007; Yalcin et al., 2008). FOXO3, which is associated with exceptional human longevity, appears to be particularly important for the maintenance of HSCs and NSCs, as its deletion is sufficient to result in the depletion of HSCs and NSCs (Miyamoto et al., 2007; Paik et al., 2009; Renault et al., 2009; Tothova et al., 2007). FOXO1 is also crucial for the homeostasis of spermatogonial stem cells (SSCs) in adult mice (Goertz et al., 2011). Finally, FOXO1 has recently been found to be important for the pluripotency of both human and mouse ESCs (Zhang et al., 2011c), and FOXO4 upregulates proteasome activity, which is pivotal for human ESC pluripotency (Vilchez, et al., 2012). Although FOXO3 does not appear to control proteasome activity in human ESCs (Vilchez et al., 2012), it can regulate pluripotency in mouse ESCs (Zhang et al., 2011c). Thus, FOXO family members are important for the maintenance of adult stem cells and the pluripotency of ESCs, but the respective contribution of different FOXO isoforms can differ as a function of stem cell type.
In NSCs and HSCs, FOXOs act by maintaining stem cell quiescence (infrequent cell cycle entry), a key feature of adult stem cells (Fig. 2). In the absence of FOXOs, more committed progenitors overproliferate, thereby exhausting the pool of quiescent stem cells. FOXOs upregulate the expression of proteins that are involved in cell cycle arrest, including p27KIP1, p57KIP2 and cyclin G2 (encoded by Cdkn1b, Cdkn1c and Ccng2, respectively), which are likely to contribute to maintaining quiescence (Paik et al., 2009; Renault et al., 2009; Tothova et al., 2007). FOXOs also directly repress the expression of abnormal spindle-like microcephaly-associated protein (ASPM), which is required for proliferative divisions of neural stem and progenitor cells (Paik et al., 2009), an activity that can also promote NSC quiescence. Interestingly, although FOXOs tend to promote quiescence in stem cells, FOXO function in non-cycling, differentiated cell types, such as neurons, appears to be largely to promote apoptosis in response to cellular stress (Salih and Brunet, 2008).
Stem cell self-renewal is sensitive to oxidative stress (Ito et al., 2004) and FOXOs help maintain stem cells by preventing the accumulation of ROS, which can disrupt genomic and protein integrity. Indeed, some, but not all, of the consequences of FOXO loss on the HSC and NSC compartments can be rescued by the antioxidant N-acetyl cysteine (NAC) (Paik et al., 2009; Tothova et al., 2007; Yalcin et al., 2010). FOXOs are known to regulate several genes involved in the resistance to oxidative stress in many cell types (Dansen and Burgering, 2008). This activity not only helps to preserve the stem cell pool, but is also likely to minimize the incorporation of abnormal stem cell progeny into tissues and to avoid the transition from stem cell to cancer cell.
Interestingly, in NSCs, FOXO3 also regulates the expression of genes that are involved in hypoxia signaling (e.g. Ddit4, a known target of HIF1) (Renault et al., 2009). Accordingly, the pro-proliferative response of FOXO3-deficient NSCs to low oxygen (2%) is impaired in vitro (Renault et al., 2009). Like HIF1, FOXO3 regulates genes that are part of a 'molecular signature' for glycolysis and fructose metabolism (Renault et al., 2009). It is also worth noting that the phenotypes of FOXO3-deficient and HIF1-deficient HSCs are similar, particularly in terms of loss of cellular quiescence and premature depletion of the HSC pool (Miyamoto et al., 2007; Takubo et al., 2010). Together, these observations argue for a network of overlapping nutrient-sensing (through FOXO3) and oxygen-sensing (through HIF1) signaling.
Finally, in human ESCs, FOXO1 appears to regulate the expression of two crucial transcription factors for the stemness program, OCT4 and SOX2 (Zhang et al., 2011c). These data suggest that FOXO transcription factors are part of a transcriptional network that connects energy metabolism and ROS responses with the stem cell properties of self-renewal and potency.
An essential component of cellular and organismal metabolism in mammals is the protein kinase mTOR. mTOR is activated by amino acids or the phosphatidylinositol 3-kinase (PI3K)–AKT pathway and is part of two distinct complexes, mTORC1 and mTORC2, which coordinate cell growth, proliferation and survival (Laplante and Sabatini, 2012) (Fig. 2). At the organismal level, mTOR is involved in energy metabolism regulation, cancer and aging (Kapahi et al., 2010; Laplante and Sabatini, 2012). For example, blocking mTOR activity with the pharmacological drug rapamycin can extend the lifespan of mice (Harrison et al., 2009).
Multiple recent studies have revealed vital, yet different, roles for mTOR signaling in ESCs and adult tissue-specific stem cells (Table 1). In ESCs, mTOR is important for self-renewal; inhibition of mTOR by rapamycin or by knockdown in mouse and human ESCs reduces the expression of pluripotency markers and impairs the self-renewal of ESCs in vitro (Schieke et al., 2008; Zhou et al., 2009). Furthermore, deletion of mTOR inhibits proliferation in early mouse embryos (Murakami et al., 2004). Somewhat surprisingly, mTOR also appears to promote ESC differentiation. For example, the transition from ESCs to more differentiated cell types is associated with increased activation of mTORC1 signaling (Easley et al., 2010; Sampath et al., 2008). Furthermore, overexpression of a constitutively active form of S6 kinase 1, a substrate of mTORC1, promotes differentiation of ESCs (Easley et al., 2010). It will be important to understand the circumstances under which TOR promotes either ESC self-renewal and pluripotency or differentiation, and whether different mTOR substrates are involved in mediating these diverse functions of mTOR.
In contrast to ESCs, in which mTOR activity is necessary for self-renewal, adult stem cell self-renewal might actually benefit from reduced levels of mTOR signaling, perhaps because adult stem cells are relatively quiescent. Deletion of tuberous sclerosis protein 1 (TSC1), a negative regulator of mTORC1, leads to overproliferation of HSCs as well as defects in multilineage differentiation and the capacity for bone marrow reconstitution (Chen et al., 2008). Consistently, treatment of old mice with the mTORC1 inhibitor rapamycin confers 'youthful' phenotypes to old HSCs and improves the function of their immune system (Chen et al., 2009). Because mTOR signaling increases dramatically in HSCs with age (Chen et al., 2009), mTOR might be a primary effector of HSC aging, although it remains unknown what causes this age-dependent increase in mTOR signaling in this stem cell compartment. The observation that maintaining lower mTOR activity prevents adult stem cell exhaustion is not limited to HSCs. In the mouse epidermis, mTOR activation by chronic Wnt signaling leads to a premature depletion of epidermal stem cells, which manifests itself as premature loss of hair (Castilho et al., 2009). Although maintaining lower TOR activity is beneficial for adult stem cells, a complete loss of mTOR activity is detrimental. Indeed, deletion of Raptor, a key component of the mTORC1 complex, leads to defects in HSC function upon transplantation (Kalaitzidis et al., 2012). Finally, although mTOR appears to affect stem cells mostly by acting in a cell-autonomous manner (Kalaitzidis et al., 2012; Magri et al., 2011), it can also influence adult stem cells (e.g. intestinal stem cells) in a non-cell-autonomous manner by acting on the stem cell niche (Yilmaz et al., 2012).
How does mTOR hyper- or hypoactivation affect stem cell metabolism? mTOR hyperactivation is associated with increased numbers of mitochondria and higher ROS levels in adult HSCs (Chen et al., 2008). Lowering ROS levels by treatment with the antioxidant NAC partially rescues these HSC defects (Chen et al., 2008), which are reminiscent of HSC phenotypes that lack FOXOs (Tothova et al., 2007). Hypoactivation of mTOR owing to loss of Raptor is associated with changes in metabolism, in particular, the lipid and cholesterol metabolism in HSCs (Kalaitzidis et al., 2012). The relative contributions of mTOR targets, such as ribosomal S6 protein kinase 1 (S6K1, also known as RPS6KB1), eukaryotic translation initiation factor 4E-binding protein 1 [(4E-BP1), also known as EIF4EBP1] and SGK1 (Fig. 2), to these metabolic phenotypes in stem cells remain to be determined.
Together, these studies highlight that mTOR signaling is essential for ESC growth and proliferation, yet excessive mTOR activation can be ultimately detrimental for adult stem cell pools and lead to early aging phenotypes. Both mTOR and FOXO are downstream mediators of insulin signaling, which leads to mTOR activation and inhibition of FOXOs. Consistently, FOXOs and mTOR have largely antagonistic functions in stem cells; FOXOs promote the maintenance of stem cells in adulthood and help minimize oxidative stress, whereas overactive mTOR signaling leads to premature stem cell depletion and accumulation of oxidative stress. Collectively, these observations support the idea that a certain degree of cellular quiescence is required to preserve the pool of adult stem cells (Kippin et al., 2005; Morshead et al., 1994). Although stem cell populations are considered 'immortal', there might be a limit in the number of times a stem cell can undergo cell division before losing its self-renewal capacity in vivo. These findings also support the idea that high levels of oxidative stress contribute to stem cell dysfunction. Minimizing oxidative damage is likely to be more important in stem cells than in differentiated cells, as stem cells give rise to daughter stem cells and therefore must maintain overall cellular integrity, including genomic, protein and organelle content in order to ensure normal tissue function and avoid tumor development.
AMPK in stem cell mitosis and mitochondrial homeostasis
AMPK is a central 'fuel gauge' that is activated by a wide range of stimuli, including low energy or cellular stress. AMPK becomes active when intracellular levels of AMP or ADP are higher than that of ATP, and its activation requires the presence of one of several upstream kinases, including the tumor suppressor liver kinase B1 (LKB1, also known as STK11) and Ca2+-calmodulin-dependent protein kinase kinase β (CAMKKβ) (Kahn et al., 2005) (Fig. 2). AMPK switches off energy-consuming pathways and triggers energy-producing pathways by phosphorylating many substrates that are involved in glucose and lipid metabolism, autophagy and mitophagy, transcription, and cell cycle regulation (Banko et al., 2011; Mihaylova and Shaw, 2011). AMPK has been shown to be crucial for longevity (Greer et al., 2007; Mair et al., 2011), the prevention of type II diabetes (Li et al., 2011) and tumor suppression (Shaw et al., 2004).
Although the importance of AMPK in stem cells has not yet been extensively studied, it is known that AMPK functions in adult HSCs to influence mitochondrial homeostasis. HSCs that lack both catalytic α-subunits of AMPK have decreased levels of ATP and mitochondrial DNA (Nakada et al., 2010). Numbers of HSCs in the bone marrow are substantially reduced several months after AMPK activity is abrogated (Nakada et al., 2010), suggesting that the regulation of mitochondrial homeostasis by AMPK contributes to the control of HSC proliferation. However, AMPK activity is not necessary for HSCs to reconstitute the blood in bone marrow transplantation assays (Nakada et al., 2010). Furthermore, AMPK does not appear to mediate the majority of the actions of its upstream regulator LKB1 in the maintenance of HSCs, suggesting that AMPK-related kinases are important for the function of LKB1 in this context (Gan et al., 2010; Gurumurthy et al., 2010; Nakada et al., 2010). Given that AMPK activity relies on a high ratio between [AMP] and [ATP], the functional relevance of the observed AMPK-dependent phenotypes might depend on the nutrient status of the organism.
AMPK can also regulate stem cell mitosis in the nervous system. For example, in the developing mouse brain, abrogating normal AMPK activity leads to defective mitosis of neural progenitor cells and abnormal brain development (Dasgupta and Milbrandt, 2009). This possible effect is consistent with the recent identification of a role for AMPK substrates in mitosis (Banko et al., 2011). Because AMPK is active under low energy conditions, it appears counterintuitive that it promotes stem cell proliferation given the high-energy demands of cellular division. It is possible that under low energy conditions, AMPK activity ensures the completion of mitosis, because cell cycle arrest at this stage could have disastrous consequences for the genomic stability of a cell. Much still remains to be determined with regard to the roles of AMPK in stem cells, the metabolic conditions under which it is most important, and the substrates that mediate its actions in stem cells.
SIRT1 in the proliferation, differentiation and genomic integrity of stem cells
The protein deacetylase Sirtuin 1 (SIRT1) is one of seven mammalian Class III deacetylases (also called Sirtuins) that become active when the ratio between [NAD+] and [NADH] is high, a state associated with low energy as well as oxidative stress (Imai and Guarente, 2010; Webster et al., 2012). SIRT1 is the Sirtuin with the greatest homology to the yeast Sir2 deacetylase, which is known to extend the replicative lifespan of yeast (Kaeberlein et al., 1999). In mammals, SIRT1 is a crucial regulator of cellular and organismal metabolism (Yu and Auwerx, 2009), improves various markers of health (Bordone et al., 2007; Herranz et al., 2010), provides neuroprotection in a variety of neurodegenerative diseases (Zhang et al., 2011a), and has also been shown to have tumor-suppressive functions in some, but not all, contexts (Fang and Nicholl, 2011).
The effects of SIRT1 perturbation are not identical in all stem cells (Table 1). SIRT1 is highly expressed in human and mouse ESCs, and its expression declines during multilineage differentiation, suggesting that SIRT1 has a more important function in ESCs than in differentiated progeny (Calvanese et al., 2010; Saunders et al., 2010). Yet, under basal conditions, mouse ESCs that lack SIRT1 show no obvious defects (McBurney et al., 2003). However, exposure to mild oxidative stress activates SIRT1 to both promote apoptosis (Chae and Broxmeyer, 2011; Han et al., 2008) and minimize the accumulation of chromosomal abnormalities in mouse ESCs (Oberdoerffer et al., 2008). Together, these studies indicate that SIRT1 carries out anti-tumorigenic activities by regulating nuclear translocation of FOXO and p53, as well as promoting the repair of DNA damage. These findings contrast with previously demonstrated roles for SIRT1 in preventing apoptosis in response to oxidative stress in mouse embryonic fibroblasts, cerebellar granule neurons and human cancer cell lines (Brunet et al., 2004; Motta et al., 2004). It is possible that the ability of SIRT1 to induce or prevent apoptosis depends on the amount and source of oxidative stress present, or the specific cell type (stem versus differentiated).
The function of SIRT1 in HSCs is also age and context-specific. In vitro differentiation of mouse ESCs into the hematopoietic lineage is defective in the absence of SIRT1 (Ou et al., 2011), yet adult mice lacking SIRT1 display virtually normal hematopoiesis (Leko et al., 2012; Narala et al., 2008). It is possible that other histone deacetylases compensate for loss of SIRT1 in adulthood, allowing the blood constituents to form properly after development, even in the absence of SIRT1. Intriguingly, HSC maintenance in old mice is not affected by the deletion of SIRT1 despite increased proliferation levels, suggesting that HSC self-renewal can be maintained in the absence of SIRT1 (Leko et al., 2012; Narala et al., 2008). The mechanisms and specific substrates (histones or non-histone proteins) underlying the ability of SIRT1 to either inhibit or promote the expansion of a cell population in the blood lineage remain to be elucidated.
SIRT1 activity is highly responsive to changes in oxidative state given its dependence on a high [NAD+] to [NADH] ratio, and this has large implications for stem cell fate under varying oxidative conditions. For example, SIRT1 promotes proliferation of adult rat muscle stem cells (Rathbone et al., 2009) and represses their differentiation into myocytes (Fulco et al., 2008; Fulco et al., 2003). Indeed, a reduction in [NAD+]:[NADH], a state inhibitory for SIRT1 activity, is associated with mouse muscle cell differentiation and, by this means, is likely to relieve SIRT1-mediated repression of genes that promote muscle differentiation and maturation (Fulco et al., 2003). In addition, under oxidative conditions, SIRT1 skews the fate of embryonic neural progenitors towards astrocytes at the expense of neurons by repressing transcription of the proneural transcription factor ASCL1 (also known as MASH1) (Prozorovski et al., 2008). Such an activity might be relevant in neurodegenerative conditions that are associated with high levels of oxidative stress, such as amyotrophic lateral sclerosis (ALS), Parkinson's Disease and Alzheimer's Disease (Emerit et al., 2004).
Interestingly, pathways that respond to nutrient availability, such as those involving insulin–FOXO, mTOR, SIRT1 and AMPK, interact with each other and with other factors that are involved in metabolic regulation, forming a 'signaling and metabolic network' (Fig. 2). For example, FOXO and the oxygen-sensor HIF1 share common target genes (Renault et al., 2009), and HIF1 translation is regulated by mTOR (Wouters and Koritzinsky, 2008). Additionally, AMPK can activate SIRT1 by upregulating the biosynthesis of NAD+ (Cantó and Auwerx, 2009; Cantó et al., 2009; Cantó et al., 2010; Price et al., 2012). These studies raise the intriguing question of how the activity of metabolic regulators is altered by their interactions with niche constituents, such as oxygen concentration and secreted signaling molecules. Finally, given that FOXO, mTOR, SIRT1 and AMPK all have important functions in the metabolic homeostasis of the whole organism (Gross et al., 2008; Hardie et al., 2012; Laplante and Sabatini, 2012; Satoh et al., 2011), it remains to be explored how the regulation of organismal metabolism by these energy-responsive molecules can have non-cell-autonomous effects on stem cells.
Metabolic regulators in somatic cell reprogramming
The identification of important roles for metabolic regulators, such as FOXOs, mTOR, AMPK and SIRT1, in affecting stem cell fate has motivated the investigation of their influence on the transition from differentiated cell into iPSCs. One could expect that experimental manipulations that promote ESC self-renewal and pluripotency would also enhance reprogramming into iPSCs. However, despite the fact that mTOR is important for maintaining ESC pluripotency and proliferation (Table 1), mTOR inhibitors actually positively affect cell reprogramming (Chen et al., 2011). Conversely, elevating mTOR activity inhibits reprogramming of differentiated cells into iPSCs (He et al., 2012). What are the molecular mechanisms by which mTOR activity regulates cellular reprogramming? Because mTOR is necessary for mitochondrial oxidative function (Cunningham et al., 2007), it is probable that excessive mTOR activity inhibits reprogramming by preventing the switch to a glycolytic metabolism (Menendez et al., 2011). Surprisingly, even though mTOR and AMPK usually act antagonistically, activation of AMPK by metformin or its specific activator A-769662 also represses cellular reprogramming (Vazquez-Martin et al., 2012), potentially by shifting metabolic dependence towards oxidative phosphorylation. These studies contribute to the emerging idea that metabolic state, in particular, the balance between glycolysis and oxidative phosphorylation, crucially impacts the establishment of stem cell characteristics. However, it is still unclear why the activation of either AMPK or mTOR has similar effects on reprogramming, given the normally antagonistic role of these two pathways. More consistent with such opposing functions of mTOR and AMPK, it has been shown that resveratol and fisetin, two compounds known to activate Sirtuins and the AMPK pathway, among other pathways, increase the reprogramming efficiency of mouse embryonic fibroblasts sixfold (Chen et al., 2011), although the mechanism underlying this enhanced reprogramming remains unclear. It is possible that mTOR, AMPK and SIRT1 contribute both to the metabolic changes that occur in the transition between a differentiated cell and a stem cell, and to stem cell properties per se. Thus, understanding the function of these pathways in cellular reprogramming will require more detailed metabolic, gene expression, chromatin and proteomic analyses over the reprogramming time course.
Concluding remarks: implications of fluctuations in organismal metabolism for stem cells
The numerous observations that stem cell properties are affected by energy-responsive molecules and signaling pathways raise questions about the fate of stem cells under conditions when metabolic homeostasis is perturbed (Fig. 3). Studies suggest that abnormal endocrine signaling in organisms with extreme metabolic states has a substantial impact on proliferation and differentiation of multiple stem cell populations throughout the body (Fig. 3). It is also possible that variations in metabolism during gestation could contribute to observable phenotypes in offspring through their effects on stem cells. For example, low energy levels and the associated hormonal signals that occur in the pregnant mother could be directly transmitted to the offspring through the placenta, resulting in transient or permanent changes to stem cells in the embryo (Fig. 3). Further exploration into how stem cells are affected by systemic metabolic states might reveal exciting new roles for metabolism during development, and might also help explain complex diseases and phenotypes, such as obesity, diabetes and aging.
Box 1. Induced pluripotent stem cells and reprogramming
In a landmark, Nobel prize-winning study, Takahashi and Yamanaka showed that the introduction of four transcriptional regulators (Oct4, Sox2, Klf4, Myc) was sufficient to convert mouse differentiated cells into ESC-like cells (Takahashi and Yamanaka, 2006). This cellular reprogramming was subsequently demonstrated in human cells (Takahashi et al., 2007; Yu et al., 2007). These pluripotent and self-renewing cells, termed induced pluripotent stem cells (iPSCs) appear to have most of the cellular and molecular properties of bona fide ESCs. Like ESCs, iPSCs are able to differentiate into all three germ layers (endoderm, mesoderm and ectoderm). When injected into a blastocyst, mouse iPSCs can produce viable chimeras that contribute to germline production (Okita et al., 2007). In the past few years, great strides have been made in generating iPSCs from a variety of mouse and human differentiated cell types using different combinations of reprogramming factors, chemicals and delivery methods (Feng et al., 2009; Wang and Na, 2011). Importantly, iPSCs have been derived from patients that are affected by various diseases (Grskovic et al., 2011), leading to patient-specific in vitro disease modeling. Patient-derived iPSCs facilitate the exploration of the genetic and molecular bases of human diseases and enable in vitro drug screening for these diseases. iPSCs also have benefits over ESCs for therapeutic applications, including eliminating the possibility of graft-versus-host disease and avoiding ethical concerns of human embryo-derived cells.
Box 2. Technologies enabling studies of stem cell metabolism
The comprehensive identification of potentially new metabolic states in stem cells will require unbiased methods. Advances in detection technologies, together with a developing excitement for understanding how metabolic state can influence cellular properties, has enabled the unbiased profiling of large numbers of metabolites in a single experiment, a field of study termed metabolomics. Metabolites are typically profiled by using liquid chromatography coupled with mass spectrometry or by using nuclear magnetic resonance. Emerging studies suggest that metabolomics studies can be performed on small numbers of cells (or even single cells) directly after their isolation and purification from tissue using fluorescence-activated cell sorting (FACS) methods (Rubakhin et al., 2011), which will aid our understanding of the metabolite profile of stem cells in vivo. Metabolic profiling of pluripotent stem cells has already determined that a bias towards a glycolytic metabolism is conducive to the acquisition of a pluripotency state (Folmes et al., 2011; Panopoulos et al., 2012). It has also been demonstrated that mouse ESCs possess more unsaturated molecules (containing double- and triple-bonded carbons) than differentiated cell types (Yanes et al., 2010). Specific unsaturated signaling molecules, such as the lipid second messengers arachidonic acid and diacylglyercol, appear to be crucial for ESC properties and subsequent multilineage differentiation (Yanes et al., 2010). Performing these types of metabolomic studies in additional contexts, for example, in adult stem cells, should allow the unbiased identification of 'metabolic signatures' of stem versus differentiated cells. Such metabolic signatures could then be coupled with other types of signatures (e.g. transcriptional or epigenetic signatures) to help to truly define 'stemness'. Another technique called multi-isotope imaging mass spectrometry should also aid the characterization of stem cell metabolism through the high-resolution tracking of heavy isotope-labeled molecules as they are being utilized by the cell (Steinhauser et al., 2012). Knowing the differences in metabolic profiles as a function of stem cell type or external stimuli will be a key step in determining how metabolic properties of stem cells, in particular adult stem cells, are connected to quiescence and proliferation, differentiation potential and age-related changes (Rando, 2006).
This work is supported by a National Institute on Aging grant [grant number P01 AG036695 to A.B.]; a California Institute for Regenerative Medicine New Faculty Award; an Ellison Medical Foundation Senior Scholar Award; the Glenn Foundation for Medical Research (to A.B.); a National Institute of Neurological Disorders and Stroke (NINDS) Graduate Fellowship [grant number 5F31NS064600 to V.A.R.]; and a Stanford University Dean's Post-doctoral Fellowship (to E.M.). Deposited in PMC for release after 12 months.
- © 2012. Published by The Company of Biologists Ltd


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ML4000 Documents
Download brochures, user guides and other documents for this product.
ImportantAllen & Heath + macOS Catalina
The correct operation of this product with macOS Catalina is not yet verified by our development and test departments. As a result, macOS Catalina is not currently supported.
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This software controls the console internal computer. The same software works with both the ML3000, ML4000 and ML5000 consoles and sidecars. Hardware links on the console cpu board automatically determine the console type. The software is loaded into the console through its RS232 port. Make sure you update both the console and any sidecars to run the same version.
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MIGDAL HAEMEK, Israel, May 09, 2016 (GLOBE NEWSWIRE) -- TowerJazz (NASDAQ:TSEM) (TASE:TSEM) today reported results for the first quarter of 2016 ended March 31, 2016.
2016 First Quarter Financial Highlights
- Record revenues of $278 million, representing 23% year over year growth and 9% quarter over quarter growth;
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- Completed San Antonito fab acquisition from Maxim in February 2016;
- Strong second quarter revenue guidance with mid-range of $300 million, representing 27% year over year and 8% quarter over quarter growth.
2016 First Quarter Results Overview
Revenues for the 2016 first quarter were a record $278 million, reflecting 23% growth as compared with the first quarter of 2015 and 9% higher than the previous quarter.
Gross profit for the first quarter of 2016 was $61 million as compared with $33 million gross profit in the first quarter of 2015, and with $65 million gross profit in the immediately preceding quarter. Operating profit was $31 million for the first quarter of 2016, as compared with $2 million reported in the first quarter of 2015 and $34 million operating profit in the immediately preceding quarter. EBITDA for the first quarter totaled $78 million. This represents a 51% increase as compared with $51 million EBITDA in the first quarter of 2015 and represents an increase from $76 million EBITDA in the immediately preceding quarter.
Net profit for the first quarter of 2016 was $66 million, or $0.78 in basic earnings per share, as compared with $22 million or $0.28 per share in the immediately preceding quarter and compared with a loss of $73 million or $1.15 basic loss per share in the first quarter of 2015, which was primarily due to non-cash financing expenses resulting from the successful accelerated conversion of Series F debenture.
The $66 million net profit recorded for the first quarter of 2016 includes $41 million net gain from acquisition. The gain from acquisition, net is a result of the fair value assigned to the assets and liabilities of the San Antonio fab, which are provisional. Based on ASC-805 "Business Combinations", we are required to reflect the purchase price allocation immediately following acquisition date and complete it in a period not exceeding one year. The fair value of the assets acquired, net of liabilities, in the amount of $81 million, exceeded the $40 million purchase price by $41 million, thereby creating a net gain from acquisition. In accordance with GAAP, the final valuation values may vary from the provisional valuation performed during the first quarter of 2016, which could result in adjustments to the net acquisition gain, to be recorded during 2016, if any. Net profit for the quarter, excluding the net gain from acquisition is $25 million, representing 12% quarter over quarter increase.
The Company also provides financial information in this release, which it refers to as "adjusted financial measures" and is described and reconciled in the tables below, such as adjusted net profit for the first quarter of 2016 which was $32 million, as compared with adjusted net profit of $26 million in the immediately preceding quarter and $8 million adjusted net loss for the first quarter of 2015.
Cash and short-term deposits balance as of March 31, 2016 was $245 million, as compared with $206 million as of December 31, 2015. During the first quarter of 2016, the Company generated $77 million cash from operations (or $81 million excluding interest payment) and invested $57 million in fixed assets, resulting in $20 million positive free cash flow, which includes $15 million of customer prepayment used for capacity expansion.
Shareholders' equity as of March 31, 2016 was $504 million, an increase of 73% as compared with $292 million as of March 31, 2015 and an increase of 31% as compared with $386 million as of December 31, 2015. Net debt amounted to $65 million as of March 31, 2016, as compared with net debt of $162 million as of March 31, 2015 and $105 million as of December 31, 2015.
Business Outlook
TowerJazz expects revenues for the second quarter of 2016 ending June 30, 2016 to be $300 million, with an upward or downward range of 5%, representing approximately 27% year over year revenue growth as compared with the second quarter of 2015 and 8% growth as compared with the first quarter of 2016.
CEO Comments
Mr. Russell Ellwanger, Chief Executive Officer of TowerJazz, commented, "We are pleased with our first quarter financial results; continued revenue and EBITDA growth above previous records. During the quarter, we completed the acquisition of the San Antonio factory, a key strategic move, increasing our business relationship with Maxim while providing additional capacity in close proximity to our large US customer base. We have already qualified and taped-out multiple RF flows for key customers that will provide revenues in the fourth quarter this year and a strong ramp through 2017."
Ellwanger concluded, "Based upon customers' demand, organic capacity increases and strong assurance of revenue growth within our Japanese factories, we expect significant performance in 2016, top and bottom lines."
Debt Refinancing
During 2015, the Company reduced its net debt from $318 million to $105 million. The Company is currently exploring opportunities to replace its existing Israeli banks' facility agreements totaling $78 million with a new series of long term un-secured straight bonds which would further strengthen its balance sheet and provide better financial and business flexibility by removing the bank contract's extensive restrictions and covenants. For this purpose, the Company is filing a shelf prospectus to replace its recently expired 2013 shelf prospectus and is targeting to issue long term straight bonds, for which it recently received an "A" rating from Standard & Poor's Maalot (a rating company which is fully owned by S&P Global Ratings). The long term bonds would be non-convertible, un-secured and enable the Company greater financial and business flexibility. The documentation to this extent will be filed subject to the prospectus approval process by the Tel Aviv Stock Exchange and the Israeli Securities Authority.
Teleconference and Webcast
TowerJazz will host an investor conference call today, May 09, 2016, at 10:00 a.m. Eastern time (9:00 a.m. Central time, 8:00 a.m. Mountain time, 7:00 a.m. Pacific time and 5:00 p.m. Israel time) to discuss the Company's financial results for the first quarter 2016 and its second quarter 2016 outlook.
This call will be webcast and can be accessed via TowerJazz's website at www.towerjazz.com, or by calling: 1-888-407-2553 (U.S. Toll-Free), 03-918-0610 (Israel), +972-3-918-0610 (International). For those who are not available to listen to the live broadcast, the call will be archived for 90 days.
The Company presents its financial statements in accordance with U.S. GAAP. Some of the financial information in this release, including in the financial tables below, which we refer to in this release as "adjusted financial measures" are non-GAAP financial measures as defined in Regulation G and related reporting requirements promulgated by the Securities and Exchange Commission as they apply to our Company. These adjusted financial measures are calculated excluding one or more of the following: (1) amortization of acquired intangible assets; (2) compensation expenses in respect of equity grants to directors, officers and employees; (3) gain from acquisition, net, (4) other non-cash financing expense, net associated with Bonds Series F accelerated conversion; and (5) other non-recurring items such as acquisition related costs, non-recurring tax items and Nishiwaki Fab restructuring costs and impairment. These adjusted financial measures should be evaluated in conjunction with, and are not a substitute for, GAAP financial measures. The tables also present the GAAP financial measures, which are most comparable to the adjusted financial measures as well as reconciliation between the adjusted financial measures and the comparable GAAP financial measures. As used in this release, the term Earnings Before Interest Tax Depreciation and Amortization (EBITDA) consists of profit or loss, according to U.S. GAAP, excluding Nishiwaki Fab restructuring costs and impairment, gain from acquisition, net, acquisition related costs, interest and other financing expenses (net), taxes, non-controlling interest, depreciation and amortization and stock based compensation expenses. EBITDA is reconciled in the tables below from GAAP operating profit. EBITDA is not a required GAAP financial measure and may not be comparable to a similarly titled measure employed by other companies . EBITDA and the adjusted financial information presented herein should not be considered in isolation or as a substitute for operating profit, net profit or loss, cash flows provided by operating, investing and financing activities, per share data or other profit or cash flow statement data prepared in accordance with GAAP. Net debt, as presented in this release, is comprised of the outstanding principal amount of banks' loans (in the amounts of approximately $245 million, $246 million and $192 million as of March 31, 2016, December 31, 2015 and March 31, 2015respectively) and the outstanding principal amount of debentures (in the amounts of approximately $65 million, $65 million, and $104 million as of March 31, 2016, December 31, 2015 and March 31, 2015, respectively), less cash and deposits (in the amounts of approximately $245 million, $206 million, and $134 million as of March 31, 2016, December 31, 2015 and March 31, 2015, respectively).


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It's 'Footloose' meets 'Mean Girls' as high school freshman Bloom moves to a town where there's no place to dance – except the school dance team! But when the boyfriend of the team's lead girl falls for her, she'll have to fight to win her place amongst these venomous girls. Breaking Legs is sure one to kick your boots off and pull up your heels, as these kids dance the field away to compete for the homecoming crown at R. Murray High School. Will it be newbie Bloom, or her arch nemesis and Dance Team leader, Harmony? Watch as the two square off in this fun but odd match to the finish. Someone is doomed to 'Break a Leg' on the dance floor, or rather, the football field!
Watch Breaking Legs (2017) Online
- Director: Mark Marchillo
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What happened
Shares of The Finish Line Inc. (NASDAQ:FINL) climbed as much as 14% early Monday, then settled to trade up around 6.3% as of 2 p.m. EDT. Susquehanna analyst Sam Poser reiterated his argument that the athletic footwear retailer will be acquired.
More specifically, Poser says that while The Finish Line is still facing a number of fundamental headwinds, there's still a 75% chance that U.K.-based Sports Direct International (LSE:FRAS) will purchase the company to propel itself into the United States market. Poser also reiterated his $12-per-share price target on The Finish Line stock -- a roughly 23% premium to Friday's closing price -- and predicted a buyout could happen at $13.30 per share. Poser also noted that at current prices, the market seems to be assuming a roughly 30% chance that a buyout will occur.
So what
For perspective, Poser's call arrives on the heels of Finish Line's somewhat encouraging fiscal second-quarter results on Friday, which left shares up modestly at the end of last week; the company's earnings arrived at the high end of its latest financial guidance.
To be fair, that guidance was drastically reduced when Finish Line announced preliminary results in late August, causing shares to plunge almost 20% in a single day. At that time Finish Line also adopted a new shareholder-rights plan, or so-called "poison pill," to stave off any potential unfriendly takeovers -- something that Poser speculated was directly related to Sports Direct's 8% stake in the company.
Now what
To Poser's credit, now would seem like a perfect opportunity for Sports Direct to make its move. During last week's formal earnings announcement, Finish Line CEO Sam Sato said that his company endured a "very promotional marketplace for athletic footwear" during the quarter, and warned that they're "planning for a challenging retail environment in the near term."
But Sato also stated that Finish Line would focus on managing expenses and inventories as long as these near-term challenges persist, and insisted the company is well positioned to "deliver increased shareholder value over the long term." So it seems Finish Line is content to ride out this storm without selling out to an international suitor.
That's not to say it won't happen, as there's always a chance Sports Direct will make an offer that Finish Line shareholders simply can't refuse. But I think investors should be careful about placing too much weight on a buyout as a central part of their thesis for owning Finish Line stock.


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Why You Should No Longer Worry About Cholesterol in Food
Food contains cholesterol, yes. But here is why you no longer need to worry about high-cholesterol foods.
For years, we've been told to avoid high-cholesterol foods for heart health, but those days may be coming to an end.
Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy
A top nutrition advisory committee says people no longer have to be concerned about eating foods that are high in cholesterol. The committee's report, which was released today, will help shape the next version of the U.S. Dietary Guidelines, set to be released later this year.
High levels of "bad" cholesterol in the blood, which have been linked to heart disease, are still a health concern. What's changed is that many researchers and physicians now believe that eating cholesterol-rich foods such as eggs may not affect the cholesterol that is in your blood.
However, people with certain health problems, such as diabetes, should continue to avoid cholesterol-rich foods, the report says.
Cholesterol is a waxy substance that ultimately ends up in the walls of arteries. It causes the plaques that lead to heart attacks and strokes. The current U.S. Dietary Guidelines call for a daily cholesterol limit of 300 milligrams.
Researchers are beginning to understand in greater depth that the relationship between cholesterol and the body is extremely complicated.
Research is beginning to show that your genetic makeup – not diet – is the driving force behind cholesterol levels, says cardiologist Steven Nissen, MD.
The body creates cholesterol in amounts much larger than what you can eat, Dr. Nissen says. So avoiding foods that are high in cholesterol won't affect your blood cholesterol levels very much.
"About 85 percent of the cholesterol in the circulation is manufactured by the body in the liver," he says. "It isn't coming directly from the cholesterol that you eat."
The greater danger for everyone is in foods that are high in trans fats, Dr. Nissen says.
"Those often appear on food labels as hydrogenated oils or partially hydrogenated vegetable oil," Dr. Nissen says. "Those types of fats do tend to raise cholesterol and do tend to increase the risk of heart disease."
The new U.S. Dietary Guidelines are expected to be announced later this year.
More information


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The Apprenticeship Council of Ireland together with the Department of Education & Skills in association with Solas have launched a new call for industry led proposals to meet new growing demands for skills across several industry sectors.
Proposals which can be between 2-4 years in duration will provide QQI qualifications from Levels 5-10 thus delivering real meaningful qualifications to apprentices matched with on the job real life learning. Flexible delivery of all learning modules is permitted and apprentices will be employed by industry throughout the duration of their apprenticeship. This 2017 call presents an opportunity for collaboration between industry sectors and educational providers to ensure a strong pipeline of talent continues to service a growing Labour market. Further information on Generation Apprenticeship 2017 is available here


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Experience a charming and authentic hotel in Montpellier just minutes from the old town.
Soak up the sophisticated atmosphere of a 19th century mansion where the age-old elegance meets modern comfort.
Hôtel des Arceaux in the centre of Montpellier has 18 tastefully renovated rooms and a charming shady garden providing a peaceful haven in the heart of the city.
Guests are provided with free Wi-Fi and private car park (on booking).
There are just 3 stations and 5 minutes between the tram stop 150m from the hotel in Montpellier and Place de la Comédie and the station.


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Dallas Willard on Cussing
Recently cultural observers have noted the overwhelming rise in the use of filthy language, especially among young people. Curiously, few have been able to find any grounds for condemning it other than personal taste. How strange! Can it be that they actually find contempt acceptable, or are unable to recognize it? Filthy language and name calling is always an expression of contempt. The current swarm of filthy language floats upon the sea of contempt in which our society is now adrift.


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How to take control of data hacking from Public Wi-Fi?-Gaining admittance to the open Wi-fi in eateries, bistros or lodgings can leave your significant data to open to the spyware and information burglary. Here how you can rehearse cybersecurity on open Wi-Fi. Tips to contemplate while you think to secure your information... Read More
What leads to the upsurge of online scams in Singapore?-norton.com/setup
Online scams are still trending in Singapore even after the fall in cyber threats.(www.norton.com/setup) What leads to the upsurge of online scams in Singapore?-As we as a whole realize that individuals of Singapore saw fewer instances of online tricks during a previous couple of years, yet it isn't the situation now. As... Read More
Protect your online identity with Dark Web Monitoring-norton.com/setup
Protect your online identity with Dark Web Monitoring-norton.com/setup Protect your online identity with Dark Web Monitoring-www.norton.com/setup- The dull web is a shrouded stage in the darker back streets of the Internet where cybercriminals used to exchange stolen data without anybody keeping an eye on them. At... Read More
How formjacking is affecting online buyers?-norton.com/setup
How formjacking is affecting online buyers? (www.norton.com/setup)- Have you at any point known about "formjacking"? In the event that not, at that point this article may assist you with having bits of knowledge into this type of digital wrongdoing and furthermore the approaches to remain shielded from this. This term is... Read More
How to establish a secured network with Norton Core?-norton.com/setup
How to establish a secured network with Norton Core?-norton.com/setupWith Norton Core Wi-Fi switch, you can secure your home systems and other boundless quantities of associated gadgets against infections, and digital dangers. You can deal with your home system from the associated cell phones, by getting to Norton... Read More
How To Block Norton Antivirus Pop-Ups?
How To Block Norton Antivirus Pop-Ups?-norton.com/setup Norton Antivirus is a well-perceived and trusted antivirus program that a large number of individuals have been using each other day to give the most extreme security to their PC's protection and information. Norton holds a wide range of helpful highlights and... Read More
Social Media: Staying safe with Norton
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Try Norton Free trial products before downloading from norton.com/setup
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How to Install Norton antivirus on your Computer via Norton.com/setup?
How to Install Norton antivirus on your Computer via Norton.com/setup? In this article, we will give a speedy walkthrough to help introduce Norton Internet security suite on your PC. These days, when everybody is associated through any advanced stage or cloud administrations, it is as simple as going for a stroll in a... Read More
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Hundreds of thousands of people who bought Kevin Trudeau's book "The Weight Loss Cure 'They' Don't Want You to Know About" after watching his deceptive infomercials will get money back, thanks to the FTC.
Kevin Trudeau's run-ins with the FTC began back in the late 90's when he agreed to settle an FTC charge that he hosted a series of deceptive infomercials designed to look like radio and TV news interviews. But Trudeau didn't change his ways after the settlement. Instead, he claimed in a new infomercial – without any proof – that "Coral Calcium Supreme" could treat or cure cancer and other diseases. In 2004, the FTC had him banned from infomercials. But Trudeau used a narrow exception in the ban to promote a new item: a book about a weight loss plan.
In the ads, Trudeau claimed that the weight loss plan outlined in the book was easy to follow, could be done at home, and allowed people to eat whatever they wanted. However, when people purchased the book, they discovered it described a complex plan that required near-starvation level dieting, daily injections of a prescription drug that consumers could not easily get, and lifelong restrictions on what people could eat.
In 2009, a federal judge ordered Trudeau to repay consumers millions of dollars for violating the 2004 court order. However, he claimed he was completely broke and couldn't afford to repay consumers – although he lived in an expensive home and he spent lavishly on jewelry, cigars, and other luxury goods. After more court proceedings, the FTC located millions of dollars Trudeau hid, and we continue to search for more.
As for the millions already found, it's coming back to the people who paid for the book. If you get a check, deposit or cash it as soon as possible. You may receive more money in the future. And as for Trudeau, his violations led to a 10-year prison sentence.
For more information about the refund process, visit ftc.gov/trudeau.
If you have questions about your refund, contact the FTC's refund administrator at 844-828-4437. And remember, the FTC never requires you to pay money or give financial information to get a refund check.
by Andrew Johnson
Division of Consumer and Business Education, FTC
Caption: Kevin Trudeau, Photo: RailbirdJAM/Wikipedia


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Round out your research with photos: These digital databases contain thousands of historical images of American Indians — and some may shed light on how your ancestors lived. Search on your ancestor's name, tribe, location, nearby mission, BIA district or Indian school.
American Indians of the Pacific Northwest
<content.lib.washington.edu/aipnw>: More than 2,300 photographs are searchable by subject, title or description.
Denver Public Library History of the American West 1860-1920
<memory.loc.gov/ammem/award97/codhtml/hawphome.html>: This 30,000-strong collection encompasses all of Western history, including more than 40 American Indian tribes. A keyword search on Indian produced 5,000 hits.
Edward S. Curtis's The North American Indian Photographic Images
<memory.loc.gov/ammem/award98/ienhtml/curthome.html>: More than 2,000 keyword-searchable images that span 1907 to 1930 and cover 80 tribes from states west of the Mississippi.
Indian Peoples of the Northern Great Plains
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<www.asu.edu/lib/archives/schwarz>: Browse 270 of missionary Augustine Schwarz's photos of the Pima, Papagos and Apache peoples.
Online Archive of California
<www.oac.cdlib.org>: This vast archive includes 3,000 American Indian photographs from the C. Hart Merriam Collection.
Wisconsin Historical Society Indians of North America
<www.wisconsinhistory.org/whi>: Browse 182 images or search by keyword.