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The drive by the North to control the growth and distribution of the world's food is worrying to say the least. The sovereignty of small farmers and their agricultural systems especially in the South are under constant threat; indeed, far too many have already succumbed.
In his 1974 collection of essays, Small is Beautiful, EF Schumacher intimated that agriculture as an industrial process is flawed and at odds with nature The two are essentially different in that "agriculture deals with living substances … its products the result of processes of life, while industry deals with the elimination of living substances". Schumacher saw industry as an assault on the unpredictability, unpunctuality, and general waywardness of living nature, including human beings.This modern drive for a global industrial agriculture has enormous social and ecological implications. Devinder Sharma, a food and trade policy analyst who is anti-GE quite rightly says, "the end result can only be two kinds of agricultural systems: the North growing staple foods and shipping them throughout the world, while the South is left to produce only [cash crops]". This is anathema to all who believe that power and self-determination is essential for all peoples, cultures and nations if we are to eliminate poverty and hunger, and have peace and permanence in our world.
The biotech and grain companies continue their onslaught on agriculture; they continually attempt, with the approval of the US government and the European Union, to patent seeds and cereals that they have no rights to. Their success will ensure that most farmers in the South can no longer save seeds from one crop to another, but have to pay northern owned transnational companies for the means to plant future crops.
While global food production per capita has increased since the 1970s so too has world hunger. In South America the number of people going hungry rose by 19% while at the same time per capita food production rose by 8%; in Asia hunger and food per capita both rose by 9%. Sharma, also says: "If the food currently available were to be evenly and equitably distributed among the 6.4 billion people on the planet, there would still be a surplus left for 800 million." He points out that "hopeless cases" such as Ethiopia have demonstrated how a combination of people-centred and natural resource based policies can recreate self-sufficiency in food. For biotechnology companies to insist that only they can provide the hungry and malnourished with their "novel and … functional foods," is to, "mock the inability of the poor to access two square meals a day." He goes on, "In India, the 12 million malnourished people ... are the people who produce enough food, but cannot buy the food they grow".
This being so, and if control of the staples are more and more in the hands of northern business people, whose experience in life is no more than an abstract notion of a mathematical concept which we all know as "money", then control is increasingly being taken away from those who understand the land and what best to grow on it for the greater good of themselves, their families and their neighbours, and can only exacerbate the problems.
There is an inherent conflict of interest here. The farmer understands that a bag of grain will diminish in value the longer he/she holds on to it (natural deterioration or being eaten by other things), it is nature's way, so it makes sense to realise its worth in the short term. Diminishing value is abhorrent to economists – money, the lifeblood of the financial world can, in theory, grow in value ad infinitum. It is, however, related to nothing in the natural world, and is in fact at odds with it as its value to the system is always greater than the product it is used to buy.
The growth capital economy is a violation of the 2nd Law of Thermodynamics, and this corrupted value system of the industrialised North has become pervasive in almost all societies through globalisation and the idea of "the free market" that we are told is good for us all.
Noam Chomsky, one of America's most popular speakers on US foreign policy says of the "free" market: "Nobody in the corporate world or the government takes the doctrines [of free trade] seriously. The parts of the US economy that are able to compete internationally are primarily the state subsidized ones". Cheap subsidised food exported to the South destroys any idea of competition and bankrupts local farmers. Subsidies need a whole chapter of their own. Vandana Shiva says in GATT, Agriculture and Third World Women, an essay in the 1993 book Eco-Feminism: "Free trade will lead to a 26.2% reduction in human consumption of agricultural produce". At a time when we are producing more food than ever before, when the world population is increasing, there is a corresponding relative reduction in consumption of food. If Shiva is correct, and there is no reason to doubt her, it can only mean that Sharma is correct also, and equity and distribution are the main problems. When Shiva goes on to say: "the growth of free trade implies the growth of hunger", it is difficult to disagree.
Also, we in the North have reduced our edible crop diversity to a minimum, with a reduced number of species per crop. This is the agri-culture we have created and it is easy to see why some find it difficult to understand that other cultures find economic benefits in a wider range of crops and species within them, many of which we would call weeds. Shiva points out that what are weeds to companies like Monsanto are food, fodder and medicines for 3rd world women; that in West Bengal 124 "weed" species … have economic importance for farmers … in Mexico, peasants utilise 435 wild plants and animal species of which they eat 229".
Cover and mixed crop planting, widely used policies in the South, help enrich and preserve soils, but the increased use of Roundup Ready crops eliminates this type of planting and is a recipe for soil erosion. Glyphosate (Roundup) can act similarly to antibiotics and is known to disrupted the symbiotic mycorrhizal process, while antagonists in the soil that normally control soil-based pathogens are destroyed. In effect, these chemicals devastate the natural ecology of the soil.
There is a further problem with this industrialised view of agriculture that is being paid scant attention. Most food grown under northern control would have a huge increase in food miles, at a time when the atmosphere of the planet needs us to reduce such things. Local produce will become a luxury for the very few. One wonders how we can convince our politicians of such things when the leader of the main opposition party in the UK in an attempt to sound environmentally aware says: 'what we need is another Green Revolution', his ignorance is frightening.
The green revolution did nothing to alleviate hunger at its source. Too many people could not afford to buy food in the 60s and even more cannot afford to buy food today. The narrow distribution of equity then, is an even narrower distribution of equity now. We can learn to grow as much food as we like – if the starving cannot afford to buy it then they will continue to starve. In the mean time the number of dispossessed and disenfranchised joining the ranks of the chronically hungry is increasing through the "structural adjustment" and "resource retirement" policies of the IMF and the World Bank. Not only are local people removed from their lands, they are removed from any part of the decision making process in their own countries. These policies ensure a flow of resources in favour of the North. People in the South must be free to grow their own food crops in their own way if hunger is truly to be defeated.
Imposing a Northern view of food production on the South is cultural imperialism of the worst kind, it serves only the interests of around 20% of the world's population while having severe adverse affects on so many of the other 80%. It can only create more suffering and resentment and is not conducive to global sustainability. Even though, at the moment, we are able to grow more food than we actually need, around 2 billion people [30%] of the world's population are nutritionally stressed with 850 million suffering hunger "every single day". 30,000 people a day die of hunger, 75% of them under the age of 5 years – that is almost 1,000 every hour. This is unacceptable in a world of plenty!
It is obvious that something is very wrong. Could it be that corporate boardrooms are not the place to decide what should be grown, where it should be grown and by whom; that local community stakeholders, and not remote and invisible private shareholders, should take priority, and that social and environmental justice are more important than corporate bank balances?
The key to it all is the growth capital economy and the delusion that it can be sustainable – that it can continue to grow in a finite world. There are alternatives, but it would probably mean a shift in political power and the notion of wealth to adopt any of these. It takes only the merest of glances into any Sustainable Development project to see the flaw: There may be three pillars of sustainability but the one that take precedent every time is Economy. There is no convincing the operators of anything other than Economy must be served first, Society second and Environmental considerations last. Sustainability in the North is, in effect, based on Affordability. However, without a suitable, life nurturing Environment, could human Society as we know it exist in any degree of comfort? The answer is No. So, if there was no Society what would be the point of an Economy?
Maybe it is time to get our priorities right.
till next time


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(c) Pocumtuck Valley Memorial Association, Deerfield MA. All rights reserved.
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This is a memorial to the employees who lost their lives in World War II (WWII) who worked for the Parts Manufacturing Company. During World War II (WWII), local companies in Greenfield, Massachusetts, displayed great pride and patriotism in their efforts on the home and war front. When their workers made the supreme sacrifice, efforts were made to remember them. This company was well-known for its manufacture of parts for military aircraft.
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We take great pride in the premium soft pretzels we offer customers. Our pretzels are processed using the authentic Bavarian style Natronlauge of pretzel making which produces a hearty, rustic, Old World flavor. Our tasty options include:
BAVARIAN SOFT PRETZEL: Our signature Jumbo Soft Pretzels are two pretzels twisted together to make one unique Jumbo Bavarian soft pretzel; our top selling pretzel for restaurants and for Oktoberfest celebrations.
NEW YORK Style: This pretzel allows your patrons to take a quick visit to the "Big Apple" where for decades residents and visitors have been devouring the famous twisted treats on subway trains, sport stadiums, and while walking along the city streets. The robust pretzel flavor, rustic crust, and soft center demonstrate out commitment to produce the finest New York soft pretzel experience.
MUNICH Style: Your customers will experience one of the world's oldest snacks. Our Munich soft pretzels are rolled into the classic Swabian shape of Southern Germany, offering two distinct textures, thin crunchy arms and a doughy body; a truly epicurean soft pretzel experience - great for Oktoberfests.
PHILLY Style: The unique shape of the Philly soft pretzels are a result of bakers striving to fit as many pretzels in the oven at once, typically baked in chains of 10 – 12 pretzels. Our Philly soft pretzels are baked in pairs so that each pretzel is a preferred "end" piece that maximizes freshness and flavor.
SOFT PRETZEL PUFFS: We've taken our finest authentic Bavarian pretzels and made them into small bite size pieces. Puffs are great for dipping or covered with a cheese sauce.
PRETZEL DINNER ROLLS: Dinner rolls are available in 2 ounce. (10" Breadstick)
CUSTOM SHAPED RRETZEL AND ROLLS: Because all of our pretzels and rolls are made by hand and not made by a machine, we have the flexability to shape our dough into anything you and your customer's hearts desire. We will be happy to discuss all the possibilities with you.


text:
Philip Koopman
John DeVale
Carnegie Mellon University
Pittsburgh, Pennsylvania
IEEE Transactions on Software Engineering, Vol. 26, No. 9, September 2000 Copyright (c) 2000 Institute of Electrical and Electronics Engineers, Inc. All rights reserved.
Operating systems form a foundation for robust application software, making it important to understand how effective they are at handling exceptional conditions. The Ballista testing system was used to characterize the handling of exceptional input parameter values for up to 233 POSIX functions and system calls on each of 15 widely used operating system (OS) implementations. This identified ways to crash systems with a single call, ways to cause task hangs within OS code, ways to cause abnormal task termination within OS and library code, failures to implement defined POSIX functionality, and failures to report unsuccessful operations. Overall, only 55 percent to 76 percent of the exceptional tests performed generated error codes, depending on the operating system being tested. Approximately 6 percent to 19 percent of tests failed to generate any indication of error despite exceptional inputs. Approximately 1 percent to 3 percent of tests revealed failures to implement defined POSIX functionality for unusual, but specified, situations. Between 18 percent and 33 percent of exceptional tests caused the abnormal termination of an OS system call or library function, and five systems were completely crashed by individual system calls with exceptional parameter values. The most prevalent sources of these robustness failures were illegal pointer values, numeric overflows, and end-of-file overruns. There is significant opportunity for improving exception handling within OS calls and especially within C library functions. However, the role of signals vs. error return codes is both controversial and the source of divergent implementation philosophies, forming a potential barrier to writing portable, robust applications.
Paper: pdf file (878 KB)
Ballista Home Page


text:
Ask Ed Your Wine/Beer Making Question
Do you have a wine making or beer brewing question that you'd like some expert help with? Ask your question below, and we will feature your question (with the answer) on our blog!
Do you have a wine making or beer brewing question that you'd like some expert help with? Ask your question below, and we will feature your question (with the answer) on our blog!
I am a beginner in fruit wine making. After the month of secondary fermenting and racking for the 2-3 month long haul aging do I still put on the airlocks or just put the rubber stoppers? I can't find any articles that says one way or another..
Thank you,
Hi Ed,
I made red grape wine for the first time and I am not using any wine kit. At this point my wine is in the secondary fermenters and I have two 25 litre carboys and have been fermenting for about a month. Yesterday one of the carboys stopped fermenting so I checked the SG with the hydrometer and it seems that the fermentation is done so I racked only the carboy that stopped bubbling to another clean carboy and added campden tablets. My problem is that the other carboy is still slowly bubbling through the airlock and I dont know if this is normal since both carboys were racked at the same time from the primary fermenter.
Thanks Would appreciate any help.
Hi Ed,
Quick question, I just started making wine at home and two days after I began the process I went on vacation. I had a balloon with pinholes as a makeshift airlock and when I returned after a week the balloon had still not inflated. I'm not sure if the holes I poked were too large or if they expanded, but the wine had stopped fermenting. I quickly replaced the balloon and it is fermenting again but I am wondering if it is too late for this batch and I should just start over or if it is okay because it started fermenting again. I know oxygen is okay in the beginning but not after a certain amount of time and since I don't know when the balloon failed I am not sure if it has just constantly been exposed or if the fermentation process was halted in the middle. Any help you could give would be greatly appreciated!
Absentee Wine Mom


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Chronic circadian disruption due to shift work or frequent travel across time zones leads to jet‐lag and an increased risk of diabetes, cardiovascular disease, and cancer. The development of new pharmaceuticals to treat circadian disorders, however, is costly and hugely time‐consuming. We therefore performed a high‐throughput chemical screen of existing drugs for circadian clock modulators in human U2OS cells, with the aim of repurposing known bioactive compounds. Approximately 5% of the drugs screened altered circadian period, including the period‐shortening compound dehydroepiandrosterone (DHEA; also known as prasterone). DHEA is one of the most abundant circulating steroid hormones in humans and is available as a dietary supplement in the USA. Dietary administration of DHEA to mice shortened free‐running circadian period and accelerated re‐entrainment to advanced light–dark (LD) cycles, thereby reducing jet‐lag. Our drug screen also revealed the involvement of tyrosine kinases, ABL1 and ABL2, and the BCR serine/threonine kinase in regulating circadian period. Thus, drug repurposing is a useful approach to identify new circadian clock modulators and potential therapies for circadian disorders.
Chronic circadian misalignment has long term consequences on our health and leads to increased risk of developing diabetes, cardiovascular disease and cancer. Using a drug repurposing approach, dehydroepiandrosterone (DHEA) was identified as an important circadian clock modulator.
Approximately 5% of the screened drugs altered circadian period.
DHEA shortened circadian period in cells and tissues.
When fed to mice, DHEA shortened circadian period and significantly reduced jet‐lag.
ABL1/2 tyrosine kinases and BCR serine/threonine kinase are involved in regulating circadian period.
Drug repurposing is a useful approach to identify new circadian clock modulators.
Circadian clocks are highly conserved, endogenous timers present in virtually all living organisms. These clocks regulate near 24‐h rhythms in numerous behavioral and physiological processes, including our sleep–wake cycles and metabolism. In mammals, these daily rhythms are controlled by a central circadian pacemaker, the suprachiasmatic nucleus (SCN), located in the anterior hypothalamus (Ralph et al, 1990; Klein et al, 1991). Most peripheral tissues and cells also contain self‐sustained circadian oscillators (Balsalobre et al, 1998; Yamazaki et al, 2000; Yoo et al, 2004), which are driven by transcriptional–translational feedback loops composed of circadian clock genes and proteins (Takahashi, 2015). The basic helix‐loop‐helix proteins CLOCK and BMAL1 heterodimerize to form a transcriptional activator complex and activate the PER and CRY repressor genes, whose protein products, in turn, repress their own transcription.
Disruption of the circadian clock due to shift work or travel across time zones leads to circadian desynchrony, or jet‐lag, and reflects a mismatch between the internal biological clock and external time cues (Arendt, 2009). Chronic circadian misalignment has long‐term consequences on our health and often leads to an increased risk of diabetes, cardiovascular disease and cancer (Davidson et al, 2006; Scheer et al, 2009; Buxton et al, 2012). Recent circadian studies have identified several genes that by mutation, chemical inhibition or knockdown, significantly reduce jet‐lag, including the vasopressin V1a and V1b receptors, casein kinase 1 epsilon (CK1ε), and salt inducible kinase 1 (Sik1; Jagannath et al, 2013; Yamaguchi et al, 2013; Pilorz et al, 2014). Injection of the neuropeptide vasoactive intestinal polypeptide (VIP) into the mouse SCN also accelerates re‐entrainment to new light–dark (LD) cycles (An et al, 2013). However, there are currently no orally available drugs or supplements, except melatonin perhaps, to combat the complex behavioral and metabolic consequences of jet‐lag.
The development of new pharmaceuticals, from drug discovery to market approval, is costly and hugely time‐consuming with a high rate of failure. Drug repurposing, or identifying new functions for existing compounds, is therefore a popular approach to fast track potential drugs through to clinical trials (Rennekamp & Peterson, 2015). We used a high‐throughput chemical screening strategy to isolate new circadian clock modulators (Hirota et al, 2008; Isojima et al, 2009; Chen et al, 2011), with the aim of repurposing known bioactive compounds. We tested over 1,000 small molecules from two chemical libraries, including US Food and Drug Administration (FDA)‐approved drugs and the International Drug Collection (IDC), and we identified nearly 60 chemicals that altered circadian period, including the period‐shortening molecule DHEA. When tested in mice in vivo, DHEA significantly shortened circadian period of locomotor rhythms and accelerated re‐entrainment to advanced LD cycles, suggesting that DHEA might serve as a convenient over‐the‐counter treatment for jet‐lag. Our chemical screen also identified several tyrosine kinase inhibitors that modulated clock function, implicating this class of kinases in the control of circadian period. Thus, drug repurposing is a useful strategy to identify potential treatments for circadian misalignment and new clock regulators.
Identification of new circadian clock modulators
Using a human osteosarcoma U2OS cell line stably expressing the clock reporter Bmal1‐dLuc (Oshima et al, 2015), we screened over 1,000 molecules from an FDA‐approved drug library and the IDC to identify new circadian clock modulators. To reduce the number of false positives, all compounds were tested in triplicate at two different concentrations (10 and 1 μM) in a 384‐well plate format. Primary screening identified several potential hit compounds based on period change. Drugs that lengthened circadian period by 1 or more hours or shortened period by 0.5 or more hours (Fig 1A) were selected for additional screening, although some chemicals, whose effects were clearly dose‐dependent but below threshold values, were also included. Of these 72 potential hit compounds, 59 were validated in a secondary screen for dose‐dependency (Appendix Fig S1), with 46 chemicals lengthening and 13 compounds shortening circadian period. Thus, ~5% of drugs currently on the market or in clinical trials altered circadian period. This indicates that, depending on the dose and duration of treatment for other ailments, one "side effect" of these drugs might be perturbation of the circadian clock. Therapeutic classification revealed eight different categories of hit compounds, including (i) anti‐cancer and immunosuppressive drugs, (ii) disinfectants and antiseptics, (iii) hormones and contraceptives, (iv) drugs targeting the central nervous system, (v) dermatological agents, (vi) gastrointestinal drugs, (vii) vitamins and minerals, and (viii) cardiovascular agents (Fig 1B). Importantly, some of these compounds have been previously identified in circadian drug screens (i.e., DNA damage agent, mitoxantrone; Hirota et al, 2008), whereas others affect pathways that have been implicated in regulating circadian rhythms (i.e., EGF receptor inhibitor, erlotinib; Kramer et al, 2001), thus validating our screening protocol. One obvious advantage of screening existing drugs is that they frequently have known mechanisms of action (Rennekamp & Peterson, 2015). All known targets of hit compounds identified in our screen are listed in Table EV1. In addition, the top six categories of drug targets are shown and include DNA, the androgen receptor (AR), DNA topoisomerase 2α, the nuclear receptor subfamily 1 group I member 2 (NR1I2), the retinoic acid receptor α (RARα)/retinoid X receptor β (RXRβ), and the tubulin β chain (Fig 1C).
DHEA primarily shortens circadian period
Relatively few chemicals identified in our screen shortened circadian period, so we initially focused on characterizing some of these compounds. Interestingly, the steroid hormone DHEA and its derivative DHEA acetate showed clear dose‐dependent shortening of circadian period in U2OS cells (Fig 2A and Appendix Fig S1). Recent reports, however, have shown that high doses of DHEA (e.g., 100 μM) lengthen circadian period and decrease amplitude (Rey et al, 2016; Putker et al, 2017), which we have confirmed (Fig EV1). In humans, DHEA is a steroid hormone produced in the adrenal gland, gonads, and brain and is one of the most abundant circulating hormones. It functions as an androgen precursor and can be converted to testosterone or estrogen (Appendix Fig S2). To determine whether DHEA itself or one of its precursors or metabolites modulates circadian period, we treated U2OS cells with several endogenous steroid hormones and monitored bioluminescence. These results show that deoxycorticosterone (21‐hydroxyprogesterone), 11‐deoxycortisol, and testosterone lengthened circadian period (Appendix Fig S2). Some of these hormones were included in our primary drug screen, but were not identified as hit compounds, because their effects on circadian period were below threshold values. In contrast, progesterone and 17α‐hydroxyprogesterone lengthened period by more than 1 h and were indeed classified as hit compounds (Appendix Figs S1 and S2). Interestingly, DHEA was the only endogenous steroid hormone tested that shortened period in U2OS cells. Notably, its metabolite DHEA sulfate had no effect on circadian period (Appendix Fig S2).
To determine whether the effects of DHEA on the circadian clock were cell type‐ or tissue‐specific, we treated mPer2Luc mouse embryonic fibroblasts (MEFs) with DHEA. Similar to our observations in U2OS cells, DHEA shortened circadian period in MEFs (Fig 2B). We then prepared explant cultures of SCN and lung from mPer2Luc mice and treated them with DHEA. Although slightly higher concentrations were required, we observed significant shortening of circadian period in both of these tissues (Fig 2B). These results indicated that DHEA indeed shortens circadian period in cells and tissues, including the SCN.
Numerous studies in mice have shown that DHEA can be administered orally (Milewich et al, 1995). Therefore, to test its effects in vivo, we added DHEA directly to powdered food and assessed circadian clock function by monitoring wheel‐running activity. We also surgically implanted temperature devices into mice to measure body temperature rhythms. Mice were initially fed powdered food without drug and exposed to a light–dark cycle (12L:12D) for 1 or 2 weeks to entrain their circadian clocks (Fig 2C). Animals were then transferred into constant darkness (DD) for about 1 week to measure free‐running circadian period. Mice were then given either normal powdered food or powdered food mixed with 0.5% DHEA (w/w) for 6 days. This dose was then increased to 1% DHEA (w/w) for another 6 days. Importantly, these concentrations of DHEA have been previously tested in mice and shown to be safe (Milewich et al, 1995). Mice were then returned to normal powdered food until the end of the experiment. These results show that DHEA had a profound effect on behavior and appeared to shorten circadian period of both activity and body temperature rhythms in a dose‐dependent manner (Figs 2C and EV2, respectively). Surprisingly, after return to normal powdered food, activity onset returned to its original phase (i.e., to the phase before drug treatment; Fig 2C). Although DHEA is known to readily cross the blood–brain barrier (Stárka et al, 2015), these data suggest that its effects on behavior were independent of the SCN clock and might be acting through extra‐SCN circadian pacemaker(s) (Pezuk et al, 2010).
Dietary administration of DHEA reduces jet‐lag in mice
By temporarily speeding up or slowing down the circadian clock, drugs that shorten or lengthen period, respectively, might accelerate re‐entrainment to new light–dark (LD) cycles, thereby reducing jet‐lag (Fig EV3). To test this hypothesis, we performed a jet‐lag experiment and examined the effects of DHEA on re‐entrainment to a 6‐h phase‐advanced LD cycle (Fig 3). We fed mice normal powdered food, as above, and exposed them to a LD cycle to synchronize their circadian clocks. After ~1 week, mice were given either normal powdered food or food mixed with DHEA, and the LD cycle was advanced by 6 h (Fig 3A). Chronic administration of DHEA led to a dramatic phase advance in activity onset compared to controls. In drug‐treated mice, this advance occurred almost immediately to the new LD cycle, but surprisingly, subsequently appeared to free‐run, even under LD conditions (Fig 3A). In some mice, this phase advance in activity onset appeared to stabilize ~4–6 h prior to lights off (Fig EV4). We wondered whether adjusting the treatment time of DHEA might be sufficient to reduce jet‐lag to a 6‐h phase‐advanced LD cycle. Therefore, in the next experiment, treatment with DHEA was limited to the first 3 days of the new LD cycle (Fig 3B). Mice were then returned to normal food for the remainder of the experiment. These results show that mice given an acute dose of DHEA shifted much more rapidly to the new LD cycle and re‐entrained within 1–3 days compared to the 6–7 days required for control mice (Fig 3B). In addition, body temperature rhythms in DHEA‐treated animals appeared to shift and reset more rapidly to the new LD cycle compared to controls (the trough more so than the peak; Fig 3C). To determine whether acute DHEA treatment did, in fact, advance the circadian clock, we again treated mice with DHEA and exposed them to an advanced LD cycle for 3 days. Animals were then returned to normal food and transferred into DD (Fig 3D). These results show that the clock has indeed shifted more in DHEA‐treated animals than in control mice. Thus, by adjusting the treatment time of DHEA to 3 days, it was possible to phase shift the circadian clock and accelerate re‐entrainment to an advanced LD cycle, thereby reducing jet‐lag with dietary DHEA.
Involvement of ABL and BCR kinases in the circadian clockwork
Two tyrosine kinase inhibitors were identified in our screen, dasatinib and nilotinib, that lengthened and shortened circadian period, respectively, and both were effective in the nanomolar range (Fig 4A). These drugs are second‐generation inhibitors of the BCR‐ABL tyrosine kinase and approved for treatment of chronic myelogenous leukemia (CML; Molica et al, 2017). Most cases of CML are caused by a chromosomal translocation, called the Philadelphia chromosome, in which the break point cluster (BCR) gene on chromosome 22 and the Abelson (ABL) non‐receptor type tyrosine kinase gene on chromosome 9 are fused, resulting in the chimeric oncogene, BCR‐ABL (Faderl et al, 1999). Although much is known about the consequences of the BCR‐ABL fusion protein in CML, the function of BCR and ABL in intact animals is not well understood (Schwartzberg et al, 1989; Tybulewicz et al, 1991; Voncken et al, 1996).
Nilotinib is a selective BCR‐ABL tyrosine kinase inhibitor, while dasatinib is a multi‐targeted inhibitor of BCR‐ABL tyrosine kinase and SRC family kinases (Ciarcia et al, 2016; Marfe et al, 2016). There is also some evidence that dasatinib may inhibit the circadian clock kinase CK1 (Karaman et al, 2008), which may explain its period‐lengthening effects (Fig 4A). When we examined additional BCR‐ABL tyrosine kinase inhibitors, we found that the more selective inhibitors, imatinib and bafetinib, acted similarly to nilotinib and shortened circadian period, while the less selective, multi‐targeted inhibitors bosutinib and ponatinib, lengthened circadian period (Fig EV5).
To determine whether the ABL1, ABL2, BCR, and SRC kinases are indeed the targets of these chemical inhibitors, we next examined the effect of siRNA‐mediated knockdown of each of these genes in U2OS cells. Knockdown of either ABL1 or BCR shortened circadian period (Fig 4B and Appendix Fig S3), consistent with previous results from a large‐scale circadian RNAi screen (Zhang et al, 2009). siRNAs to ABL2 also shortened circadian period, but those to SRC had no significant effect (Fig 4B and Appendix Fig S3). Together, these results indicate that ABL1, ABL2, and BCR are possible targets for the period‐shortening inhibitors, nilotinib, imatinib, and bafetinib, and implicate these kinases in the regulation of circadian period (Fig 4B). Interestingly, the Abl1, Abl2, and Bcr genes, and even Src, are expressed in the mouse SCN, although their expression does not appear to be rhythmic (Fig 4C and Appendix Fig S4).
Due to the high cost and time‐consuming nature of developing new pharmaceuticals, drug repurposing approaches have become increasingly popular. With this strategy in mind, we screened over 1,000 existing drugs for new circadian clock modulators. This led to the discovery of 59 period‐changing compounds, including the steroid hormone DHEA, which primarily shortened circadian period and accelerated re‐entrainment to advanced LD cycles in mice. DHEA is one of the most abundant circulating steroid hormones in humans; however, its circulating levels are significantly lower in mice than in humans (0.28 versus 1.83 nM, respectively). Therefore, it is not yet known whether the results from our study could be translated to humans, particularly the high, albeit safe, doses used in mice. Clearly, further investigation is required to evaluate the effectiveness of DHEA for the treatment of jet‐lag in humans.
In humans, DHEA is produced by the adrenal gland, gonads, and brain. Studies in primates have shown that, like cortisol, adrenal secretion of DHEA displays a robust circadian rhythm and peaks in the early day (Lemos et al, 2006). This steroid hormone appears to function primarily as a precursor to testosterone and estrogen. Indeed, previous circadian studies in mice have revealed that treatment with testosterone leads to significant changes in locomotor behavior, including shortening of circadian period and increased wheel‐running activity (Daan et al, 1975). This indicates that some of the effects we observed with DHEA in vivo might be due, in part, to its conversion to testosterone. Surprisingly, however, testosterone treatment of U2OS cells lengthened circadian period, reflecting clear in vivo versus in vitro differences, which we do not yet fully understand. Interestingly, of the endogenous steroids tested, DHEA was the only one that shortened circadian period in U2OS cells.
Dehydroepiandrosterone has been the subject of numerous investigations due its protective effects from a variety of disorders, including obesity and diabetes to cardiovascular disease and cancer (Milewich et al, 1995). More recent studies have focused on its role in aging, and it is currently being sold in the USA as an anti‐aging supplement (Baulieu et al, 2000; Corona et al, 2013). Reports have shown that DHEA levels in humans steadily decline with age and that treatment of elderly subjects with 50 mg/day over 1 year improved general health and well‐being without harmful consequences (Baulieu et al, 2000). Although DHEA appears to be relatively safe, whether it could be used to treat circadian disorders in humans, as mentioned above, requires further investigation.
Previous circadian studies have identified several genes, chemicals, and signaling pathways involved in reducing jet‐lag. One important factor in accelerating re‐entrainment to new LD cycles appears to be the reduction of intercellular communication between SCN neurons. Yamaguchi et al (2013) reported that mice lacking the vasopressin receptors V1a and V1b (V1a−/−V1b−/−) were resistant to jet‐lag and immediately re‐entrained to phase‐shifted LD cycles. The authors proposed the crucial role of interneuronal communication within the SCN in this process. Indeed, they revealed by luminescent imaging of slice cultures that SCN neurons from mutant mice were more vulnerable to perturbation than those from wild‐type mice, and it was this instability or lack of communication that enabled mutant mice to re‐entrain more rapidly to new LD cycles. They also demonstrated that administration of V1a and V1b antagonists directly into the SCN accelerated re‐entrainment and proposed vasopressin receptors as therapeutic targets for the treatment of circadian misalignment due to travel or shift work (Yamaguchi et al, 2013). Similarly, administration of high concentrations of VIP into the SCN has been shown to reduce intercellular synchrony, increase phase‐shifting, and accelerate re‐entrainment in mice (An et al, 2013). This study also emphasized the role of decreased intercellular communication among SCN neurons in reducing jet‐lag. Thus, SCN‐specific chemicals and peptides that reduce intercellular communication appear to be effective in combating jet‐lag (Yamaguchi et al, 2013; Doi et al, 2016). However, the development and administration of drugs that target the SCN specifically appears to be quite challenging.
It is well established that circadian clocks are present, not only in the SCN, but also in peripheral tissues and cells (Balsalobre et al, 1998; Yamazaki et al, 2000; Yoo et al, 2004). The SCN synchronizes and establishes an appropriate phase relationship with circadian clocks in the periphery. Therefore, to combat jet‐lag, this phase relationship between the SCN and peripheral clocks must be maintained. However, this appears to be quite difficult because SCN and peripheral tissues have different sensitivities to different time cues (Wallach & Kramer, 2015). We hypothesize that period‐changing drugs acting on multiple tissues may accelerate re‐entrainment to phase‐shifted LD cycles. Indeed, DHEA shortened circadian period of cells and explanted tissues, including the SCN and lung. Furthermore, dietary administration of DHEA shortened the circadian period of wheel‐running activity and body temperature rhythms under constant dark conditions. Although it is not yet clear whether the period‐shortening and phase‐advancing effects of DHEA were independent of the SCN, dietary administration dramatically accelerated re‐entrainment to a 6‐h phase‐advanced LD cycle. These results suggest that period‐changing drugs acting on peripheral tissues could aid in curing jet‐lag. A chemical cocktail composed of both central and peripheral tissue‐targeted drugs, such as DHEA, might therefore be a more effective treatment for jet‐lag.
The mode of DHEA action is clearly of great interest. According to the DrugBank database (version 5.0.11 released 2017‐12‐20: www.drugbank.ca) (Wishart et al, 2018), there have been at least 12 targets of DHEA reported in humans (Table EV1). Among these, nuclear receptors, such as the androgen receptor (AR), the nuclear receptor subfamily 1 group I member 2 (NR1I2: pregnane X receptor, PXR) and 3 (NR1I3: constitutive androstane receptor, CAR), and the estrogen receptor β (ERβ), are of particular interest. Mice lacking Cry1 or Cry2 exhibit changes in free‐running period (van der Horst et al, 1999), and recently, direct interactions between CRY1/2 proteins and these nuclear receptors have been reported (Kriebs et al, 2017). These data suggest a potential mechanism for DHEA action, as one of these nuclear receptors might be a direct target of DHEA and influence the regulation of circadian period by CRY1/2. It would therefore be interesting to test the effects of DHEA in mice lacking these nuclear receptors, as well as in mice lacking Cry1 or Cry2. An additional target for DHEA is the NMDA receptor (Table EV1), which is known to be involved in the phase‐shifting effects of light on the circadian system (Colwell et al, 1991; Ding et al, 1994; Mintz et al, 1999; Asai et al, 2001). It is possible that DHEA might be affecting behavior by targeting the NMDA receptor and influencing this neural pathway. Interestingly, DHEA sulfate has been proposed to induce phase advances via GABAA receptors when administered during the subjective day (Pinto & Golombek, 1999), suggesting another possible mode of action for DHEA. Clearly, additional studies are required to identify the actual target(s) of DHEA responsible for reducing jet‐lag in vivo.
Phosphorylation plays an important role in the circadian clock mechanism and regulates the stability and subcellular localization of clock proteins. Several protein kinases, including CK1δ, CK1ε, and CK2, AMP‐activated kinase (AMPK), and glycogen synthase kinase 3β (GSK3β), have been shown to regulate circadian period and are therefore important for clock function (Hirota et al, 2008; Isojima et al, 2009; Chen et al, 2011; Takahashi, 2015). The vast majority of protein targets are phosphorylated on serine and threonine residues. Although tyrosine residues can also be phosphorylated, they constitute less than 1% of the total targets (Hunter, 2009). There are 90 tyrosine kinase genes in the human genome, but the physiological function of most of these proteins remains largely unknown. Using a chemical genetic approach, we discovered several tyrosine kinase inhibitors that affected circadian period and suggested the involvement of ABL and BCR protein kinases in the regulation of the mammalian circadian clock. The ABL1 gene is ubiquitously expressed, and Abl1‐null mutant mice die within 1–2 weeks after birth (Schwartzberg et al, 1989; Tybulewicz et al, 1991). Therefore, it has not yet been possible to test the role of the ABL genes in circadian timekeeping using forward or reverse genetic approaches. To further understand the physiological function of the ABL1 and ABL2 genes, identification of their downstream targets is necessary, in addition to the generation of conditional knockouts of the ABL1 and/or ABL2 genes within the adult SCN.
By screening known bioactive compounds, we have discovered new circadian clock modulators. One compound, DHEA, shortens circadian period and reduces jet‐lag in mice. Although further extensive testing is required, it is tempting to speculate that DHEA might be used for the treatment of jet‐lag in humans. We have also suggested a role for non‐receptor type tyrosine kinases ABL1, ABL2, and the BCR protein kinase in determining circadian period. Thus, drug repurposing is a useful approach to identify potential therapeutic treatments for circadian misalignment and understanding the underlying mechanisms of the circadian clock.
Materials and Methods
The SCREENWELL FDA‐approved drug library V2 containing 741 compounds was purchased from Enzo Life Sciences (Hayashi Kasei Co., Ltd.), and the International Drug Collection (IDC) containing 311 compounds was purchased from MicroSource Discovery Systems, Inc. (Namiki Shoji Co., Ltd.). Aldosterone (A9477), DHEA (D4000), dehydroisoandrosterone 3‐sulfate (D5297), and Reichstein's substance S (also called 11‐deoxycortisol; R0500) were obtained from Sigma. Androstenedione (A0845), cholesterol (C0318), corticosterone (C0388), estriol (E0218), hydrocortisone (H0533), and stanolone (also known as dihydrotestosterone; A0462) were purchased from Tokyo Chemical Industry (TCI). 17‐α hydroxypregnenolone (SC223186) and 21‐hydroxyprogesterone (also called deoxycorticosterone; SC231274) were obtained from Santa Cruz Biotechnology. Tyrosine kinase inhibitors imatinib mesylate (sc‐202180), nilotinib (sc‐202245), dasatinib (sc‐358114), bosutinib (sc‐202084), bafetinib (sc‐503249), and ponatinib (sc‐362710) were purchased from Santa Cruz Biotechnology, Inc. Chemical stocks (10 mM in DMSO or ethanol for cholesterol) were either obtained from the manufacturer (chemical libraries) or prepared (individual chemicals) and stored at −20°C.
Cell culture
Human U2OS cells containing a Bmal1‐dLuc reporter gene were cultured as described (Oshima et al, 2015) in DMEM supplemented with 10% FBS, 2 mM l‐glutamine, 100 unit/ml penicillin, and 100 μg/ml streptomycin. Mouse embryonic fibroblasts (MEFs) were prepared from heterozygous PER2::LUC mice at embryonic day 10 as described (Yagita et al, 2002). MEFs were cultured as described in DMEM supplemented with 10% FBS, 2 mM l‐glutamine, 100 unit/ml penicillin, and 100 μg/ml streptomycin.
Drug screening
U2OS cells were seeded at a density of 4,000 cells/well in 384‐well plates and incubated for 2–3 days until confluent. Using a Caliper Life Sciences ALH 3000 Workstation, chemical library stocks were initially prepared at 5 and 0.5 mM in DMSO and then diluted to 10 and 1 μM, respectively, in assay media for measuring luminescence. This results in a final DMSO concentration of 0.2% in control and drug‐treated samples. Luminescent assay media (also called "air" or recording media) was composed of DMEM (Sigma D2902), 10 mM HEPES, 3.5 g/l D‐glucose, 0.35 g/l sodium bicarbonate, 100 unit/ml penicillin, 100 μg/ml streptomycin, 2% B27 (Life Technologies), 0.1 mM luciferin (Wako), and 100 nM dexamethasone (Sigma). Diluted chemicals were pipetted into triplicate wells of a 384‐well plate containing U2OS cells (prepared above), and bioluminescence was monitored for 5–6 days in a Churitsu CL384 Series luminometer (Churitsu Electric Corporation). Circadian period was determined using NINJA SL00‐01 software for time series analysis (Churitsu Electric Corporation), and potential hit compounds were identified based on changes in circadian period. Drugs that lengthened circadian period by 1 or more hours or shortened period by 0.5 or more hours were selected. Compounds whose effects were clearly dose‐dependent but below threshold values were also included as potential hits. These compounds were retested in a secondary screen for dose‐dependency (0.5–20 μM in 0.2% DMSO).
Substrate availability has been shown to influence circadian parameters in luciferase reporter assays (Feeney et al, 2016). To ensure that the effects we observed with DHEA were robust and not due to insufficient substrate, we tested different concentrations of luciferin. Despite small increases in both luminescence and period with 0.2 mM compared to 0.1 mM luciferin, treatment with 20 μM DHEA consistently and significantly shortened circadian period (Appendix Fig S5A).
To verify that the effects of DHEA are independent of dexamethasone, corticosterone or other steroid hormones in the assay media, which might influence the circadian clock (Balsalobre et al, 2000a), we used charcoal‐stripped fetal bovine serum, in which steroid hormones have been selectively removed (Thermo Fisher 12676029). In addition, we compared a 2‐h dexamethasone pulse to tonic dexamethasone in the recording media. Despite a small increase in circadian period in cells pulsed with dexamethasone, our results show that 20 μM DHEA significantly shortened circadian period in U2OS cells under all conditions tested (Appendix Fig S5B). This indicates that the effects of DHEA are consistent and unlikely to be caused by perturbing the effects of steroids in the media.
To ensure that the effects of tyrosine kinase inhibitors dasatinib and nilotinib are not dependent on insulin in the media, which might affect the circadian clock (Balsalobre et al, 2000b), we prepared assay media with Xeno‐free B27 supplement with or without insulin (Thermo Fisher A1486701, A3695201). At a concentration of 1 μM, dasatinib and nilotinib lengthened and shortened circadian period, respectively, in the presence or absence of insulin (Appendix Fig S5C). Thus, these two inhibitors appear to act on the circadian clock independently of insulin/insulin receptor tyrosine kinase.
Explant cultures
Tissues were dissected from male and female mPer2Luc knockin mice, ~2–6 months old, and cultured essentially as described (Yoo et al, 2004) in 35‐mm dishes containing Millicell cell culture inserts (Millipore) in assay media for measuring luminescence (same as above). Dishes were sealed with silicon grease and parafilm, and bioluminescence was measured in a LumiCycle 32 (Actimetrics) for 6 days. Circadian period was determined by using the LumiCycle Analysis software (Actimetrics), and samples with goodness of fit values over 80% were used in the analysis. P‐values were determined by a Welch's t‐test, and those below 0.05 were considered significant.
siRNA‐mediated knockdown
Gene‐specific packages of four preselected siRNAs to human ABL1, ABL2, BCR, SRC, and positive control CRY2, as well as a single negative control siRNA, were obtained from Qiagen (FlexiTube GeneSolution siRNA). These siRNAs were introduced singly, or as a mixture of two or four siRNAs into U2OS cells using a reverse transfection protocol in 96‐well plates (Hirota et al, 2008) or 384‐well plates (Zhang et al, 2009). Bioluminescence was monitored in an EnSpire Multimode Plate Reader (Perkin‐Elmer) for 96‐well plates or a Churitsu CL384 luminometer for 384‐well plates. The TaqMan Gene Expression cells‐to‐Ct Kit (Ambion, Life Technologies) was used to lyse cells and reverse transcribe mRNA into cDNA. This cDNA was used for qPCR following the manufacturer's instructions (Applied Biosystems QuantStudio 3 Real‐Time PCR system) using gene‐specific TaqMan probes (Applied Biosystems Assay ID: Hs01104728_m1 for ABL1, Hs00943652_m1 for ABL2, Hs01036532_m1 for BCR, Hs1082246_m1 for SRC, Hs00323654_m1 for CRY2, Hs02758991_g1 for GAPDH). ΔCt was determined using GAPDH as a reference gene, and relative expression was then calculated using the ΔΔCt method by comparing gene‐specific siRNA samples to the negative siRNA control.
Behavioral analysis
Male Mus musculus C57BL/6J wild‐type mice (8–10 weeks of age) were used in each experiment, with eight controls and 16 drug‐treated mice, or 12 controls and 12 drug‐treated mice. These mice were housed in individual cages equipped with running wheels, and activity was recorded using the Chronobiology Kit (Stanford Software Systems, Stanford, CA). Cages were placed in light‐tight boxes, where light was provided by fluorescent lamps (Panasonic FHF32EX‐N‐H; 1,000–2,000 lux at the top of the cage). Mice were maintained on a 12:12 LD cycle, unless otherwise indicated, and fed ~50 g of powdered food (with or without drug) weekly. DHEA powder was added directly to powdered food at a concentration of 0.5% (w/w) or 1.0% (w/w) and administered at noon ~1 week after transfer into DD, or the day before a 6‐h phase advance, where the dark phase was shortened by 6 h. Body temperature was measured using temperature data loggers (Thermochron type‐SL; KN Laboratories) surgically implanted into mice, and the data were retrieved using RhManager software (KN Laboratories). This study was approved by the Animal Experiment Committee of Nagoya University.
In situ hybridization
Mice were maintained for several days on a 12:12 LD cycle. At the indicated zeitgeber time (ZT), mice were killed and brains were dissected and frozen immediately on dry ice. Non‐perfused frozen sections (20 μm) were prepared and probed with 33P‐labeled oligonucleotides (Yoshimura et al, 2000). Three to four oligonucleotides were designed for each gene and used to increase sensitivity. Hybridization was carried out overnight at 42°C, and two high‐stringency post‐hybridization washes were performed at 55°C. Sections were air‐dried and exposed to BioMax MR film (Eastman Kodak). Listed below are the probe sequences for each gene examined:
Abl1. tccttggagttccatcgagctgcttcgctgagaccctggggctca; catgtagagcagtaccacggcgctcacctcctgccggttacactc; gccggtcagaggggttccactgccaacatgctcgcatgagctcgt; tctcagtccttctccaggtgggccggccttggtggggtcagtgtt
Abl2. tgatcgtgctgggtgaagacgttgaagccggcgtctgcggtacgc; ctcagggtcctcgtcttggaaggaagcagcggtaaccgaggcagg; cggagagtcactctctgtgatggctggatcaggggctctcaaggg
Bcr. tcgctggaggtgaggttctcgttggagctgcagtccggcgtgtag; cagctctaccataaagctgtccttcagcagctgccggtgctctcc; ctgctgctctcggatgctttctctccactcggctcgctcatagtc; actcggtagatgcccacctcctccataccccggcgctcgatctct
Src. gaggtgacggtgtccgaggagttgaagcctccgaagagcttgggc; aaggtccctctcgggttctcggcgttgagcagcagccgctctgat; gcctcctgcaggaaggcctctggggacatggtgcctggcttcaga; ggaccacacatccgacttgatggtgaacctgccgtacagagcagc
The paper explained
Disruption of the circadian clock is becoming ever more common due to the prevalence of shift work and frequent travel across time zones. This leads to circadian desynchrony, or jet‐lag, which reflects a mismatch between the internal biological clock and the environmental light–dark cycle. Chronic circadian misalignment has long‐term consequences on our health and often leads to an increased risk of diabetes, cardiovascular disease and cancer. However, there are currently no orally available drugs, except for perhaps melatonin, to combat the complex behavioral and metabolic consequences of jet‐lag.
We used a high‐throughput chemical screening strategy to isolate new circadian clock modulators, with the aim of repurposing or finding new functions for existing drugs. We discovered that the steroid hormone dehydroepiandrosterone (DHEA) significantly speeds up or shortens the period of the circadian clock in cells and tissues. When fed to mice, DHEA also shortened circadian period and significantly reduced jet‐lag.
Although further studies are required, our results suggest that DHEA might serve as a convenient over‐the‐counter treatment for jet‐lag.
Author contributions
TY conceived and designed research; TKT, YN, WO, AK, MI, TNO, and TY performed research and analyzed data; NK, KI, KY, YS, MS, and AS contributed new reagents; TKT and TY wrote the article; all authors commented on the article.
Conflict of interest
The authors declare that they have no conflict of interest.
Expanded View
Expanded View Figures PDF [emmm201708724-sup-0002-EVFigs.pdf]
Table EV1 [emmm201708724-sup-0003-TableEV1.xlsx]
We thank Dr. Joseph S. Takahashi for providing mPer2Luc knockin mice and Drs. Daisuke Ono and Tsuyoshi Hirota for technical advice. This work was supported by the JSPS KAKENHI "Grant‐in‐Aid for Specially Promoted Research" (Grant Number 26000013) and "Grant‐in‐Aid for Young Scientists (B)" (Grant 17K17797), Human Frontier Science Program (RGP0030/2015), and Research Foundation for Oriental Medicine. WPI‐ITbM is supported by the World Premier International Research Center Initiative (WPI), MEXT, Japan.
FundingResearch Foundation for Oriental Medicine
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license


text:
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text:
Essay on Organizational Behavior
Essay on Barriers to effective communication in a group:
Effective communication is very significant for the determination of the company's trend. It is important to note that effective communication fosters the attainment of the group's preset goals. Conversely, miscommunication leads to delivery of invalid information hence decline in the productivity of the group. In severe cases, lack of effective communication promotes misunderstanding between the involved parties thus may end up in conflicts. In order for communication to hold and be effective, the mode of information transmission ought to be reliable, and this will deem complete upon the reception of the feedback. However, it is difficult to attain effective communication owing to various barriers that deem detrimental. The management of every organization should enact policies governing communication within the hierarchy of the group to avert the encroaching barriers.
Lack of trust
Trust is one of the fundamental elements of any successful team. As highlighted, the level of trust progresses positively or negatively in each interaction amongst members of a given group (Robbins and Tim 316). When trust cease to exist between various parties within the group, then the information may not reach the intended destination in its original form. Lack of trust hinders the communication process in the sense that some group members may distort some information aimed at enhancing communication. This implies lack of trust is an impetus to information distortion and manipulation that lead to miscommunication hence making the organization less effective. Trust instills confidence amongst the group members hence the increased openness amongst the group members. This boosts the efficiency of the communication….


text:
At its core, Kendo UI Mobile makes it easy create cross-platform mobile apps using HTML5 and JavaScript. And more than any other framework, Kendo UI Mobile helps your apps automatically adapt to look and feel native on different platforms, like iOS and Android. But did you know that Kendo UI Mobile can also help build apps that look and feel native on different form-factors?
"Universal" apps allow you to build and deploy a single app that automatically presents phone-specific UI on phones, and tablet-specific UI on tablets.
The concept is familiar to iOS developers, where Apple introduced universal apps to support iPhone and iPad app development, but the same can be achieved with cross-platform results using HTML, JavaScript, and Kendo UI Mobile. You build one app, with UI for phones and tablets, and deploy to iOS, Android, and Blackberry.
Let's examine the technique.
When building mobile apps to reach phone and tablet users, there are two options for supporting tablets:
The first option is the easiest and least expensive because it only requires one app design. It eliminates the need to work through a second design for an app that is optimized for tablets.
Of course, Option #1 also fails to treat tablets like a unique form factor. More than a bigger screen, tablets have unique UI conventions not found on smartphones, such as the split views common in iPad apps. Developers serious about targeting tablets should aim to deploy apps that are optimized for these unique usability requirements. Building one app with one UI is easy, but it's not enough to properly target multiple form factors.
Universal apps simplify the deployment of two distinct app experiences, while simultaneously making it easier for developers to share common app code between phone and tablet app variants (like common data handling code). When developers take the time to design unique experiences for both form factors, universal apps help put the right experience on the right device.
Fortunately, Kendo UI Mobile provides both tablet and phone specific UI widgets. Developers can leverage these widgets to create a perfectly tailored UI for both form factors, and then apply the following universal technique to easily deploy the results.
Building a universal mobile app using Kendo UI Mobile is not automatic, but it is very simple. There are 3 steps involved in the entire process:
That's it. Like I said, easy. The result allows the same deployed app to look like this on phones:
And like this on tablets:
In code, handling a universal app looks something like this:
<!--Initial tablet mobile app views/splitview go here-->
<!--Initial phone mobile app views/layouts go here-->
() {
//isTablet: Must be mobile OS AND tablet
isTablet = kendo.support.mobileOS && kendo.support.mobileOS.tablet,
appElement =
appLayout =
//Get the correct app HTML container based on tablet status
appElement = (isTablet) ? $(
) : $(
appLayout = (isTablet) ?
//Initialize the app with the selected container
app =
kendo.mobile.Application(appElement, {
layout: appLayout,
//Adjust visibility of proper app container (used to prevent FOUJUI)
You can try a live example using this jsFiddle. To test the behavior, I recommend using Chrome and the built-in Developer Tools to override the browser's User Agent. Try changing between an iPhone and iPad UserAgent to see how the app initializes differently (refresh the page to see the app reinitialize).
REMINDER: Kendo UI Mobile only supports Webkit browsers today, so the previous demo will not work in IE or Firefox. Please use a mobile device or Chrome/Safari to view the demo.
In english, the prior code snippet is conceptually doing this:
When using the universal app approach, the "Flash of Uninitialized JavaScript UI" (or FOUJUI) can be particularly distracting because the initial HTML page contains markup for both the tablet and mobile views. To provide a polished loading experience and avoid displaying unsightly HTML, it is important to address FOUJUI with some simple CSS and JavaScript.
In the example linked above, I use this technique:
As you can see, both HTML containers for the tablet and phone views are initially hidden via CSS. As part of the loading process, the correct container is shown after the Kendo UI Mobile application has been initialized:
//Where appElement is either the phone or tablet container
You could make the effect even fancier with CSS3 transitions and opacity:
#tabletApp, #phoneApp {
Now the correct app will fade in to view (hardware accelerated by CSS), and the unused views will remain properly hidden. No flash of uninitialized HTML. No ugly plain HTML displayed to users before your app is ready to go.
After trying this technique, the question often arises: "Why doesn't Kendo UI Mobile automatically adapt phone UI for tablets?"
The answer is simple: we don't know how. It's not that we're technically incapable, but adapting a phone UI to a tablet UI is not so dissimilar from trying to automatically adapt desktop UI to a phone. They are fundamentally different platforms with different usability considerations, and something that makes sense on phones may or may not belong on tablets. There is no predictable way to automatically transpose phone UI to tablet-specific UI.
Of course, Kendo UI Mobile apps can be built to run on both tablets and phones with a single UI, but as with any "one size fits alls" app, you will lose the benefit of optimizing for specific platforms.
What about responsive design, you ask?
Responsive design is great for creating mobile sites, but it's not as useful for creating mobile apps. Responsive design can help you hide, show, resize, and reformat UI for screens of varying size, but it is less suited for presenting completely different modes of usability on different form factors.
This is where we need your feedback again. We think the process for creating and configuring universal apps with Kendo UI Mobile is easy today, but clearly we could do more to make the process even easier to configure.
What else would you like Kendo UI Mobile to do for you if you're building universal apps? Should we make it easier to define the entry points to the phone/tablet app UIs? Should we enhance any of the APIs?
Let us know. Sound-off in the comments and on the Kendo UI UserVoice site: feedback.kendoui.com.
For now, have fun building (and deploying) universal mobile apps created with Kendo UI Mobile!
Todd Anglin is Vice President of Product at Progress. Todd is responsible for leading the teams at Progress focused on NativeScript, a modern cross-platform solution for building native mobile apps with JavaScript. Todd is an author and frequent speaker on web and mobile app development. Follow Todd @toddanglin for his latest writings and industry insights.
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text:
Blissful Indolence Made Simple
Vacation Special, August 1997
Blissful Indolence Made Simple
A Florida stream, an inner tube, and no ambition in sight.
By Bucky McMahon
There are two ways to tube down north-central Florida's Ichetucknee River: the easy way and the easier. Let's examine the easier first, assuming it's a radiant midsummer day, air temperature about 95, humid enough to confuse a frog.
Lie on your back, hindquarters submerged in the 72-degree water, gazing drowsily up through the overarching canopy of Spanish moss. Recall the First Law of tubing physics: The chill of the booty is directly proportional to the circumference of the vulcanized vessel. Fail to think of a Second Law. As the black rubber heats up, regulate body temperature by idly flicking water onto your belly and sighing.
Among Florida's many artesian springs, famous for their mermaids and manatees, none is more beloved by inner tubers than this perfect conduit for the indolent. Though parts of the Ichetucknee are narrow and serpentine, its banks are buffered by a luxuriance of eelgrass that will gently catch and release your tube with a soft, whispering sound. Do not attempt to steer the tube, except in slow circles to rotate the sky and invite musings on the immensity of the ether, which is frankly miraculous and ultimately exhausting. It's possible at any moment to be struck by a falling stinkpot, a turtle known to climb high into the canopy and leap into the water when startled. Possible, but unlikely. Disregard the threat, or think to yourself, If the blow must come, let it be fatal. Drifting, drifting, you've made your peace.
With the easier path, it's more likely you'll fall asleep, only to be wakened by the laughter of other tubers. You've gone aground in a shaded eddy, your mouth comically gaping. Sit up, blinking and grinning sheepishly. Now is a good time to tackle the easy way.
This way is more gear-oriented (a mask and snorkel). Flop onto your belly and, chin resting on rubber or head slightly elevated, survey the banks for stalking egrets, sunning Suwanee cooters, or periscope-nosed softshell turtles. You might see otters and beavers, but by and large this is wilderness writ small, though with startling clarity. Because many springs feed the Ichetucknee as it winds through pines, hardwood hammocks, and swampland, visibility is forever. It opens wee mysteries like a microscope slide.
Plunge your mask into the stream. Now you see the spring's power, pumping an average of 233 million gallons a day. The fish, you see, the bream and bass and little sailfin mollies, are working hard not to drift. The eelgrass is waving as if in a gale. You see breaks in the streambed, phosphate pits and sudden overhanging caverns. Unable to resist, you slither from the tube like a gator and dive deep, and are rewarded by a chance meeting with a siren, a three-foot-long legless salamander. Which is thrilling and, ultimately, quite chilling.
You'll need to get warm again. Clamber back aboard the tube like a cooter (from kuta, an African word for "turtle"), and take it easier.


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Hazelnut is my least favorite nuts, compared to walnuts, almonds, pecans, or cashews. So when I saw this on the rotation schedule, my reaction should have been: "I'm gonna skip that." But I feel like baking this weekend and I really need to make up for lost time of being absent all summer, so here I am participating (do I get brownie points for this? :)).
This is a really interesting recipe. It's really easy to put together and the bonus is you learn a cool trick from Rose on how to easily peel hazelnuts. When I saw in the recipe that the first step is to peel the hazelnuts, I thought it's only because you don't want the bits of skin in the cookie dough. But then I realized that by peeling the hazelnuts, it allows you to roast them at a good temperature without burning them. I've made roasted mixed nuts before and the hazelnuts burn faster - I have thrown away a batch because I roast them at the same 350 degree temperature as walnuts and they burn and made my kitchen smell horrible. Now I know what to do - peel the skin!
I am also glad I made this recipe as these cookies are sooo good! They don't taste very strong like hazelnuts and more like yummy butter crunchy sweet stuff. I already ate a bunch and I'm gonna have to give the rest away to my friend so I don't eat all of them today.
Step by step photos:
Boiling the hazelnuts. I boiled them for 7 minutes.
Dunk the boiled hazelnuts in cold water (I use a couple of ice cubes) then peel the skin off. The skin came off really easily. Then placed the hazelnuts on clean dish towel to dry.
Then roast the nuts in a 350 degree oven.
Make the caramel. It is darn difficult to watch 1/2 a recipe of this to boil and not burn it. Fortunately, I knit next to the stove!
Rearranged the toasted nuts so they are together and pour the itty bitty quantity of caramel over them.
It then gets to be let cooled for 20 minutes before pulverized in a food processor.
I used pyrex bowl to store it in the fridge for an hour.
Hazelnut praline balls!
Flattened into 1 1/2 inch round.
Baked, served, eaten.


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a room equipped for taking a bath or shower
toilet (def )
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excessive pride in one's appearance, qualities, abilities, achievements, etc
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an instance or display of this quality or feeling
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lack of real value; hollowness; worthlessness:the vanity of a selfish life
something worthless, trivial, or pointless
vanity case
dressing table
a wide, counterlike shelf containing a wash basin, as in the bathroom of a hotel or residence, often equipped with shelves, drawers, etc
, underneath
a cabinet built below or around a bathroom sink, primarily to hide exposed pipes
compact (def )
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the contents of a bowl:a bowl of tomato soup
a rounded, cuplike, hollow part:the bowl of a pipe
a large drinking cup
festive drinking; conviviality
any bowl-shaped depression or formation
an edifice with tiers of seats forming sides like those of a bowl, having the arena at the bottom; stadium
Also called bowl game
a football game played after the regular season by teams selected by the sponsors of the game, usually as representing the best from a region of the country:the Rose Bowl
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Counting Candles is one of my absolute favourite math games! I am a little sentimental about it too. It has been with me right through my From the Pond life - from eBay to website, and now including my own illustrations onto TpT.
The basic idea with this activity is that students roll a standard die, count out a set of candles and place them on their cake. They keep rolling and counting to practice and eventually compare cakes with a friend to determine the 'winner'.
Like everything in the classroom though, there are multiple ways to differentiate and utilise the equipment. Here are just a few ideas - some of which I shared on a Facebook Live video today as I played this game with my sweet boy.
1. Addition.
Roll the die twice, make 2 groups and find the total. Record on a whiteboard.
2. Patterns
Create and build repeating-patterns with the candles.
3. Take-Away
Commence the game with a big stack of candles on your cake, and play in reverse. Take candles OFF the cake (tell the kiddos they are blowing them out) as they roll.
4. Alternative Equipment
Use plastic plates, popsticks and play dough for cakes and candles! Just a warning though, this can quickly become a 'I want to play with the play dough' the situation quickly if students are not given very explicit instructions. It is very tempting to handle the dough!
Make the basic game more challenging with a differentiated selection of dice.
1. standard dot dice
2. double dice (add)
3. numeral + dot dice (encourage counting-on)
4. 2 x numeral dice (addition with mental strategy)
5. Multiplication
Play with lots of cakes and candle cards. Students roll the dice twice and make a problem - e.g. 3 x5 by rolling a 3 and a 5. They then build an arrangement of cakes with candles to find the total and model multiplication.
Thanks so much for stopping by my page today - have a wonderful day!


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I have recently purchased a Lumie Bodyclock Starter 30 Wake-Up Light Alarm Clock with Sunrise and Sunset Features. I bought this hoping that it would help me to get up in the mornings and ready for the day. Even before the clocks went back for Daylight Saving here in the UK I struggled to get out of bed. I know my depression is getting worse when I struggle to get out of bed. Recently I woke up with three loud alarms, 15 minutes apart. I turned them all off and slept for another hour! The sunrise effect of this clock is designed to start the day in a peaceful and happy way, rather than a blaring alarm waking you with a jolt! I wanted to stop pressing snooze and start the day more positively and less sleepily.
The Lumie Bodyclock
The main reason that I purchased this particular wake up light (there's lots on the market now) is that the Lumie Bodyclock is supposed to be the original and best. I also really liked its unique lighting effect which fans the light out in rays.
Setting up the clock and the alarm settings is fiddly and confusing. Lumie recognise this and include detailed instructions and a link to a video. I think it is so confusing because it only has three buttons so you have to cycle through multiple settings rather than just pressing a button. You set the alarm for the time you want to get up and it starts to light up 30 minutes before this time. You also have the option to have a noise go off at full light. So the time that you set the alarm for is the time that it is brightest and beeps. It took me ages to work this out and in the end I had to google it!
Waking up happier with the sunrise
In theory this clock uses light to gradually wake you up so by the time your alarm goes off you're already awake and ready to face the day. For me, it hasn't quite worked like the photos on the side of the box. On the box the lady gradually wakes up with a smile on her face as the light increases but I haven't woken up before the alarm goes off! However, it is harder to go back to sleep with the light on (notice I say harder but not impossible!)
Going to sleep happier with the Sunset
My favourite feature of the clock so far is using it as a bedside light as a sunset. When you want to go to sleep you press the button for 2 seconds and the light gradually turns down over the next 30 minutes. In the evenings I have been reading and putting my book down when I can't see anymore. As it gets darker I feel sleepy and it's really helping me to drift off.
Morning Routine
I think what I need to do to really make this sunrise clock work for me is to be stricter with myself. It is not going to be a magic cure for my desire for more sleep! What I really want to do is develop a morning routine. This will help me to have some me time filled with self care activities. I want to start my day off positively and improve my mental health. I hope that waking up with a sunrise will help me do this.
What do you think of the bodyclock?
What helps you get up in the morning?
Do you have a morning routine?
Edit: I have now been using the Lumie Bodyclock Starter 30 Wake-Up Light Alarm Clock with Sunrise and Sunset Features for a couple of months and highly recommend it. It took me a while to get used to it but it definitely helps me get up in the mornings and feel sleepy in the evenings.
Disclosure: this post includes affiliate links to amazon. This means that if you click on the link and purchase this clock or other items I will receive a commission. Thank you for your support.