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Tag Archive
Scouting Report: Miami Heat
With their magic number down to one, the Hawks (36-43) have three games left, beginning with a match-up tonight against the Heat, who currently are the top seed in the Eastern Conference — which would make them the Hawks' first round opponent. The Heat easily disposed of the Pacers last night to reclaim their... »
Hawks Beat Heat For Third Straight Win at Philips
The Hawks (21-19) got a victory over the reigning NBA champion Miami Heat in a high-scoring affair, 121-114. Atlanta had seven players get into double figures and shot 51.9% from the field (38.7% from three) along with going 25-of-27 (92.6%) from the free throw line in the win. Miami's offense shot well too, particularly... »
Hawks vs. Heat MLK Day Game Preview
The Hawks will take on the Heat on Dr. Martin Luther King, Jr. Day in what will be the first of two visits by the reigning NBA champions to Atlanta this season. The Heat went through a three-game losing streak recently, but rebounded with back-to-back wins over the Sixers and the Bobcats on Friday... »
Hawks Fall In Overtime to Heat
Paul Millsap set a career-high with seven three-pointers (7-of-10) finishing with 25 points and 10 rebounds and Jeff Teague led the Hawks with 26 points and eight assists but the Hawks (15-13) were unable to close out the Heat (21-6) in Miami, as they squeaked out the 121-119 win. Hawks vs. Heat Photo Gallery Stats... »
Scouting Report: Miami Heat
The second-place Hawks make their second and final regular season visit to Miami hoping to gain a game on the first-place Heat in the division Monday night. Atlanta played well for three quarters in Miami before things unraveled in a 104-88 loss last month. Preventing The Heat from getting going off the dribble will... »
Scouting Report: Miami Heat
The two-time defending NBA champions enter Tuesday's matchup against Atlanta with a 7-3 record, though they're 6-1 since a sputtering 1-2 start. The Heat have been very efficient on both sides of the ball, but especially offensively in the early going. They lead the Eastern Conference in field goal percentage, three point percentage and... »
Scouting the Opposition: Miami Heat
For every home game this season, we'll be gathering some intel on the opposing team from someone who knows them best — a team employee, a rival blogger, beat writer or broadcaster. For the Hawks' home game Friday night against the Heat, we reached out to Surya Fernandez, who writes about Miami for the... »


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Physicans in New York Use Cholesterol Panels to Screen for Heart Disease
Your Upper East Side doctor, Marina Gafanovich uses cholesterol panels to screen patients for current or potential heart disease.
"Cholesterol panels" is a lay term for what people in the medical profession describe as "lipid panels". These blood tests are used by doctors in the screening process for heart disease. The body uses lipids (fats) as a source of energy. However, when there is too high a level of these fatty substances in the bloodstream it can, over time, lead to aortic blockage.
These panels measure:
- Your total cholesterol level
- Triglycerides
- Your HDL ("good" cholesterol) levels
- Your LDL ("bad" cholesterol) levels
Dr. Gafanovich may widen the scope of the panel depending upon your particular previous diagnostics to include the "Very-low density lipoprotein" (VLDL) levels, as well as, perform other comparative measurements as a part of her cholesterol screening process.
Prior to taking this test, New York Doctor, Dr. Marina Gafanovich, will give you specific instructions in regards to eating and drinking.
Call (212) 249-6218 to schedule your appointment today.

subset: commoncrawl


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Your chest voice and your head voice are two of many areas you are able to sing in. A lot of men tend to love to stay in their chest voice, while many women prefer singing in their head voice only. Listen as Joe explains why it's important to mix both voices.
Tag Archives: singers
Muscle Memory
In this video, Joe Genuardi explains the importance muscle memory, and training your singing muscles.
If you have been singing for a long time, like many of us, you may have developed some singing habits that cause strain on your voice. Using the True Connected Voice method, training your vocal cords will improve your singing quality by developing muscle memory.
The concept of muscle memory is when you condition your voice to sing in the True Connected Voice style, your singing muscles will adapt and be conditioned over time to automatically shape and move in a way that maximizes your vocal quality.
Muscle memory can be developed by a series of exercises that we will train you with. These exercises are easy to learn and practice. This method will develop you into a singer that sings freely, with no strain and pure tone all while maintaining a healthy voice.
Vocal Compression
In this video Joe Genuardi explains how vocal compression works.
Vocal compression is the idea of holding air back when you sing. Your voice does not need extreme amounts of air to sing higher. It cut actually needs less air.
When you zip up your vocal folds, the space between them gets smaller as the pitch you are singing gets higher. Therefor less is is required to sing higher.
In this video, Joe explains how vibrations work in your voice, and different vocal registers.


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Shunyata: How Emptiness Leads to Enlightenment.
Part four in a series on Buddhist meditation awareness practice. Click here for part one, here for part two and here for part three.
To practice prajnaparamita (see article III of Awareness Practice) is to mix mind with space without sliding into nihilistic absorption, without "spacing out."
To meditate in this way is to rest awareness in space while being wide awake. Words can point to this experience, but the experience is indescribable. Yet it is helpful to know that dwelling on space as a reference point is still dualistic confusion.
Shunyata or emptiness is non-dwelling on anything. Enlightenment is realizing that thoughts and emotions and the world of form are all the play of the mind, appearance-emptiness. We can actually practice this until we are no longer caught in the duality of subject and object, internal and external, I and other. Such concepts are removed through the understanding and repeated experience of emptiness or shunyata.
As Trungpa Rinpoche says, "having thrown everything away, we begin to feel the living quality of peace…(which) has a strong character, an invincible quality, an unshakable quality, because it admits no gaps of hypocrisy."[1]He goes on to say, "Complete openness is complete victory because we do not fear, we do not try to defend ourselves at all."
So this openness or emptiness is not sterile, it is also the origin of all the natural enlightened qualities, such as compassion. For when there are no boundaries, compassion naturally arises.
Then we truly wish the "Four Immeasurables" for everyone:
May all sentient beings enjoy happiness and the root of happiness.
May they be free from suffering and the root of suffering.
May they not be separated from the great happiness devoid of suffering.
May they dwell in the great equanimity free from passion, aggression, and prejudice.
The point of practicing awareness is to be open-hearted and open-minded. That is why the Heart Sutra's exponent of prajnaparamita, Avalokiteshvara, is also the bodhisattva of compassion (see Awareness article III). There is no separation between the experience of spacious openness and post-meditation compassion. If our discursiveness and conflicting emotions are not gradually diminishing, we should question ourselves. Self-reflection is the willingness to see our short-comings and is another valuable form of prajna.
Are we really putting attention on the breath? Are we then relaxing into the space to which the breath takes us? Or are we seduced by every thought? If this is happening, do we remember to look at the mind that thinks? What happens then? Are we recognizing and letting go of habitual patterns? Do we have the motivation and stamina for daily practice?
Such questions wake up practice. We do not need to judge ourselves or give ourselves a hard time for having a hard time. That would be what Trungpa Rinpoche called "double negativity." But simple self-reflection keeps us honest.
The good news is that every time we return to the breath or remain in the openness of space, we are undoing habitual patterns of wandering and fixating. And even if we only once in a session glimpse the true nature of mind, we are uncovering again that clarity-emptiness, energy-emptiness, awareness-emptiness. And then post-meditation we may discover that we are less fixated and more flexible and available to others.
Trungpa Rinpoche encourages us: "Sudden enlightenment comes only with exhaustion. Its suddenness does not necessarily mean that there is a short cut…Meditation is…fully being in the nowness of this very moment."
But enlightenment is not usually a do-it-yourself project. A meditation master is essential for mind to mind transmission, which can happen formally or in a casual encounter. This master teacher can be whoever you thoroughly connect with. The sixth patriarch was an illiterate layman, yet Korean, Vietnamese, Chinese, and Japanese Chan and Zen traditions trace back to him.
The present Seventeenth Karmapa says, "Resting evenly in this free expanse that is the mind's nature is practicing deep insight."
If we are not able to do so, perhaps we need a meditation master.
[1] VCTR, Cutting Through Spiritual Materialism, 'Shunyata" chapter.
Ed: Edith L.
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10 Responses to "Shunyata: How Emptiness Leads to Enlightenment."
Merry Christmas Linda!
Thank you Linda.
Many practitioners these days do not have the resource of a meditation master. There is a plethora of written material as well as on line access to teachers yet the master teacher may be difficult for most to affiliate with for direct transmission. Some may feel at a loss due to this absence despite their dedication to practice and the three jewels.
What might help mitigate this sense of "missing teacher" for those remote practitioners.
Thank you.
I look forward to your articles.
Actually, living in North America we are blessed with quite a few master teachers, but one does need to make an effort to connect with any one of them. Here in Nova Scotia and frequently in Colorado is Sakyong Mipham R., who is currently doing a retreat in Kalapa Valley, Cape Breton. There is also Dzongzar Khyentse R. who teaches in BC and California annually, and who just finished a retreat with his students in India. There is Ponlop R based in Seattle, Washington, who travels and teaches. Mingyur Rinpoche is currently in the midst of a 3 year wandering-hidden yogi retreat probably somewhere in Northern India or Nepal who will come out of retreat and teach brilliantly again. And then last spring/early summer we had the teaching visit of Tsoknyi R here in Halifax, NS. You can go on line and check out these teachers' teachings, and then try to make a point to be where the one with whom you seem to connect will be teaching next. Being a pilot, you have the advantage of getting around! Good luck. But you won't need luck if you make it a priority!
HI Linda:
It seems there is an attempt here to reverse engineer enlightenment — in otherwords, emptiness as a practice vs a result? I encourage you to read my own experience of a sudden awakening/transmission. One thing that is so clear now: The seeker (the meditator, the yogi practictioner, the student) dissolves instantly and it is seen that it was inessential. The waking/realisation reveals all the efforting, was the mind working at achieving what is a matter of grace.
very best,
Lori Ann
There's no instant enlightenment without gradual practice. Sudden enlightenment does come, but after much practice. All practitioners who really meditate have glimpses, and temporary experiences. It's even easy intellectually to understand impermanence without practicing. But to see the lack of self and the lack of any substantial entity in phenomena takes time, as our habitual ignorant pattern is to think there is a self to put first. Once we see emptiness, that experience needs to be stabilized.
Many of us are on the path to enlightenment, it is our birthright, but do we realize this full time? One sign is unconditional compassion, not tit for tat compassion, not hoping to get anything back from generosity, not fearing consequences, just on the spot open heart full time. Are you like that? How many people do you know like that? The best examples I can think of tend to be the Tibetan gurus in the comment above, or Zen masters, Thic Nat Hahn, etc. People who have spent their lives dedicated to dharma and living it.
[…] Emptiness is sublime. Though it is a void, it is transparent and vivid. See if you can find a way to allow some emptiness into your life. Reflecting on a fear or a recent loss can bring you to a place that feels like the edge of a cliff. Instead of pushing those feelings away, find a safe way to experience them for a moment or two. […]
[…] Shunyata: How Emptiness Leads to Enlightenment. (elephantjournal.com) […]
[…] Teaching emptiness to the Western student is the most difficult thing, because as soon as I teach emptiness they think about psychological emptiness. Psychological emptiness of having a big hole in your heart. Or you're lonely or depressed or depleted. Meaninglessness. Something is not there and they need to fill. They think emptiness is that, very negative. […]
[…] Shunyata: How Emptiness Leads to Enlightenment. (elephantjournal.com) […]
when Avalokiteshvara, the bodhisattva of compassion, in the Heart Sutra famously said as Gautama Buddha sat in samadhi in front of him, "emptiness is form, form is emptiness," he did not mean the world of form; he meant the form that is the first skandha; the cornerstone of ego; that is why the Vajracharya Chogyam Trungpa Rinpoche said (still says), Shunyata is not about the emptiness of the world, it is about the emptiness of our perceptions of the world.


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The locking mechanism can have some sticky moments; cleanliness is key and you might want to get a rifle cleaning rod to get up in the top section on a regular basis with a scrap of rag. Otherwise it has not failed me or ever come loose.
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They are exceptionally light and easy to carry.
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It takes a while to get used to the "funky" nature of the locking mechanism. You might be turning the section for 15 seconds...30 seconds... ...60 seconds...wondering if it's ever going to "catch." Thankfully it always did.
The boot wore out after 500 miles. The metal tip poked through the rubber bottom. I really liked the boot, as it took most of the shock out of each pole plant. Plus it kept the tip from getting caught in cracks.
As the lightest pole on the market I never experienced fatigue holding it all day long. It was indispensable in negotiating terrain that made Maine's Mahoosuc Notch seem like child's play in comparison.
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FTP Surfer User Reviews
out of 119 user reviews
Version: FTP Surfer 1.0.7
i liked it a lot.. fast, easy to use, gets the job done, what else do you need..
"nice ftp program with good features"
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Very easy to use, I needed mainly the permissions feature, and it worked perfectly! :)
"easy to use"
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easy to use ftp client.
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Version: FTP Surfer 1.0.7
I found this ftp client poor in comparison to most of the others I have tried. It seemed very hard to get it to do what you wanted and had no uninstaller. It changed some settings on Windows, making Windows use one of it's .dll files, so you cannot fully remove it (at least not easily). All in all I'd stay clear, why bother when if you want something free you can use Leech or WS...
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Familiar interface and will resume broken downloads (important for modem connections). Allows drag & drop and editing in place with double click by means of a background transfer to your windows\temp directory and then ftp it back after you save your documents. Went freeware Nov2001.
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» Views
Don't let the past shape Asia's future
Publication Date : 21-09-2012
Asia has been roiling in turmoil over territorial disputes in recent days, with China at loggerheads with Japan, and the latter at loggerheads with South Korea, and the region engaged in increasingly fractious exchanges among claimants over overlapping claims to the oil- and gas-rich South China Sea.
Worse, these long-simmering spats are boiling over at a time of growing economic uncertainty and social unrest.
But pioneering Singapore diplomat Barry Desker remains confident about the region's future.
"I'm not so pessimistic about Asia," he said in an interview last Friday (September 14), noting how much surer, calmer and richer the region is today compared to the 1960s and 1970s, when it was pockmarked by communist elements and aflame with anti-colonial protests.
Desker, 65, is dean of the the S. Rajaratnam School of International Studies (RSIS), a think-tank here that hosts the third instalment of its Singapore Global Dialogue today. The dialogue is a high-profile forum for global thinkers to discuss strategic security issues.
Recalling just how insecure Asia was in 1970, when he first started out at the Ministry of Foreign Affairs (MFA), he said: "Southeast Asia in the 1970s was a cockpit of controversy... the picture did not look promising. Yet today, its situation is probably more hopeful than in south-eastern Europe, which was ravaged by conflict after the Cold War ended and with Yugoslavia splitting up."
Southeast Asia, in particular, was once known in diplomatic circles as "the Balkans of the East". But it avoided being "Balkanised" or riven by ethnic strife, noted Desker.
This was in part thanks to Asean, the now 10-member regional grouping that, among other things, welcomed the once-communist Indochinese states of Vietnam, Cambodia and Laos into its fold unconditionally in the 1990s.
"You had a coming together of diverse states, particularly because Asean took them in without any conditions or a process where they learnt about the nature of the organisation that they were coming into, and the need for consensus among members," Desker mused.
That consensus, however, is being increasingly rattled by some of its members' competing claims over the South China Sea, a 3.5 million sq km body of water that China claims as its own too.
In 2009, for example, Vietnam and Malaysia put in their claims to the sea, based on an extended continental shelf, which prompted China to submit in May that year - for the first time at the United Nations - its Nine Dashed Lines map, demarcating about 90 per cent of the waterway as its entitlement.
By doing so, Desker said, China risked "undermining the goodwill" that it had amassed for itself in Asia.
In fact, he argued, China's muscle-flexing on the issue was what led to the recent United States "pivot to Asia" in the first place.
So might all this be leading to Cold War 2.0, with China replacing the former Soviet Union in a global face-off with the US?
It's too early to make such an assertion, Desker said. "My view on those who argue that a Cold War is in an incipient stage is that one should not look only at the maps of the past to derive the maps of the future.
"The future is in our hands and we can help to shape it and we need not merely be (led along) by the flow of events in the past."
Already, as a Reuters report had it in May, by asserting its Nine Dashed Lines, China was now in a Catch-22 situation: On the one hand, if it did not fend off claimants to the waterway, its increasingly nationalistic population would see its leaders as shrinking Chinese territory.
On the other hand, China is party to the 1982 United Nations Convention on the Law of the Sea
(Unclos), and its insistence that it owns most of the South China Sea would go against Unclos and anger its neighbours.
Either way, as one China foreign policy expert Sun Yun told Reuters, China cannot win. Can't it, though?
The key to ending the impasse, Desker said, is for China to engage all the claimants to the disputed sea and to reach a consensus with them.
Up till now, China has been bent on dealing with claimants one by one, which made things "difficult" given the overlapping nature of many of the claims.
The South China Sea spat would be better dealt with through some form of adjudication, if not arbitration, and certainly through more consultations beyond just bilateral talks, he reckoned.
Desker has a longer view on the restive region than most people: He headed the MFA's South-east Asia section in the early 1970s.
He rose to become Singapore's ambassador to Indonesia from 1986 to 1993. He then headed the Trade and Development Board from 1994 to 2000, and then moved on to join the think-tank world.
Asia, he mused, is a perennial lightning rod for conflict, having been bedevilled in the 1960s and 1970s by attempted coups in Indonesia and Thailand, communist insurgencies in Malaysia and Indochina, and protracted battles such as the Vietnam War, in which the US was embroiled.
Fortunately, he added, the region had Asean and its commitment to consensual decision-making, which has helped Asia keep the peace for 45 years.
Of course, he allowed, "when there were difficulties in reaching a consensus, the Asean Way meant the lowest common denominator (view) would hold".
Might that Asean spirit of consensus be dissipating, though?
In July, for the first time in its history, Asean's 10 members could not agree on a customary joint declaration at their summit in Phnom Penh.
That was because they locked horns over one paragraph in the draft declaration concerning some of the members' competing claims to the South China Sea.
But there is good news, Desker said. Since the Phnom Penh summit, Indonesian Foreign Minister Marty Natalegawa has quietly visited all other Asean members to get their consensus on a stand on the South China Sea, based on six principles.
Asean is poised to issue a joint declaration on this issue when its ministers meet in New York later this month for the UN General Assembly.
Desker stressed, however, that Asean itself wants no part in negotiating the South China Sea issue, but it is pushing for negotiators to abide by a code of conduct to resolve the conflict as peaceably as possible.
Asia, he said, will be where the world's most pressing concerns will play out from now on.
As it is, trade across the Pacific Ocean is already much greater than that across the Atlantic, and global decision-making would soon follow suit.
This also means that Asia could become the stomping ground for future global conflicts. So "the test for diplomats is how one could help to avoid such an outcome".
Away from the madding tensions over lands and seas, said the old Asia hand, the region has longer-range problems that require concerted action to tackle.
That is to say, can its many diverse communities form cohesive societies? Can it close the growing urban-rural gap even as more Asians crowd into cities? Can its governments really involve their increasingly vocal netizens in decision-making?
Last but not least, can it free its people from the middle-income trap, in which the middle class grows too comfortable to want to be more competitive and try new things?
Desker said such challenges are so great that they require seismic shake-ups in many areas, including enabling more of the region's children to complete at least secondary school so that they can better seize opportunities to do business or innovate.
"The difficulty in this," he said, "is that the tendency has been to be very comfortable with what we have and want to improve only incrementally."
While this concern does not apply to Singapore today, he said the Republic's sterling economic success presented a delicate problem: "How do you change a model that has worked so successfully? Or challenge the dogmas of the past?"
Desker, who was among Singapore's first President's Scholars in 1966, has roots in Singapore that go deep. Desker Road was named after his great-grandfather, butcher Andre Filipe Desker.
The think-tank he heads turned six this year. In January, RSIS was, for the first time, listed among the world's top 50 think-tanks outside the US, in the University of Pennsylvania's Global Go-To Think Tanks Report; it was 48th.
Desker said: "I'm always sceptical of such surveys because, in a sense, they are based on reputation... Every year, those who carry out such surveys change the parameters so that there is movement up and down the ranks."
Such volatility, he added, was "part and parcel of the game" of global institutional rankings.
» Other Views
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● ITANAGAR: India earmarks $23m for Himalayan ecosystem study
● HONG KONG: No dual listing preserves HK stock market's integrity


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Modafinil for Atypical Depression
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The purposes of the study are to: 1) evaluate the short-term efficacy and safety of modafinil in atypical depression; and 2) to evaluate the efficacy of modafinil in preventing relapse of atypical depression. The hypothesis is that modafinil is safe and effective in the treatment of atypical depression.
Atypical Depression
Drug: modafinil
Phase 2
Phase 3
|Study Type:
|Study Design:
|Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double-Blind
Primary Purpose: Treatment
|Official Title:
|A Study of Modafinil for Atypical Depression
- HAM-D-29 (Hamilton Depression 29-Item Scale, with Atypical Features)
- ADDS (Atypical Depression Diagnostic Scale)
- CGI-S (Clinical Global Impressions Severity Scale)
- CGI-I (Clinical Global Impressions Improvement Scale)
- SCL-90 (Symptom Checklist 90)
- ESS (Epworth Sleepiness Scale)
- BFI (Brief Fatigue Inventory)
- FSS (Fatigue Severity Scale)
- SOS (Severity of Symptoms Scale)
|Estimated Enrollment:
|Study Start Date:
|February 2003
|Estimated Study Completion Date:
|April 2005
This study on the safety and efficacy of modafinil on atypical depression has an initial 12-week open label treatment period with modafinil that is followed by a 12-week double-blind, randomized parallel treatment period with either modafinil or matching placebo. Patients who demonstrate at least minimal improvement after 12 weeks are randomly assigned to either continuing treatment at their current dose or switched to matching placebo for 12 weeks.
|Ages Eligible for Study:
|18 Years to 65 Years
|Genders Eligible for Study:
|Accepts Healthy Volunteers:
Inclusion Criteria:
- adults 18-65 years of age
- DSM-IV criteria for major depressive episode with atypical features as assessed by the Atypical Depression Diagnostic Scale
- minimum score of 18 on the Hamilton Depression Scale (29-item version) at baseline
- baseline Clinical Global Impressions Severity score of 4 or more
- written informed consent
- negative serum pregnancy test for women of childbearing potential
Exclusion Criteria:
- any current primary DSM-IV Axis I disorder other than depression
- history of DSM-IV diagnosis of bipolar I disorder, schizophrenia or other psychotic disorder, mental retardation or other pervasive developmental disorder, or cognitive disorder due to a general medical condition
- history of substance abuse or dependence within the last 3 months
- suicide risk or serious suicide attempt with the last year
- clinically significant medical condition or laboratory or EKG abnormality
- history of non-response to three prior adequate trials of antidepressants
- women of childbearing potential who are unwilling to practice an acceptable method of contraception
- history of hypersensitivity to modafinil
- use of an investigational medication within the last 28 days
- use of antidepressant medication with 28 days of screening
Please refer to this study by its ClinicalTrials.gov identifier: NCT00215176
|Principal Investigator:
|Jonathan Davidson, M.D.
|Duke Univeristy Medical Center
No publications provided
|ClinicalTrials.gov Identifier:
|NCT00215176 History of Changes
|Other Study ID Numbers:
|Study First Received:
|September 20, 2005
|Last Updated:
|June 17, 2013
|Health Authority:
|United States: Food and Drug Administration
Keywords provided by Duke University:
atypical depression
Additional relevant MeSH terms:
Depressive Disorder
Behavioral Symptoms
Mental Disorders
Mood Disorders
Central Nervous System Agents
Central Nervous System Stimulants
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses
Wakefulness-Promoting Agents
ClinicalTrials.gov processed this record on October 13, 2015


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Photos from the Maple Leafs' game against the New Jersey Devils at the Air Canada Centre Sunday night in Toronto.
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Jacqui Lambie hits back at 'Boganland' title, saying 'I'm for the underdogs'
- From: Mercury
- December 05, 2013
PALMER United Party Senator-elect Jacqui Lambie has hit back at a senior colleague's label of "Boganland", describing herself as a champion of the underdogs who live in the real world.
In an email obtained by the Mercury, the PUP's Queensland state MP Alex Douglas delivered an unflattering assessment of Australian battlers.
But Ms Lambie shrugged off the criticism, saying people who referred to others as bogans should get in the real world.
"Bogan is a derogatory term," she told the Mercury yesterday.
"I am from the underdog world. Some people call them bogans, I call them underdogs.
"It is hard to keep getting up each day, trying to put food on the table, when there is no employment."
Are you offended by the term "bogan"?
In an email to then Tasmanian PUP candidate Marti Zucco on September 27, Dr Douglas bemoaned the influence of "demanding" bogans.
"Bogans have ... inherited the earth and the world is full of them demanding their right, in an odd way, to be heard," Dr Douglas wrote.
"It is no longer satisfactory that they will just buy [and wear] Ugg boots, watch Big Brother, choke on a diet of grease, dye their bright purple [sic], tatoo [sic] and rejoice in their ignorance."
The former Gold Coast GP went on to write that Ms Lambie was "from a world we see daily and quietly hope will disappear".
"It won't, and nor at present, will she," he wrote.
"We have thought about it and will focus on training her, initially."
But Dr Douglas also described how Ms Lambie's connection with battlers could be an asset to the PUP.
"The interesting observation about Boganland is not just how common it is now but how the sufferers just copy one another so quickly with each trend ... happy with trinkets and false gold who never care to question why. That's where Jacqui comes from but curiously she wants bogans to have a better deal, whatever it is they want.
"I am assuming beyond TVs, rubbish foods, tacky clothing and empty lives. She could be an ace up our sleeves.
"What do you really know about bogans? I have seen them for 30 years as patients. They are good bell weathers [sic] of community angst/happiness and sometimes what current issues are really important."
Dr Douglas last night confirmed the emails to Mr Zucco.
"They were basically between myself and Marti to say that I was very unhappy about certain things that were going on," he said.
The email revelations followed a new EMRS poll released yesterday that showed the PUP had enjoyed a boost in popularity in Tasmania.
Polling showed support for the PUP up 4 percentage points from September to 5 per cent.
Mr Zucco yesterday said he had called upon party leader Clive Palmer to clear up the spat between himself and Ms Lambie.
"I would have thought the best way forward was to get both of us to sit down and discuss the issue," he said.
"That is the way to resolve issues and move forward. I would have assumed the party would have done so. I did offer to fly to Queensland at my own cost to do so."
He again raised concerns about the PUP's future in Tasmania.
"There has been no clear direction since the 21st of November," Mr Zucco said, referring to the day a state director for the party was appointed.
Mr Zucco said he had moved on and was focused on his role as an independent candidate.
"I just want to get on to the state campaign and look at getting some new and exciting projects going forward.
"I do want to send a message to Will Hodgman, Lara Giddings and Nick McKim, if I happen to be elected and possibly hold the balance of power, that I am quite happy to work with whoever has the majority of support."
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Comments on this story
Kitty Phelan of NSW Posted at 3:32 PM December 08, 2013
The people who use the name 'bogan' give me more cause for concern.
edmond shaw of bellerive Posted at 1:07 PM December 06, 2013
D.D always at the ready to run down the liberals with his what if attitude, I'll play along David what if liberal win with a majority? you always have them needing another party just what if they stand on their own two feet, no deals, no labor/green/pup. Many think they will wipe the floor with their opposition at the next election so just wait and see David. Labor may need the Greens or they may need to be put on a short lease with Pup, but I'm betting Tasmanian's have learnt by their past mistakes.
Paul Carroll of Lindisfarne Posted at 10:38 AM December 06, 2013
Errr Nick all that is on the PUP website and with Palmer talking about just that!
pat wilson of hobart town Posted at 8:40 AM December 06, 2013
David Dobbin of Launceston. POSTED AT 12:23 AM TODAY. You claim that a majority Liberal government in 2014 "guarantees no Liberal policies get implemented in Tasmania" After 4 years of apathetic, unstable and incompetent Green/Labor governance, what evidence do you have to uphold the notion that it would be advantageous, in terms of Liberal policy implementation, in Tasmania, were the Liberals to ever form government in partnership with The Greens? I'll tell you for free: NONE! You're plucking at straws yet again david, perhaps in blind pursuit of your will to have restrictive Green ideologies in government? If you consider how destructive the Green/Labor farce has been to Tasmanians, and indeed, Labor as a party, why would the Liberals foist Green ideologies upon Tasmanians and indeed themselves by seeking to govern with The Greens? Just look at how unpopular the Green/Labor minority is in Tasmania. You need to get out more david.
pat wilson of Hobart town Posted at 6:31 AM December 06, 2013
Anna Barbauld 4:14pm. The state Green/Labor gov't recently had the audacity to openly say that Tasmania's low socio-economic status was the cause of our problems. Of course, true to form, the Green/Labor had no answers or solutions as to how they might start addressing the problem. Such apathy and inaction we have not seen in government for many a term.
David Dobbin of Launceston Posted at 12:23 AM December 06, 2013
Nick - I repeat my question to you - here are the choices you face as a Liberal supporter if the Libs do not win a majority in 2014. 1. Four more years in Opposition 2. A Liberal government in partnership with the Greens 3. A Liberal government in partnership with PUP (if they win a seat) 4. A Liberal government in partnership with Labor That's it. Which of the above is the best way to get Liberal policies implemented in Tasmania? Hodgman clearly prefers Option 1, which guarantees NO Liberal policies get implemented in Tasmania. What about you?
Clare Hawkins of Hobart Posted at 11:09 PM December 05, 2013
I have always felt really uncomfortable with the term bogan. I originate from the UK and as yet I haven't detected much difference between the word bogan in Australia and the word pleb in the UK. The latter is generally considered an unhealthy symptom of the UK's class-consciousness, and in most respects Australians seem to be, and take pride in being, a country that rejects such attitudes. Of course there are a range of differences across society relating to education, wealth etc., but the regular use of words that highlight those differences in a negative fashion doesn't seem to be a good way to help us all get along with each other. But maybe I've misunderstood this? - I know I still have plenty to learn about my adopted country...


text:
Hampshire Constabulary would rather scrap bikes than send them to Africa
"We might get sued", they offer as the facts take a back seat
Meadowbrook, an Isle of Wight Day Centre which collects bikes for distribution to Africa via Colchester-based charity Re~Cycle, has been told by Hampshire Constabulary that they can no longer have unwanted bikes recovered by the force – because the Police might get sued if someone gets hurt.
We spoke to Tony Harding at Meadowbrook, who told us, "We collect up the bikes and send them to Colchester in batches of about 120. Re-Cycle do some repair work there, and other bikes are shipped out to Africa where the charity employs people to fix them up. Then the bikes are given out in towns and villages for people to use. It's a brilliant scheme because it gives the people both work and transport."
"We used to get about 10-15 bikes a month from the Police on the island. They only have a small garage so they were more than happy to offload them to us. Everyone was happy until this edict came along."
And the reason for stopping the supply? Constabulary property manager Lucy Jenkins told the Isle of Wight County Press, "It would be irresponsible for Hampshire Constabulary to release bicycles to charities without first assuring they are safe for the public to use. Unfortunately, the force does not have the resources available to conduct the necessary checks on every bicycle in its possession."
"If the force released bicycles without appropriate checks and someone was injured due to the bicycle being unsafe, any compensation paid to that person by the force would come from the public purse, diverting funds from other policing areas."
Since the bikes aren't ridden until they get to Africa, it's difficult to see how there's going to be any comeback, and Meadowbrook seem to have been affected by a blanket ban put in place to protect the force which applies to all charities. However, despite explaining their situation the day centre hasn't been able to get the ban lifted, and the bikes will now be scrapped rather than given to the charity. We've approached the Constabulary for a response, we'll update this story if we get one.
For more information on Re~Cycle, visit http://www.re-cycle.org
Health and safety nonsense gone mad by some bureaucrat who ticks boxes without thinking.
posted by OldRidgeback [2579 posts]
22nd September 2009 - 14:00
Nincompoop Barristers strike again!! Likely angling for a shot at drawing up a Liability Release Agreement....
posted by andy42 [14 posts]
22nd September 2009 - 17:52
posted by Dave Atkinson [7854 posts]
22nd September 2009 - 22:08
what happened to the shouty comment? was a bit unusual but it wasn't offensive
posted by TheHatter [811 posts]
23rd September 2009 - 18:46
posted by Dave Atkinson [7854 posts]
23rd September 2009 - 19:40


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The Defective Doll That Actually Ate My Friend's Hair
In 1996, Mattel introduced the Cabbage Patch Kids' Snacktime Kid, a doll with a motorized mouth that allowed it to "eat". In some ways, you have to give Mattel credit: the Snacktime Kid countered the typical unrealistic body type of other dolls with a chubby baby that showed children it was fun to eat. On the other hand, you can't give too much credit because it turned out that the doll was dangerous and ate kids' fingers and hair. After the indiscriminately masticating toy injured a few dozen children, Mattel had no choice but to remove Snacktime Kids from the shelves and offer full refunds to people who had already purchased them.
By chance in 2003, I found a Cabbage Patch Snacktime Kid at a thrift store. Priced for just a couple of dollars, I knew I needed to buy it. Firstly, I thought it might be valuable – since the doll was recalled, that might make it a collector's item. Secondly, and more importantly, I always figured that the media reports on the doll were exaggerated to make for a funny news story or to win lawsuits, so owning it would give me the opportunity to see if the doll really did have the taste for human flesh. As a proud new father, I named the doll "Baby Gray Davis" after the similarly recalled former Governor of California.
Immediately, I wanted to test out the doll's risk factor, but my hair wasn't long enough and none of my friends were dumb enough to volunteer. Instead, we fed Baby Gray Davis crumpled up pieces of paper, which the doll would chew and then "poop" out into her backpack. Once that got boring, we let it nibble on our fingers, which unfortunately didn't hurt much. Still not satisfied, we stripped it naked (let's just say that the doll's representation of the digestive system is not the only part that's not anatomically correct) where we found a fake, plastic pretzel stick hiding in her underwear.
Baby Gray Davis merrily munched on the pretzel, but it was no fun watching it eat something it was designed to devour, so the next day, I decided to execute a real hair-eating experiment. I chose my friend Meggie as the test subject because she had beautiful, long, thick hair. The only problem was that she didn't see it coming – literally. As she walked down the hall, I crept up behind an unsuspecting Meggie, grabbed a few strands of her hair, and placed them into the doll's mouth. The doll started chewing on Meggie's locks before she could even react.
"What are you doing?" Meggie yelled, causing me to jump back and let go of the doll. Alas, the doll had already successfully chomped down on Meggie's hair, so the ten-pound baby dangled from her head. All the while, Baby Gray Davis kept on chewing more and more hair while Meggie struggled to remove it from the doll's mouth without ripping it out of her scalp. Meanwhile, even as Meggie cried for help, I was laughing so hard that I had to hold on to the wall to regain my composure. Go ahead and judge me.
Both the chewing and the weight of the baby hanging from her hair were so painful that Meggie had to lay down on the ground in an effort to make it stop. By this point, the screaming and laughter had attracted a crowd, so several people came to aid with the situation. Still, Baby Gray Davis had resolve and refused to let go of Meggie's hair. The hair was entangled in the motor, so each time someone tried to yank the hair out, it seemed to only enable the doll to get a better grip on the strands and swallow them further.
That is when we realized that the doll's fatal flaw was that you couldn't make it stop. The Snacktime Kid didn't come with an off switch – as long as something was in its mouth, the motor kept on whirring, trying to eat whatever was in its path. Altogether, I think it took more than ten minutes for us to carefully extricate her hair from the doll's mouth without ripping too much of it off.
The experiment was a success, if you'd like to call it that. Those dolls really were evil, and I am, too, I guess. I swear that I did it in the name of science… or maybe just mischief. Meggie ultimately proved to be a good sport about the whole incident, though I can't say I blame her for finding it more traumatizing and less hilarious than I did.
I never pulled that stunt again, though later, Meggie's roommate – willingly, mind you – tried to breastfeed the doll. Unlike Meggie, she claimed to find the experience "pleasurable". Perhaps instead of recalling the doll, Mattel should have just rebranded it.


text:
France: Nursery assistant wins reprieve over hijab sacking
Israeli PM apologizes to Turkey after Obama push
Thailand: Over 60 Karens killed by brushfire at Thai refugee camp
Pakistan: 25 dead as bus collides with pylon in Sheikhupura
Egypt's Muslim Brotherhood legalised
10 killed in Nigeria central north village attack
Lebanon: Clashes rock Tripoli, killing 6
Egypt: Gunshots wound protesters in fresh Cairo clashes
Lebanon: Mikati announces his resignation
Central African rebels 'reach gates of capital Bangui'
The Netherlands: Congo atrocities suspect arrives at International Criminal Court
Lights out as World Wildlife Fund celebrates Earth Hour to combat climate change
The Muslim News Awards for Excellence gala dinner event
UN demands halt to settlements as Israel vows expansion
Cyprus shuts down banks until next week
Central African Republic: Rebels enter capital Bangui
Pakistan: Suicide attack kills 17 soldiers in NW Pakistan
Pakistan: Musharraf lands in Karachi
The death toll from a landslide in Guatemala rose to 73 on Saturday,
Multiple bomb blasts – including a suicide attack on a police station – have killed 15 people in Abuja.
US bombing of hospital in Kunduz killed 19 people, including 3 children, 37 were injured.
Seven fishermen were feared dead as strong tropical storm exited Philippines' area & headed toward China.
Indonesian rescue teams continued to search for small passenger plane that went missing with 10 people on board.
20-year-old shooter who opened fire at a community college in Oregon killing several, targeted Christians.
Trial of an evangelical pastor from Northern Ireland who derided Islam has been set for December.
Germany has been praised in helping thousands of refugees but also warned about rise of racism and intolerance.
Palestinian flag was raised for first time at UN HQ in New York in "historical moment in struggle of Palestinian people."
Scores of Jewish settlers backed by Israeli security forces stormed Al-Aqsa Mosque compound for 3rd day in a row.
PM David Cameron dismissed Jamaican calls to make reparations for Britain's role in slave trade.
Taliban seizing border district in Kunduz as US-led coalition forces deployed ground troops.
Cham Muslim woman described suffering inflicted upon her & other Muslims under Pol Pot's dyspotic regime.
Myanmar election officials have released final list of candidates to stand in general elections. Muslim candidates are excluded.
A ground breaking conference under theme Reporting Islam & Muslims in Britain' is being held in London.
The UK will take only 4,000 Syrian refugees this year. Prime Minister, David Cameron, confirmed to Parliament on September 7 that under the Vulnerable Persons Relocation Scheme (VPR), in place since early 2014, the UK will accept up to 20,000 Syrians living in camps in Syria, Turkey and Jordan but only over the next 5 years.
former Shadow Justice Secretary, Sadiq Khan, saw off five other Labour candidates to win the Party's nomination to stand for the Mayor of London next year.
The UK, along with the rest of Europe, were shamed into reacting after the publication of shocking photos of Aylan Kurdi, a dead Syrian toddler, who washed up on a Turkish beach. Cameron had originally refused to take in any refugees. In addition the funding for the refugees are coming out from the already allocated existing foreign aid budget.
Corbyn has certainly shaken up politics which can only be a good thing. Many mountains yet lie ahead to climb but we wish him success as long as he remains sincere
In an exclusive interview Conservative London mayoral candidates MEP Syed Kamall and Richmond Park MP Zac Goldsmith vow to tackle the capital's rising Islamophobia figures which jumped by a whopping 70% from last year.
Flemming Rose responsible for the 2005 publication of Prophet Muhammad cartoons in Denmark has been awarded £80,000 from the free speech group Fritt Ord.
A number of councils in France have refused to accept any of the 24,000 Muslim Syrian refugees the President had agreed to accept over the next two years, with one town claiming they "cut off boss's heads"
Neo-Nazi extremist Zack Davies was given a life sentence on September 11 for a racially motivated attack on an Asian man.
The Muslim News Awards for Excellence 2015 was held on March in London to acknowledge British Muslim and non-Muslim contributions to the society.
The Muslim News Awards for Excellence 2015 was held on March in London to acknowledge British Muslim and non-Muslim contributions to the society.


text:
- Vanderbilt Magazine - http://www.vanderbilt.edu/magazines/vanderbilt-magazine -
The Thief, the Pocket Watch, and the Dry Goods Merchant
Posted By titel On December 6, 2010 @ 3:50 pm In Fall 2010, The Classes | No Comments
Fifty years ago Vanderbilt senior Melvyn Koby made off with a little piece of Vanderbilt history: a pocket watch from the statue of Francis Furman that stands on the landing inside Furman Hall.
"It was loose, and I just lifted it off and left," Koby laughs. "I guess I just wanted a souvenir of all the hard work I'd done in the chemistry building. I passed the statue every day."
Koby returned the watch to Furman during a visit to campus for his first Quinq Reunion in October. His accomplice in the theft, fellow chemistry alumnus and Zeta Beta Tau fraternity brother Art Diamond, was not able to join him—Diamond had passed away just a few weeks earlier. Koby is an ophthalmologist in Louisville, Ky., and Diamond was a retired radiologist.
Francis Furman, the owner of Furman & Co. Wholesale Dry Goods and Notions on Nashville's Public Square from about 1870 until around 1890, had no connection to Vanderbilt. His wife, Mary, survived his 1899 death only by a few months and, in her will, left $100,000 for Vanderbilt to construct a building named for her husband.
When Furman Hall opened in 1907, it was touted as the most modern chemistry and pharmacy building in the country. A 1967 renovation turned it into a building that housed the humanities—as it still does today.
Article printed from Vanderbilt Magazine: http://www.vanderbilt.edu/magazines/vanderbilt-magazine
URL to article: http://www.vanderbilt.edu/magazines/vanderbilt-magazine/2010/12/the-thief-the-pocket-watch-and-the-dry-goods-merchant/
Click here to print.
Copyright © 2009 Vanderbilt Magazine. Vanderbilt University All rights reserved.


text:
« Thoughts on Overpublishing |
| Robo-Combing the Chemistry Literature For Mistakes »
Posted by Derek
I'd like to throw a few more logs on the ligand efficiency fire. Chuck Reynolds of J&J (author of several papers on the subject, as aficionados know) left a comment to an earlier post that I think needs some wider exposure. I've added links to the references:
An article by Shultz was highlighted earlier in this blog and is mentioned again in this post on a recent review of Ligand Efficiency. Shultz's criticism of LE, and indeed drug discovery "metrics" in general hinges on: (1) a discussion about the psychology of various metrics on scientists' thinking, (2) an assertion that the original definition of ligand efficiency, DeltaG/HA, is somehow flawed mathematically, and (3) counter examples where large ligands have been successfully brought to the clinic.
I will abstain from addressing the first point. With regard to the second, the argument that there is some mathematical rule that precludes dividing a logarithmic quantity by an integer is wrong. LE is simply a ratio of potency per atom. The fact that a log is involved in computing DeltaG, pKi, etc. is immaterial. He makes a more credible point that LE itself is on average non-linear with respect to large differences in HA count. But this is hardly a new observation, since exactly this trend has been discussed in detail by previous published studies (here, here, here, and here). It is, of course, true that if one goes to very low numbers of heavy atoms the classical definition of LE gets large, but as a practical matter medicinal chemists have little interest in extremely small fragments, and the mathematical catastrophe he warns us against only occurs when the number of heavy atoms goes to zero (with a zero in the denominator it makes no difference if there is a log in the numerator). Why would HA=0 ever be relevant to a med. chem. program? In any case a figure essentially equivalent to the prominently featured Figure 1a in the Shultz manuscript appears in all of the four papers listed above. You just need to know they exist.
With regard to the third argument, yes of course there are examples of drugs that defy one or more of the common guidelines (e.g MW). This seems to be a general problem of the community taking metrics and somehow turning them into "rules." They are just helpful, hopefully, guideposts to be used as the situation and an organization's appetite for risk dictate. One can only throw the concept of ligand efficiency out the window completely if you disagree with the general principle that it is better to design ligands where the atoms all, as much as possible, contribute to that molecule being a drug (e.g. potency, solubility, transport, tox, etc.). The fact that there are multiple LE schemes in the literature is just a natural consequence of ongoing efforts to refine, improve, and better apply a concept that most would agree is fundamental to successful drug discovery.
Well, as far as the math goes, dividing a log by an integer is not any sort of invalid operation. I believe that [log(x)]/y is the same as saying log(x to the one over y). That is, log(16) divided by 2 is the same as the log of 16 to the one-half power, or log(4). They both come out to about 0.602. Taking a BEI calculation as real chemistry example, a one-micromolar compound that weighs 250 would, by the usual definition, -log(Ki)/(MW/1000), have a BEI of 6/0.25, or 24. By the above rule, if you want to keep everything inside the log function, then say -log(0.0000001) divided by 0.25, that one-micromolar figure should be raised to the fourth power, then you take the log of the result (and flip the sign). One-millionth to the fourth power is one times ten to the minus twenty-fourth, so that gives you. . .24. No problem.
Shultz's objection that LE is not linear per heavy atom, though, is certainly valid, as Reynolds notes above as well. You have to realize this and bear it in mind while you're thinking about the topic. I think that one of the biggest problems with these metrics - and here's a point that both Reynolds and Shultz can agree on, I'll bet - is that they're tossed around too freely by people who would like to use them as a substitute for thought in the first place.
Comments (19)
+ TrackBacks (0) | Category: Drug Assays | Drug Development | In Silico
1. bhip on February 19, 2014 10:56 AM writes...
Can't overstate the impact of "the psychology of various metrics on scientists' thinking". The brain dead metrics that are often/usually applied in Phama drug discovery tend to "dissuade" biologists & chemists from taking chances. God help you if you propose or (worse) act on an idea that is outside the safe confines of dogma (or even dogma-lite).
2. Anonymous on February 19, 2014 11:02 AM writes...
((log x)/y) = log(x^(-y)) = log ((1/x)^y).
3. Christian R on February 19, 2014 11:02 AM writes...
I have to agree with Schultz on point 2. The value of log(Ki) will depend on the units you use for Ki; for instance it will change by +3 if you change units from M to mM. This does not matter as long as you just rank according to log(Ki), but when you divide with a number (HA) that varies between compounds, your ranking of compounds will (in some cases) depend on which unit you use for measuring Ki. That is not a mathematically sound construct.
4. bhip on February 19, 2014 11:04 AM writes...
Sorry- just to follow up. In case it wasn't clear, my reference to "brain dead metrics" pertains to those applied to rate some poor schmucks' performance at years end …..
5. Wavefunction on February 19, 2014 11:12 AM writes...
Metrics are crutches used by imperfect human minds to compensate for their failure to understand complex biological systems. That's how it will always be.
6. Anonymous on February 19, 2014 11:29 AM writes...
#2: Sorry, you've mistaken negation (taking a negative) and inversion (taking a reciprocal). Your equations are incorrect, but Derek is right.
(log x)/y = (1/y)*(log x) = log(x^(1/y))
7. Anonymous on February 19, 2014 11:58 AM writes...
I was just about to say, #2's equation works only if y is imaginary...
8. Anonymous on February 19, 2014 12:03 PM writes...
But in any case, you can describe a correlation with any mathematical function you like, as long as the residual is small, and you don't try to extrapolate too much beyond the existing data. Whether or not the function actually corresponds to the underlying physics is a different matter, but also quite irrelevant for the purposes of prediction, as long as the fit is good and based on enough data.
9. Anonymous on February 19, 2014 12:07 PM writes...
A bit of a math lesson:
Here's the four main log transformations-
x^(log base x of y) = y
log(x) + log(y) = log(x*y)
log(y)/log(x) = log base x of y
x * log(y) = log(y^x)
The main thing you cannot do is add two logs of unlike bases. You also need to watch out is to see whether the default log(x) has 10 or e as the base.
10. Hap on February 19, 2014 12:10 PM writes...
If differences between quantities are important, than relating the quantity on a linear axis makes sense (because differences between the quantities are represented the same no matter what the size of the quantity is).
With binding constants/IC50 values, though, people generally aren't interested in differences between the quantities but in ratios between them. In those cases, you want equivalent ratios to be shown equivalently whatever the magnitude of the underlying quantities, rather than equivalent differences being shown equivalently. Log scales allow one to show equivalent ratios equivalently.
11. Anonymous on February 19, 2014 12:21 PM writes...
"The main thing you cannot do is add two logs of unlike bases."
Sure you can! You just need to take care to include the appropriate "conversion factor".
12. dlib on February 19, 2014 12:39 PM writes...
Sadly, if you use the binding constant in won't prevent the natural inclination of med chemists to rigidify their molecules....dH/HA in conjunction might help a bit.
13. anon the II on February 19, 2014 1:03 PM writes...
@ #8
No, just no. When parameter choices exceed data points, almost always true in MedChem, correlation is easy and prediction is futile.
14. Anonymous on February 19, 2014 5:35 PM writes...
@13: If you bothered to read the end of my post you would see that we are saying the same thing: "as long as the fit is good and based on enough data." In other words, a good fit, but without over-fitting too few data with too many variables.
15. gippgig on February 19, 2014 6:40 PM writes...
One micromolar is .000001 M (one less 0).
16. Anonymous on February 19, 2014 6:41 PM writes...
Of course the log of the Kd or IC50 is really taken because it correlates linearly with ∆G which is obviously the correct frame of reference to analyse your data.
17. phil on February 19, 2014 9:22 PM writes...
How much more axe does Michael Shultz have left to grind? He should just publish one perspective with seven words: "Please think hard while designing a drug"
18. Anon on February 24, 2014 2:57 PM writes...
The criticism that Derek elevated in his post ignores another axis of Shultz's argument which, in my mind, is the most important one: LipE (or LLE if you prefer) has been repeatedly and consistently correlated with successful optimization campaigns, whereas the same cannot be said of the other metrics. Those who would say that LE is useful in "hit-to-lead" type optimizations should refer back to another key Shultz point that such milestones are company-specific and therefore no universal guideline for when they should and shouldn't be used can be proposed. In contrast, LipE has been shown to increase over the entire course of a successful optimization.
For my own part as a practicing medicinal chemist, I have successfully used LipE to drive optimizations across multiple projects, chemotypes, and therapeutic areas. I believe in its utility because in my own experience it works consistently, whereas the other metrics do not.
As many others have pointed out in the comments, no efficiency metric is a substitute for critical thinking. But if one wants to keep an eye on a metric, Shultz's argument remains compelling that LipE is the right one and the others are not.
19. shultz on February 24, 2014 4:56 PM writes...
I'm afraid I might not have made the point very well so hopefully this clarifies.
I agree with Reynolds that there is no rule that precludes dividing a log by an integer (I never asserted this) but to this point there are several results that we apparently all agree upon with regard to LE:
1) At low (and non-zero) heavy atom integer numbers, the amplitude of LE becomes ridiculously large and independent of potency.
2) At high (but still relevant) heavy atom integer numbers, the amplitude of LE becomes insignificant and independent of potency.
3) A log/integer plot is nonlinear and only approximates linearity when the delta of the integers is very low. (restatement of Reynolds' comment above).
LE is valid for comparing molecules of identical size but invalid for comparing molecules of different sizes where the error increases with the delta of heavy atoms. Therefore, the validity and utility of LE are inversely related to one another because of this non-linearity!* A simple change in the formula (LE* = pIC50-#HA) eliminates all the size dependency, etc. This isn't axe grinding, it is exactly what Reynold's stated - 'a natural consequence of ongoing efforts to refine, improve, and better apply a concept that most would agree is fundamental to successful drug discovery'. I think the previous versions of LE are flawed and invalid, I provided the rationale behind this assertion and a revised equation to mitigate these flaws. It could be further refined (as I don't think it's perfect) but it does, IMHO, have mathematical integrity.
So while the facts are non-original (LE does not normalize size for potency) it is the interpretation of why LE is still used to normalize size for potency (Point 1 from Reynolds) that I was unable to find precedent.
I guess the last observation is a reiteration of #18's comments. If there is an assertion that the LE metric improves the probability of success, then those who advocate its use should provide statistical rather than anecdotal evidence.
* The same is true for differences in potency but since this is a log scale the effective ranges are less significant but demonstrable. Since molecules are usually of different size and potency, this error becomes harder to see during practical use.
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|Accession Numbers: EG11795 (EcoCyc), b2808, ECK2803
Synonyms: positive regulator of gcv operon
Component of: GcvA-gly
"Glycine cleavage A," GcvA, is a repressor of the glycine cleavage enzyme system, which is a secondary pathway for production of C1 units [Wilson94]. It is negatively autoregulated, and it coordinately activates transcription of a small-RNA divergent gene [Wilson95, Urbanowski00].
In the absence of glycine and the presence of GcvR, GcvA represses operons involved in the glycine cleavage system [Wilson95, Urbanowski00, Ghrist01]. GcvR is an accessory protein that binds directly to GcvA, bending DNA to form a repression complex (GcvA/GcvR) in the regulatory region of the gcvT operon [Ghrist01].
Glycine binds directly to GcvR to disrupt or block the association of the GcvA/GcvR complex, whereas purines appear to promote the formation of the repression complex through an unknown mechanism [Heil02, Ghrist01]. GcvA also activates transcription of the gcv genes, via interaction with the α or σ subunits of RNA polymerase [Stauffer05].
This transcriptional dual regulator, which belongs to the LysR-family [Wilson94], has two domains: the amino-terminal domain, which appears to be involved in transcription activation and in DNA binding through its helix-turn-helix subdomain, and the carboxy-terminal domain, involved in GcvR interaction [Jourdan98, Ghrist01].
The GcvA binding sites do not show a clear conservation in their sequences except for a short 5'-CTAAT-3' region [Wilson95].
Citations: [OkamuraIkeda93]
Gene Citations: [Jin95]
Locations: cytosol
|Map Position: [2,939,672 <- 2,940,589] (63.36 centisomes, 228°)
|Length: 918 bp / 305 aa
Molecular Weight of Polypeptide: 34.402 kD (from nucleotide sequence)
pI: 8.97
Unification Links: ASAP:ABE-0009202 , CGSC:28676 , DIP:DIP-9751N , EchoBASE:EB1743 , EcoGene:EG11795 , EcoliWiki:b2808 , ModBase:P0A9F6 , OU-Microarray:b2808 , PortEco:gcvA , PR:PRO_000022762 , Pride:P0A9F6 , Protein Model Portal:P0A9F6 , RefSeq:NP_417288 , RegulonDB:EG11795 , SMR:P0A9F6 , String:511145.b2808 , UniProt:P0A9F6
Relationship Links: InterPro:IN-FAMILY:IPR000847 , InterPro:IN-FAMILY:IPR005119 , InterPro:IN-FAMILY:IPR011991 , Pfam:IN-FAMILY:PF00126 , Pfam:IN-FAMILY:PF03466 , Prints:IN-FAMILY:PR00039 , Prosite:IN-FAMILY:PS50931
In Paralogous Gene Group: 6 (42 members)
In Reactions of unknown directionality:
Not in pathways:
GcvA + glycine = GcvA-gly
GO Terms:
|Biological Process:
|GO:0006351 - transcription, DNA-templated
[UniProtGOA11, Wilson94, Wilson95]
GO:0006355 - regulation of transcription, DNA-templated [UniProtGOA11, GOA01, Wilson95]
|Molecular Function:
|GO:0003677 - DNA binding
GO:0003700 - sequence-specific DNA binding transcription factor activity [GOA01]
|Cellular Component:
|GO:0005737 - cytoplasm
[UniProtGOA11a, UniProtGOA11]
GO:0005829 - cytosol [DiazMejia09]
|MultiFun Terms:
|information transfer → RNA related → Transcription related
|metabolism → carbon utilization → amino acids
|metabolism → central intermediary metabolism → formyl-THF biosynthesis
|regulation → genetic unit regulated → operon
|regulation → type of regulation → transcriptional level → activator
|regulation → type of regulation → transcriptional level → repressor
DNA binding site length: 15 base-pairs
Symmetry: Inverted Repeat
Consensus DNA Binding Sequence: ATTAGTTTAACTAAT
Regulated Transcription Units (3 total):
Essentiality data for gcvA knockouts:
|Growth Medium
|Growth Observations
|LB enriched
|Yes [Gerdes03, Comment 1]
|LB Lennox
|Yes [Baba06, Comment 2]
|M9 medium with 1% glycerol
|Yes [Joyce06, Comment 3]
|MOPS medium with 0.4% glucose
|Yes [Baba06, Comment 2]
Subunit of: GcvA-gly
Subunit composition of
GcvA-gly = [GcvA][glycine]
GcvA DNA-binding transcriptional dual regulator = GcvA (extended summary available)
Sequence Length: 305 AAs
In Reactions of unknown directionality:
Not in pathways:
GcvA + glycine = GcvA-gly
|MultiFun Terms:
|information transfer → RNA related → Transcription related
|metabolism → carbon utilization → amino acids
|metabolism → central intermediary metabolism → formyl-THF biosynthesis
|regulation → genetic unit regulated → operon
|regulation → type of regulation → transcriptional level → activator
|regulation → type of regulation → transcriptional level → repressor
|Feature Class
|6 -> 63
|23 -> 42
Gene Local Context (not to scale):
Transcription Units:
10/20/97 Gene b2808 from Blattner lab Genbank (v. M52) entry merged into EcoCyc gene EG11795; confirmed by SwissProt match.
Baba06: Baba T, Ara T, Hasegawa M, Takai Y, Okumura Y, Baba M, Datsenko KA, Tomita M, Wanner BL, Mori H (2006). "Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection." Mol Syst Biol 2;2006.0008. PMID: 16738554
DiazMejia09: Diaz-Mejia JJ, Babu M, Emili A (2009). "Computational and experimental approaches to chart the Escherichia coli cell-envelope-associated proteome and interactome." FEMS Microbiol Rev 33(1);66-97. PMID: 19054114
Gerdes03: Gerdes SY, Scholle MD, Campbell JW, Balazsi G, Ravasz E, Daugherty MD, Somera AL, Kyrpides NC, Anderson I, Gelfand MS, Bhattacharya A, Kapatral V, D'Souza M, Baev MV, Grechkin Y, Mseeh F, Fonstein MY, Overbeek R, Barabasi AL, Oltvai ZN, Osterman AL (2003). "Experimental determination and system level analysis of essential genes in Escherichia coli MG1655." J Bacteriol 185(19);5673-84. PMID: 13129938
Ghrist01: Ghrist AC, Heil G, Stauffer GV (2001). "GcvR interacts with GcvA to inhibit activation of the Escherichia coli glycine cleavage operon." Microbiology 147(Pt 8);2215-21. PMID: 11495998
GOA01: GOA, DDB, FB, MGI, ZFIN (2001). "Gene Ontology annotation through association of InterPro records with GO terms."
Heil02: Heil G, Stauffer LT, Stauffer GV (2002). "Glycine binds the transcriptional accessory protein GcvR to disrupt a GcvA/GcvR interaction and allow GcvA-mediated activation of the Escherichia coli gcvTHP operon." Microbiology 148(Pt 7);2203-14. PMID: 12101307
Jin95: Jin T, Inouye M (1995). "Identification of the genes in multicopy plasmids affecting ompC and ompF expression in Escherichia coli." FEMS Microbiol Lett 1995;133(3);225-31. PMID: 8522138
Jourdan98: Jourdan AD, Stauffer GV (1998). "Mutational analysis of the transcriptional regulator GcvA: amino acids important for activation, repression, and DNA binding." J Bacteriol 180(18);4865-71. PMID: 9733689
Joyce06: Joyce AR, Reed JL, White A, Edwards R, Osterman A, Baba T, Mori H, Lesely SA, Palsson BO, Agarwalla S (2006). "Experimental and computational assessment of conditionally essential genes in Escherichia coli." J Bacteriol 188(23);8259-71. PMID: 17012394
OkamuraIkeda93: Okamura-Ikeda K, Ohmura Y, Fujiwara K, Motokawa Y (1993). "Cloning and nucleotide sequence of the gcv operon encoding the Escherichia coli glycine-cleavage system." Eur J Biochem 1993;216(2);539-48. PMID: 8375392
Stauffer05: Stauffer LT, Stauffer GV (2005). "GcvA interacts with both the alpha and sigma subunits of RNA polymerase to activate the Escherichia coli gcvB gene and the gcvTHP operon." FEMS Microbiol Lett 242(2);333-8. PMID: 15621456
UniProt09: UniProt Consortium (2009). "UniProt version 15.8 released on 2009-10-01 00:00:00." Database.
UniProt10a: UniProt Consortium (2010). "UniProt version 2010-07 released on 2010-06-15 00:00:00." Database.
UniProtGOA11: UniProt-GOA (2011). "Gene Ontology annotation based on manual assignment of UniProtKB keywords in UniProtKB/Swiss-Prot entries."
UniProtGOA11a: UniProt-GOA (2011). "Gene Ontology annotation based on the manual assignment of UniProtKB Subcellular Location terms in UniProtKB/Swiss-Prot entries."
Urbanowski00: Urbanowski ML, Stauffer LT, Stauffer GV (2000). "The gcvB gene encodes a small untranslated RNA involved in expression of the dipeptide and oligopeptide transport systems in Escherichia coli." Mol Microbiol 37(4);856-68. PMID: 10972807
Wilson94: Wilson RL, Stauffer GV (1994). "DNA sequence and characterization of GcvA, a LysR family regulatory protein for the Escherichia coli glycine cleavage enzyme system." J Bacteriol 176(10);2862-8. PMID: 8188587
Wilson95: Wilson RL, Urbanowski ML, Stauffer GV (1995). "DNA binding sites of the LysR-type regulator GcvA in the gcv and gcvA control regions of Escherichia coli." J Bacteriol 177(17);4940-6. PMID: 7665470
Harwani12: Harwani D, Zangoui P, Mahadevan S (2012). "The β-Glucoside (bgl) Operon of Escherichia coli Is Involved in the Regulation of oppA, Encoding an Oligopeptide Transporter." J Bacteriol 194(1);90-9. PMID: 22020646
Jourdan99: Jourdan AD, Stauffer GV (1999). "Genetic analysis of the GcvA binding site in the gcvA control region." Microbiology 145 ( Pt 8);2153-62. PMID: 10463182
McArthur06: McArthur SD, Pulvermacher SC, Stauffer GV (2006). "The Yersinia pestis gcvB gene encodes two small regulatory RNA molecules." BMC Microbiol 6;52. PMID: 16768793
Sardesai01: Sardesai AA, Gowrishankar J (2001). "trans-acting mutations in loci other than kdpDE that affect kdp operon regulation in Escherichia coli: effects of cytoplasmic thiol oxidation status and nucleoid protein H-NS on kdp expression." J Bacteriol 183(1);86-93. PMID: 11114904
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- Northern New York Newspapers
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- Lowville
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WADDINGTON Waddington will wait another week before approving a contract with the American-Canadian Hydroplane Association to hold hydroplane races along Whittaker and Island View parks.
The races in Waddington are slated for June 14 and 15. If the races are well attended, the association plans to make Waddington a permanent stop on its racing circuit, which also includes stops in Cornwall, Ontario; Brockville, Ontario; Valleyfield, Quebec; St. Felicien, Quebec; Buffalo, Boston and Beauharnais, Quebec.
The total cost to Waddington to host the event would be $82,500, Michel Poirier, representative of the promoters, said in January. The money will pay for the races itself, prize money for the four races, tow money for 60 to 70 boats, officiating, race insurance and Grand Prix rights.
Association members said the organization could cover up to half the cost of the event for the first year, and a portion of that amount thereafter for up to five years.
Joseph Sovie, who organized the races for seven years until 2007, said the event was well attended in Ogdensburg.
He suggested the board charge for camping, parking and admission. He said selling programs with local advertisements also paid for the cost of the event.
We made about $15,000 for the programs, Mr. Sovie said. By the time we turned the key in the gate Friday morning, we had it all paid for. Generally, races made about $9,000 in revenue each year. Each year the money was used to help pay for the next years races.
Waddington also will be able to garner sponsorships and charge admission to the event. Officials anticipate ticket prices will range from $10 to $20.
You want to keep the cost low enough to get everyone to come in, but you cant have it free, Mr. Sovie said. We tried that and everyone dropped their kids off and there were people you didnt want there. You were stuck baby-sitting and picking up after the general public.
But the biggest challenge was getting people to pay for tickets.
Many people would watch the races and invite friends and family to watch it from their home, he said.
The board said it would consider trailers and fencing along the river, which is predominantly New York Power Authority-owned land.
But board members held off on approving the races until they see a contract.
If we decide we are going to do it, then we can go about deciding what we will need to do it, but I would like to see a contract before we vote on it, board member William Shoen said.
The village will hold a special meeting at 6 p.m. Feb. 17 in the municipal building to review the contract. They want our decision by mid-February, Mayor Janet M. Otto-Cassada said. Either way we go, we need to move on this.
Thousands of readers like you have made Northern New York Newspapers the number one ranked website* for local news and sports coverage in the north country.
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The award-winning Velvetones include some of San Diego's finest singers, creating our unique and smooth a cappella sound. From classic rock to classical, motown to jazz, we sing it all. With diverse experience in songwriting, musical theater, opera, early music, graphic design, business, and architecture, each performer brings their own talent and fresh perspective to this group. Our voices come together to create a stirring, rich, and soulful sound that is undeniably our own... and we are not your grandpa's a cappella!
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Regulate Usage of Technology in the Correct Laws
Theme: Digital Infrastructure
Idea Status: +8 | Total Votes: 14 | Comments: 0
As we look towards our own digital strategy, we need to avoid making some of the mistakes other countries have made. As one example, the Report of the Working Group on Intellectual Property rights Intellectual Property and the National Information Infrastructure was part of the National Information Infrastructure task force work in the USA in 1994 and 1995. This report became the basis of some of the most controversial policies within Copyright, which many people consider to be harmful to not only the interests of a majority of copyright holders but also other users of digital technology.
The worst ideas that came out of that working group were incorporated in the USA's 1998 Digital Millennium Copyright Act, and can be seen in both the Bill C-61 in 2008, and the recently tabled Bill C-32. The core issue is one not related to Copyright itself, but to what many have called Paracopyright. Paracopyright This is law that protects not copyright itself, but an umbrella of tools that are separate from copyright but are claimed to be useful to copyright holders. These tools often implicate areas of law that are separate from copyright, such as laws around electronic-commerce, contract, or property, which just happen to be useful to copyright holders.
The problem is that if legal protection for usage of technology (AKA: technological measures) is not tied to the legal construct that these technologies are theoretically protecting, then the checks and balances of the law are erased. We need to ensure that technologies protecting contracting terms are protected in contract law, e-commerce in e-commerce law, and so-on.
While the example I give is in the context of inappropriate changes to Copyright law, the same concept should be applied to other modifications to law. Whenever uses of technology are protected or prohibited in law, then this policy must be added to the law that most closely matches the specific use/abuse of technology.
Further reading on this issue:
Federal Bill C-32 tramples areas of provincial jurisdiction
Q: Why is it a problem that "access controls" are protected by the DMCA and Bill C-32?
Suggested URL: Why is it a problem that "access controls" are protected by the DMCA and Bill C-32?
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Trial Attorney - Personal Injury, Wrongful Death and Criminal Defense
Trey has been in court almost five days a week since 1990, beginning with an internship in the Shawnee County District Attorney's Office, and then as an Assistant District Attorney in Johnson County, Kansas, and since 1994 as a criminal defense and personal injury plaintiff's attorney. Since starting his own law office, Trey has tried and won numerous jury trials involving serious criminal charges, significant personal injury and wrongful death. Trey has won numerous "Not Guilty" jury verdicts in criminal cases over the years including acquittals for clients charged with rape, sodomy, aggravated battery, domestic battery, sexual battery, attempted murder, DUI, felony DUI and felony theft. Trey's clients have included attorneys, professional athletes, police officers, nurses, doctors, professors and other professionals with a lot to lose.
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Trey is admitted to practice in Missouri, Kansas and the United States District Courts for Missouri and Kansas. He's tried jury trials in Kansas, Missouri and Federal Court. Trey's cases have taken him all over the United States from Maine to California. Trey has also written appellate briefs to the Kansas Supreme Court as well as the Kansas and Missouri Courts of Appeals.
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(Photo at left: The Honorable Judge John Anderson, III, just prior to his retirement, Dec. 2008)
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Like Trey, Ryan gained experience prosecuting cases before he decided to commit to the defense of private citizens charged with crimes ranging from misdemeanors to serious crimes. Prior to joining the firm, Ryan worked as an intern with the Law Offices of N. Trey Pettlon and then as an intern for the Johnson County District Attorney's Office in 1998. Ryan started defending clients as an associate in the Law Offices of N. Trey Pettlon and now is a partner in the Law Offices of Pettlon & Ginie.
Ryan does primarily criminal defense and has a great deal of experience defending both adults and juveniles who are charged. For several years Ryan gave monthly lectures on juvenile law. He is a member of the Johnson County Bar Association, the Kansas Association of Criminal Defense Lawyers, the Kansas Bar Association, and a sustaining member of the Kansas City Metropolitan Bar Association. Ryan was selected as a "Rising Star" by Super Lawyers in 2012 and 2013, just confirming what our clients have known about Ryan for years. The designation is a tremendous honor and the culmination of a lot of work on behalf of his clients and a lot of success in court.
In 2008 Ryan won a jury trial with a verdict of "Not Guilty by Reason of Mental Defect" for a man charged with a Felony for Criminal Threat. According to knowledgeable court observers, it was the first jury verdict of its kind in Johnson County, Kansas in many years.
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For more information about Ryan, please see Ryan's attorney profile.
For more information about our lawyers and our firm, contact our law firm now or follow the links below.
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Nothing is more frustrating that needing something from your attorney's office, but calling his or her office and getting voicemail because he or she is in court. You may only need to schedule an appointment or get the answer to a simple question, like "When is my next court date?"
A successful law office requires great attorneys and a great support staff. We have just that in our paralegals, Allie Mincks and Danelle Wisdom. Allie is an experienced trial assistant with experience in a large firm and then with the Law Office of N. Trey Pettlon before the Law Offices of Pettlon & Ginie was formed. Over the years she has learned from other experienced paralegals and trial assistants, and she receives continuing education as a legal assistant on an annual basis. She is reliable and committed to helping Ryan and Trey do the best job they can to win your case. Danelle joined the firm in May 2013 and after getting her paralegal degree at Rockhurst College under the tutelage of professors like Judge Rex Gabbert of the Missouri Court of Appeals and Judge Dennis Eckold, Platte County Circuit Court, hit the ground running. Her research skills are tremendous. Both Allie and Danelle are at the office Monday through Friday from 9 to 5 doing everything that has to be done behind the scenes so Trey and Ryan have the support they need to take care of you in court.
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He will head the Budget Subcommittee on Resources and Transportation, his office announced Dec. 15.
Mr. Gordon, who served 13 years as a San Mateo County supervisor, has closely followed the high-speed-rail debate and has called for creation of a new oversight structure for the authority's governing board, with greater transparency and local representation.
Other departments and agencies over which the subcommittee has authority include the state Air Resources Board, the Department of Water Conservation Resources, the Department of Fish & Game, and the Department of Transportation.
Mr. Gordon will also serve on the full Budget Committee, the Budget Subcommittee on Oversight, and the standing committees of Local Governments, Health, and Revenue & Tax Committees.
He was elected in November to represent the 21st Assembly District, which includes Atherton, Menlo Park, Portola Valley, Woodside, as well as San Carlos, Redwood City, East Palo Alto, Palo Alto, Los Altos, Los Altos Hills, Monte Sereno, Los Gatos and the Almaden Valley.
In addition to serving on the San Mateo County Board of Supervisors, Mr. Gordon was president of the California State Association of Counties in 2008-09.
"I am pleased that I will serve on a variety of committees in diverse issue areas, and I will strive to fulfill my pledge to bring better governance to Sacramento and help tackle the state budget problems dominating the state today," Mr. Gordon said of his appointments.