text:
House: Retirement age under review
Published May 11, 2019 at 8:00 am (Updated May 11, 2019 at 8:01 am)
David Burt, the Premier (File photograph by Akil Simmons)
Rise in retirement age to 68 a step closer
Retirement linked to vexing issue of immigration
MPs to debate raising retirement age to 70
Keeping mind and body in motion
The things no one tells you about retirement
David Burt statement
The retirement age should be increased to 70 over a ten-year period, a Labour Advisory Committee report recommended yesterday.
The report, tabled in the House of Assembly, said Bermuda's ageing population had put pressure on pension plans and public sector finances.
It also recommended that legislation should be amended or introduced to prevent discrimination against older employees and that a toolkit to help people prepare for retirement should be created.
An LAC sub-committee compiled the Reviewing the Retirement Age report, which was tabled by David Burt, the Premier.
The sub-committee recommended the creation of a single piece of legislation designed
• Increase the retirement and pensionable age at the same time from 65 to 70 over a ten-year period, with the retirement age to move to 68 inside a five-year period.
• Allow for annual re-employment contracts for five years after the prescribed retirement age.
• Ensure early retirement provisions were in place for workplace pensions and Contributory
Pension Fund payments.
• Ensure employers were not prevented from the retention of older employees for as long as was wanted after the retirement and re-employment periods.
Mr Burt told the House: "There is a need to stabilise pension funds, to allow working men and women the benefit of greater capacity to earn and therefore better prepare for their eventual retirement, and to use the longer life span in the modern era to the benefit of society and the people of Bermuda."
He said that a review of the mandatory retirement age of 65 for public service workers was a Throne Speech promise.
Mr Burt added that he hoped the report would win cross-party support in the House and the Senate and that the Government could then return with amendments to the Public Service Superannuation Act to introduce some of the recommendations.
The report pointed out that, except for public sector workers, there was no legislation that insisted employees retired at 65.
But Mr Burt said that was "the generally accepted practice" in Bermuda and most people agreed to finish work at that age when they signed employment contracts.
The National Pension Scheme (Occupational Pensions) Act 1998 said that the "normal retirement date" was no more than a year after a pension plan member's 65th birthday, unless an earlier date was set in the pension scheme.
The sub-committee said the island's ageing population had created "additional stress to public pension plans and public sector finances".
The report added: "Many persons who reach the retirement age are financially unprepared for retirement.
"The evidence clearly shows that there is a willingness from persons 65 and over to continue to work. Financial assistance outlays to seniors is extremely high and reinforces the point that a growing portion of our seniors are in dire need of additional financial resources."
The sub-committee said: "The reality is that if the problem is left unaddressed, the financial stress on individuals, pension plans and the Bermuda Government will grow."
It added that legislation should be created or amended to prohibit age discrimination in the workplace and to make sure people had equal rights in recruitment, hiring, compensation, benefits, training, work conditions and career development.
Claudette Fleming, the executive director of Age Concern and part of the group behind the report, said the charity was pleased that the Government had given the recommendations serious consideration.
She added: "A variety of industry leaders committed valuable time to consider the issue.
"The matter of the relevancy of the retirement age in our current existence has been left unresolved for many years."
Ms Fleming said: "Sadly, workplace discrimination based on age was not included in the 2013 amendments to the Human Rights Act.
"We look forward to seeing the extent and boldness to which the current administration will take in extending the opportunity for older adults to work beyond the age of 65 years, should they so choose."
Craig Cannonier, the One Bermuda Alliance leader supported the proposals.
He said: "By not increasing the retirement age we essentially are not taking advantage of the intellectual capital that exists within that age group.
"The work experience and life experience that they have had lends so greatly to creating effective leadership within companies.
"Whether you're in a supermarket, international business, whether you work in the public or private sector, it's vitally important that we take advantage of that.
"I know 65-year-olds who have far more energy than 35-year-olds, so I think it's a great move."
• To click on the report, and to read David Burt's statement in full, click on the PDFs under "Related Media"


text:
Никола (Коле) Хаджиев, наречен Мургаш, е български революционер, войвода на Вътрешната македоно-одринска революционна организация.

Биография
Никола Хаджиев е роден в дебърското село Райчица, тогава в Османската империя. Работи като касапин, а от април 1902 година е четник при Никола Русински. През Илинденско-Преображенското въстание е войвода на четите от селата Горно Лакочерей и Долно Лакочерей и Вапила, като участва и в нападението срещу турския гарнизон в село Сируля. След потушаването на въстанието изпълнява терористични задачи. Умира през юли 1906 година в Охридско.

Бележки

Български революционери от Македония
Дейци на ВМОРО
Хора от община Дебър
Терористи на ВМОРО

redpajama_set_name: RedPajamaWikipedia


Sotheby's has once again collaborated with the Paris-based studio Notoryou to go beyond the flat screen and bring objects to life in the beautifully curated galleries. Visitors can interact with works by artists such as Andy Warhol, Francis Picabia, Yves Klein, Jeff Koons, Arman, César, George Segal or Daniel Buren.
Retrouvez les expositions des Rencontres d'Arles en « visites immersives 3D » réalisées par Notoryou.


Survival Top 100 Items List – What Disappears First in a Disaster?
The survival top 100 items list are important to consider obtaining and storing prior to needing them.
49. Men's Hygiene: Shampoo, Toothbrush, paste, Mouthwash, floss, nail clippers, etc.
84. Socks, Underwear, T-shirts, etc.
88. Gloves: Work, warming, gardening, etc.


JPD now in stock and here's why!
In recent years it has been clear to see the uprising of the JPD Koi Food range, in the UK, Europe and most importantly Japan.
Having our own food range, naturally we are curious to learn what our Far Eastern friends feed their koi. Given that Japan is the heart and soul of our hobby, we take every opportunity to learn from the masters.
Breeders, hobbyists and dealers in Asia take the JPD food range very seriously indeed, and as they say, proof is in the pudding.
Read our indepth review and analysis of the JPD range here on our blog.
New sinking Fuyufuji. With added Vitamin C it can drastically improve the white skin, help battle disease and lower stress levels while boosting the immune system of the koi.
With added Vitamin C it can drastically improve the white skin, help battle disease and lower stress levels while boosting the immune system of the koi.
This food is perfect for feeding all year round, quarantining new koi, when you have moved fish, re-introduction of fish to your pond from a koi show etc.
Food perfect for staple diet and growth.
This food is perfect for preparing your koi before entering koi shows.


text:
TestChloe Atkinson2019-04-15T09:19:28+00:00
Accelerating the life sciences ecosystem
MedChemica Bucket List
PublicationsPatentsConference TalksMedChemica Bucket List
Can we accelerate medicinal chemistry by augmenting the chemist with Big Data and Artificial Intelligence?
Edward J.Griffen, Alexander G.Dossetter, Andrew G.Leach, Shane Montague, Can we
AI Big Data and the Medicinal Chemist
AI, Big Data and the Medicinal Chemist, Ed Griffen Linked-In
Learning Medicinal Chemistry Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) Rules from Cross-Company Matched Molecular Pairs Analysis (MMPA)
Learning Medicinal Chemistry Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET)
A first draft of a Medicinal Chemistry ADMET Encyclopedia?
A first draft of a Medicinal Chemistry ADMET Encyclopedia?; Linked
Turbocharging Matched Molecular Pair Analysis
Lukac I, Zarnecka J, Griffen EJ, Dossetter AG, St-Gallay SA,
MIDA boronates are hydrolysed fast and slow by two different mechanisms.
MIDA boronates are hydrolysed fast and slow by two different
"Matched molecular pair analysis" in Comprehensive Medicinal Chemistry III
109) "Matched molecular pair analysis" in Comprehensive Medicinal Chemistry III,
Protodeboronation of Heteroaromatic, Vinyl, and Cyclopropyl Boronic Acids: pH-Rate Profiles, Autocatalysis, and Disproportionation.
Protodeboronation of Heteroaromatic, Vinyl, and Cyclopropyl Boronic Acids: pH-Rate Profiles,
Novel N-thiazolyl piperazine-1-carboxamide CCR2 antagonists – investigation of an unexpected reaction with glutathione
106) Novel N-thiazolyl piperazine-1-carboxamide CCR2 antagonists – investigation of an
Designing hydroxamates and reversed hydroxamates to inhibit zinc-containing proteases but not cytochrome P450s: insights from quantum mechanics and protein-ligand crystal structures
105) Designing hydroxamates and reversed hydroxamates to inhibit zinc-containing proteases
A mechanistic proposal for the protodeboronation of neat boronic acids: boronic acid mediated reaction in the solid state.
104) A mechanistic proposal for the protodeboronation of neat boronic
An Orally Bioavailable, Indole-3-glyoxylamide Based Series of Tubulin Polymerization Inhibitors Showing Tumor Growth Inhibition in a Mouse Xenograft Model of Head and Neck Cancer.
103) An Orally Bioavailable, Indole-3-glyoxylamide Based Series of Tubulin Polymerization
Discovery of a series of 2-(pyridinyl)pyrimidines as potent antagonists of GPR40.
102) Discovery of a series of 2-(pyridinyl)pyrimidines as potent antagonists
Tactics to avoid inhibition of cytochrome P450s" in Tactics in Contemporary Drug Design
101) Tactics to avoid inhibition of cytochrome P450s" in Tactics
Medicinal chemistry optimisation of kinetics" in Kinetics and Thermodynamics of Drug Binding
101) Medicinal chemistry optimisation of kinetics" in Kinetics and Thermodynamics
Circumventing seizure activity in a series of G Protein Coupled Receptor 119 (GPR119) agonists
100) Circumventing seizure activity in a series of G Protein
Predicting the activity and toxicity of new psychoactive substances: a pharmaceutical industry perspective
99) Predicting the activity and toxicity of new psychoactive substances:
Cytochrome P450 substrate recognition and binding" in Drug Metabolism Prediction
98) Cytochrome P450 substrate recognition and binding" in Drug Metabolism
Identification, Optimization, and Pharmacology of Acylurea GHS-R1a Inverse Agonists
97) Identification, Optimization, and Pharmacology of Acylurea GHS-R1a Inverse Agonists
Optimization of Brain Penetrant 11β-Hydroxysteroid Dehydrogenase Type I Inhibitors and in Vivo Testing in Diet-Induced Obese Mice
96) Optimization of Brain Penetrant 11β-Hydroxysteroid Dehydrogenase Type I Inhibitors
'Big data' in pharmaceutical science: challenges and opportunities
95) 'Big data' in pharmaceutical science: challenges and opportunities Dossetter,
Achieving improved permeability by hydrogen bond donor modulation in a series of MGAT2 inhibitors.
94) Achieving improved permeability by hydrogen bond donor modulation in
Predicting the activity and toxicity of new psychoactive substances: a pharmaceutical industry perspective.
Highly diastereoselective radical cyclisations of chiral sulfinimines
92) Highly diastereoselective radical cyclisations of chiral sulfinimines. Rochette EM,
Matched Molecular Pair Analysis in Drug Discovery
91)Matched Molecular Pair Analysis in Drug Discovery, Dossetter, A.G.; Griffen,E.J.;
Experimental testing of quantum mechanical predictions of mutagenicity: aminopyrazoles
90) Experimental testing of quantum mechanical predictions of mutagenicity: aminopyrazoles.
Discovery of 4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, Potent Inhibitor of Akt
89) Discovery of 4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, Potent Inhibitor
Discovery and optimization of efficacious neutral 4-amino-6-biphenyl-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5-one diacylglycerol acyl transferase-1 (DGAT1) inhibitors
88) Discovery and optimization of efficacious neutral 4-amino-6-biphenyl-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5-one diacylglycerol acyl
Optimisation of biphenyl acetic acid inhibitors of diacylglycerol acetyl transferase 1 – the discovery of AZD2353
87) Optimisation of biphenyl acetic acid inhibitors of diacylglycerol acetyl
A monomeric form of iNOS can rationalise observed SAR for inhibitors of dimerisation: quantum mechanics and docking compared
86) A monomeric form of iNOS can rationalise observed SAR
Design and synthesis of a novel series of cyclohexyloxy-pyridyl derivatives as inhibitors of diacylglycerol acyl transferase 1
85) Design and synthesis of a novel series of cyclohexyloxy-pyridyl
Optimisation of aqueous solubility in a series of G protein coupled receptor 119 (GPR119) agonists
84) Optimisation of aqueous solubility in a series of G
A matched molecular pair analysis of in vitro human microsomal metabolic stability measurements for heterocyclic replacements of di-substituted benzene containing compounds
A matched molecular pair analysis of in vitro human microsomal
Enantiomeric pairs reveal that key medicinal chemistry parameters vary more than simple physical property based models can explain
Enantiomeric pairs reveal that key medicinal chemistry parameters vary more
Free-Wilson and Structural Approaches to Co-optimizing Human and Rodent Isoform Potency for 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors
83) Free-Wilson and Structural Approaches to Co-optimizing Human and Rodent
"Investigation of the Origins of Regiochemical Control in [4+2] Cycloadditions of 2-Pyrones and Alkynylboronates"
82) "Investigation of the Origins of Regiochemical Control in [4+2]
Identification of pyrazolo-pyrimidinones as GHS-R1a antagonists and inverse agonists for the treatment of obesity
81) Identification of pyrazolo-pyrimidinones as GHS-R1a antagonists and inverse agonists
Pharmacokinetic Benefits of 3,4-Dimethoxy Substitution of a Phenyl ring and Design of Isosteres yielding orally available Cathepsin K Inhibitors
80) Pharmacokinetic Benefits of 3,4-Dimethoxy Substitution of a Phenyl ring
A matched molecular pair analysis of in-vitro human microsomal metabolic stability measurements for methylene substitution or replacements
79) A matched molecular pair analysis of in-vitro human microsomal
78) A matched molecular pair analysis of in vitro human
Isosteric replacements for benzothiazoles and optimisation to potent Cathepsin K inhibitors free from hERG channel inhibition
77) Isosteric replacements for benzothiazoles and optimisation to potent Cathepsin
1R,2R)-N-(1-Cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carbonyl)cyclohexanecarboxamide (AZD4996): A Potent and Highly Selective Cathepsin K Inhibitor for the Treatment of Osteoarthritis
76) (1R,2R)-N-(1-Cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carbonyl)cyclohexanecarboxamide (AZD4996): A Potent and Highly Selective Cathepsin K
A System for Encoding and Searching Markush Structures
75) A System for Encoding and Searching Markush Structures Cosgrove,
"Identification, optimisation and in vivo evaluation of oxadiazole DGAT-1 inhibitors for the treatment of obesity and diabetes."
74) "Identification, optimisation and in vivo evaluation of oxadiazole DGAT-1
"Protein–Ligand Crystal Structures Can Guide the Design of Selective Inhibitors of the FGFR Tyrosine Kinase."
73) "Protein–Ligand Crystal Structures Can Guide the Design of Selective
Use of Small-Molecule Crystal Structures To Address Solubility in a Novel Series of G Protein Coupled Receptor 119 Agonists: Optimization of a Lead and in Vivo Evaluation
72) Use of Small-Molecule Crystal Structures To Address Solubility in
Protein–Ligand Crystal Structures Can Guide the Design of Selective Inhibitors of the FGFR Tyrosine Kinase
Rationally Designing Safer Anilines: The Challenging Case of 4-Aminobiphenyls
70) Rationally Designing Safer Anilines: The Challenging Case of 4-Aminobiphenyls
Oxadiazole isomers: all bioisosteres are not created equal
69) Oxadiazole isomers: all bioisosteres are not created equal Kristin
68) Enantiomeric pairs reveal that key medicinal chemistry parameters vary
"Mechanistic Studies on a Sulfoxide Transfer Reaction Mediated by Diphenyl Sulfoxide/Triflic Anhydride"
67) "Mechanistic Studies on a Sulfoxide Transfer Reaction Mediated by
"Do Glycosyl Sulfonium Ions Engage in Neighbouring-Group Participation? A Study of Oxathiane Glycosyl Donors and the Basis for their Stereoselectivity"
66) "Do Glycosyl Sulfonium Ions Engage in Neighbouring-Group Participation? A
DNA-dependent protein kinase (DNA-PK) inhibitors: Structure-activity relationships for O-alkoxyphenylchromen-4-one probes of the ATP-binding domain
65) DNA-dependent protein kinase (DNA-PK) inhibitors: Structure-activity relationships for O-alkoxyphenylchromen-4-one
"Discovery, optimisation and in vivo evaluation of novel GPR119 agonists"
64) "Discovery, optimisation and in vivo evaluation of novel GPR119
Matched Molecular Pairs as a Medicinal Chemistry Tool
63) Matched Molecular Pairs as a Medicinal Chemistry Tool Griffen,
"The Discovery of Benzanilides as c-Met Receptor Tyrosine Kinase Inhibitors by a Directed Screening approach"
62) "The Discovery of Benzanilides as c-Met Receptor Tyrosine Kinase
Quantitatively Interpreted Enhanced Inhibition of Cytochrome P450s by Heteroaromatic Rings Containing Nitrogen
61) Quantitatively Interpreted Enhanced Inhibition of Cytochrome P450s by Heteroaromatic
A statistical analysis of in vitro human microsomal metabolic stability of small phenyl group substituents, leading to improved design sets for parallel SAR exploration of a chemical series
60) A statistical analysis of in vitro human microsomal metabolic
WizePairZ: A Novel Algorithm to Identify, Encode, and Exploit Matched Molecular Pairs with Unspecified Cores in Medicinal Chemistry
59) WizePairZ: A Novel Algorithm to Identify, Encode, and Exploit
Data-mining patent literature for novel chemical reagents for use in medicinal chemistry design
58) Data-mining patent literature for novel chemical reagents for use
The rise of the intelligent machines in drug hunting?
The rise of the intelligent machines in drug hunting? Griffen,
Matched Molecular Pairs as a Guide in the Optimization of Pharmaceutical Properties; a Study of Aqueous Solubility, Plasma Protein Binding and Oral Exposure
Matched Molecular Pairs as a Guide in the Optimization of
MedChemica Publication by Year
Most highly cited indicated with ‡.
Cyanocyclopropylcarboxamides as cathepsin inhibitors and their preparation and use in the treatment of diseases
37. Cyanocyclopropylcarboxamides as cathepsin inhibitors and their preparation and use in the treatment of diseases. Dossetter, Alexander Graham; Heron, Nicola Murdoch PCT Int. Appl. (2008), WO 2009001129.
1,2-Cyclohexanedicarboxamides as cathepsin inhibitors and their preparation and use in the treatment of diseases
36. 1,2-Cyclohexanedicarboxamides as cathepsin inhibitors and their preparation and use in the treatment of diseases. Dossetter, Alexander Graham; Heron, Nicola Murdoch. PCT Int. Appl. (2008), WO 2009001128.
35. Cyanocyclopropylcarboxamides as cathepsin inhibitors and their preparation and use in the treatment of diseases. Crawford, James John; Dossetter, Alexander Graham; Finlayson, Jonathan Erle; Heron, Nicola Murdoch. PCT Int. Appl. (2008), WO 2009001127.
Preparation of amide-indoles as antagonists of gonadotropin releasing hormone (GnRH)
34. Preparation of amide-indoles as antagonists of gonadotropin releasing hormone (GnRH). Wardleworth, James Michael; Dossetter, Alexander Graham; Halsall, Christopher Thomas. (Astrazeneca AB, Swed.; Astrazeneca UK Limited). PCT Int. Appl. (2002), 61 pp. WO 2002092565
Preparation of 6H-thieno[2,3-b]pyrrole derivatives as antagonists of gonadotropin-releasing hormone (GnRh) for treating sex hormone related conditions
33. Preparation of 6H-thieno[2,3-b]pyrrole derivatives as antagonists of gonadotropin-releasing hormone (GnRh) for treating sex hormone related conditions. Foote, Kevin Michael; Matusiak, Zbigniew; Dossetter, Alexander Graham; Arnould, Jean Claude; Lamorlette, Maryannick Andree; Delouvrie, Benedicte; Hamon, Annie. (AstraZeneca AB, Swed.; AstraZeneca UK Limited). PCT Int. Appl. (2004), 215 pp. WO2004018480 A1
Amine derivatives of imidazo[1,2-a]pyridine useful as antagonists of gonadotropin releasing hormone
32. Amine derivatives of imidazo[1,2-a]pyridine useful as antagonists of gonadotropin releasing hormone. Dossetter, Alexander Graham; Kenny, Peter; McKerrecher, Darren; Wardleworth, Michael. (Astrazeneca AB, Swed.; Astrazeneca UK Limited). PCT Int. Appl. (2002), WO2002066478
Preparation of substituted imidazopyridines for antagonizing gonadotropin releasing hormone activity
31. Preparation of substituted imidazopyridines for antagonizing gonadotropin releasing hormone activity. Dossetter, Alexander Graham; Kenny, Peter; McKerrecher, Darren; Wardleworth, Michael. (Astrazeneca AB, Swed.; Astrazeneca UK Limited). PCT Int. Appl. (2002), 98 pp. WO2002066477A2
Preparation of cyanoguanidinoethylindoles GnRH antagonists
30. Preparation of cyanoguanidinoethylindoles GnRH antagonists. Wardleworth, Michael; Dossetter, Alexander Graham; Halsall, Chris T. (Astrazeneca AB, Swed.; Astrazeneca UK Limited). PCT Int.Appl. (2002), 65 pp. WO2002066459
Catalytic asymmetric cycloaddition reactions of dienes and aldehydes
29. Catalytic asymmetric cycloaddition reactions of dienes and aldehydes. Jacobsen, Eric N.; Schaus, Scott E.; Dossetter, Alexander G.; Jamison, Timothy F. (Harvard University, USA). U.S. (2001), 39 pp., US 6,130,340.
28. Asymmetric cycloaddition reactions using transition metal chiral Schiff base complexes. Jacobsen, Eric N.; Schaus, Scott E.; Dossetter, Alexander G.; Jamison, Timothy F. WO 2000050365A1
4-Amino-7,8-Dihydropyrimido[5,4-F][1,4]Oxazepin-5(6h)-One Based Dgat1 Inhibitors
27. 4-Amino-7,8-Dihydropyrimido[5,4-F][1,4]Oxazepin-5(6h)-One Based Dgat1 Inhibitors Birch, A. M.; Goldberg, F. W.; Leach, A. WO 2011121350.
Adamantyl Iminocarbonyl-Substituted Pyrimidines As Inhibitors Of 11-Beta-HSD1
26. Adamantyl Iminocarbonyl-Substituted Pyrimidines As Inhibitors Of 11-Beta-HSD1 Bennett, S. N. L.; Goldberg, F. W.; Leach, A.; Whittamore, P. R. O.; Sörme, P. US20110092526.
Pyrazine Carboxamides As Inhibitors Of DGAT1
25. Pyrazine Carboxamides As Inhibitors Of DGAT1 Birch, A. M.; Butlin, R. J.; Campbell, L.; Green, C.; Leach, A.; Murray, P. M.; Ryberg, P. O.; Waring, M. J. WO/2010/146395.
Substituted Pyrimidin-5-Carboxamides
24. Substituted Pyrimidin-5-Carboxamides Gill, A. L.; Leach, A.; Packer, M.; Scott, J. S.; Sörme, P.; Swales, J. G.; Whittamore, P. R. O. WO/2009/130496.
Carbamoyl compounds as DGAT1 inhibitors
23. Carbamoyl compounds as DGAT1 inhibitors. Bauer, U. A.; Birch, A. M.; Butlin, R. B.; Green, C.; Barlind, J. G.; Hovland, R.; Johannesson, P.; Leach, A.; Noeske, A. T.; Petersson, A. U. WO/2009/081195
Pyrrolo [2, 3 -d] pyrimidin derivatives as protein kinase B inhibitors
22. Pyrrolo [2, 3 -d] pyrimidin derivatives as protein kinase B inhibitors. Johnson, P. D.; Leach, A; Luke, R. W. A.; Matusiak, Z. S.; Morris, J. J. WO/2009/047/563.
Substituted piperidines having protein kinase inhibiting activity
21. Substituted piperidines having protein kinase inhibiting activity Woodhead, S. J.; Frederickson, M.; Hamlett, C.; Woodhead, A. J.; Verdonk, M. L.; Sore, H. F.; Walker, D. W.; Blurton, P.; Collins, I.; Cheung, K. M.; Caldwell, J.; Da Fonseca Mchardy, T. F.; Luke, R. W. A.; Matusiak, Z. S.; Leach, A.; Morris, J. J. WO/2008/075109.
Piperidine derivatives for the treatment of obesity
20. Piperidine derivatives for the treatment of obesity Butlin, R. J.; Caulkett, P. W. R.; Leach, A.; Newcombe, N. J.; O'Donnell, C. J.; Wood, J. M. WO/2008/075077.
Sulfonamide derivatives for therapeutic use as fatty acid synthase inhibitors
18. Sulfonamide derivatives for therapeutic use as fatty acid synthase inhibitors Butlin, R. J.; Caulkett, P. W. R.; Johanesson, P.; Knerr, L. D.; Leach, A.; Newcombe, N. J.; O'Donnell, C. J.; Pointon, H.; Wood, J. M. WO/2008/075070.
Pyrimidine derivatives as EphB4 inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cancer
17. Pyrimidine derivatives as EphB4 inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cancer. Kettle, J. G.; Read, J.; Leach, A.; Barlaam, B. C.; Ducray, R.; Lambert-Van der Brampt, C. M. P. WO/2007/085833.
Preparation of acylamino dibenzothiophenes as DNA-PK inhibitors
16. Preparation of acylamino dibenzothiophenes as DNA-PK inhibitors
Frigerio, Mark; Hummersone, Marc Geoffrey; Menear, Keith Allan; Finlay, Maurice Raymond Verschoyle; Griffen, Edward Jolyon; Ruston, Linette Lys; Morris, Jeffrey James; Ting, Attila Kuan Tsuei; Golding, Bernard Thomas; Griffin, Roger John; et al WO 2010136778 A1.
Preparation of 2-benzimidazolyl-6-morpholino-4-(piperidin-4-yl)pyrimidine derivatives as PI3K and mTOR inhibitors for treatment of proliferative disease
15. Preparation of 2-benzimidazolyl-6-morpholino-4-(piperidin-4-yl)pyrimidine derivatives as PI3K and mTOR inhibitors for treatment of proliferative disease
Butterworth, Sam; Griffen, Edward Jolyon; Pass, Martin WO 2008032072 A1.
Preparation of 2-benzimidazolyl-6-morpholino-4-heterocyclylpyrimidine derivatives as PI3K and mTOR inhibitors for treatment of proliferative disease
14. Preparation of 2-benzimidazolyl-6-morpholino-4-heterocyclylpyrimidine derivatives as PI3K and mTOR inhibitors for treatment of proliferative disease
Preparation of 2-benzimidazolyl-6-morpholino-4-phenylpyrimidine derivatives as PI3K and mTOR inhibitors for treatment of proliferative disease
13. Preparation of 2-benzimidazolyl-6-morpholino-4-phenylpyrimidine derivatives as PI3K and mTOR inhibitors for treatment of proliferative disease Butterworth, Sam; Griffen, Edward Jolyon; Pass, Martin WO 2008032086 A1.
Preparation of 4-benzimidazolyl-2-morpholino-6-piperazinyl-pyrimidine derivatives as PI3K and mTOR kinase inhibitors for the treatment of proliferative disorder
12. Preparation of 4-benzimidazolyl-2-morpholino-6-piperazinyl-pyrimidine derivatives as PI3K and mTOR kinase inhibitors for the treatment of proliferative disorder Butterworth, Sam; Griffen, Edward Jolyon; Hill, George Beresford; Pass, Martin WO 2008032033 A1.
"A Field Manual for Medicinal Chemistry: Towards Real AI in Drug Hunting?" Leventhal Lecture at CUP XX
Keynote lecture at Openeye Scientific's CUP XX meeting
Presented by Dr Ed Griffen March 11th 2020.
Available with notes on slideshare.
Accelerating lead optimisation with active learning by exploiting MMPA based ADMET knowledge with regression forest potency models
Poster presented by Dr Ed Griffen at the 15th German Conference on Cheminformatics in Mainz, November 2019.
Available on slideshare.
Emerging Challenges for Artificial Intelligence in Medicinal Chemistry
Presentation by Dr Ed Griffen at the IBSA Conference "How Artificial Intelligence Can Change the Pharmaceutical Landscape" – Lugano, Switzerland, October 9th 2019 now on slideshare see the video's here.
Understanding Patent SAR by network analysis
Applying graph methodology to the relationships between patent compounds described by matched molecular pair analysis we can extract critical compounds within patents, the relationships between patents and even model potency.
Poster presented at the RSC 2018 kinase meeting on slideshare
Virtual Toxicity Panels to Aid the medicinal chemist
Poster presented on interpretable machine learning methods to model critical toxicities and provide clear guidance to the medicinal chemist.
Poster on slideshare
Accelerating multiple medicinal chemistry projects using Artificial Intelligence (AI) : A review from the past 8 years of real world examples
Dr Al Dossetter will be in Boston at Merck research labs on the 30th May at the Efficient Drug Discovery through Connected Chemistry meeting. Registration is still open here.
Explainable Artificial Intelligence in Drug Hunting
Dr Ed Griffen's presentation now available on slideshare: Explainable Artificial Intelligence in Drug Hunting
Accelerating multiple medicinal chemistry projects using Artificial Intelligence (AI) – Pistoria Alliance
12th March 2019 – Presentation on slideshare
Accelerating multiple medicinal chemistry projects using Artificial Intelligence (AI)
12th March 2019 Pistoia Alliance Meeting
Learning Medicinal Chemistry ADMET Rules ukqsar Sept 2017
29th September 2017 – Learning Medicinal Chemistry ADMET Rules ukqsar Sept 2017
Pharmacophore extraction from Matched Molecular Pair Analysis
7th October 2016 – Pharmacophore extraction from Matched Molecular Pair Analysis
American Chemistry Society meeting Fall 2016
28th September 2016 – American Chemistry Society meeting Fall 2016 MedChemica – Extracting and exploiting medicinal chemistry ADMET knowledge automatically from public and large pharma data
Multi-Parameter Optimization of Pharmaceuticals: the Big-Data Way
3rd September 2013 – Cambridge Med Chemistry conference Fall 2013 Multi-Parameter Optimization of Pharmaceuticals: the Big-Data Way
The MedChemica Bucket List
BucketListPapers 100/100: Everything You Have Read Maybe Untrue…
We've made it to the last paper in our #BucketListPapers series, and for that reason we are now going to tell you everything you have read is false. Not quite, but there are concerns that a large majority of the findings in modern research are false, therefore, when reading papers there must be an element of caution to check that the research is credible.
Ioannidis constructs a statistical model to indicate whether findings within a paper are a false positive result through different assumptions. It is important to note that "negative" research is sometimes just as important as research that works. Even though there seems to be less of a drive to publish papers when "negative" research occurs. These papers were not included in this research as only ones where there were claims of relationships were considered.
One of the main contributors is bias, whether willing or unknown. These biases can include the way in which the data and analysis has been handled and reported.
Six corollaries were stated that could impact the reliability of published research. These state that:
smaller studies findings are less likely to be true
the smaller the relationship, the less likely the findings are to be true
the greater the number and the lesser the selection of tested relationships in the field, the less likely the findings are to be true
the greater the flexibility in the whole study and analysis, the less likely the findings are to be true
the greater the financial, other interests and prejudices in a field, the less likely the findings are to be true
the hotter a scientific field (with more scientific teams involved), the less likely the findings are to be true
Even though there will never be a gold standard to publishing research findings Ioannidis outlines that we all must do more in order to improve the situation. The first is that we should have larger studies with low bias. The second is that each research team addressing the same research question should be considered equal and one should not be given more significance than another, as all evidence is equal. The final one is that we should improve our understanding of R values to stop chasing statistical significance and pre-studies consider what the chance are that a true relationship is being tested or a non-true relationship. Additionally, in order to prevent false findings being published all research results should be reproducible.
Why Most Published Research Findings Are False.
John P. A. Ioannidis
PLoS Med 2(8): e124
BucketListPapers 99/100: The importance of validating statistical methods against real-world data
In this #BucketListPapers, software used for statistical analysis of fMRI data, specifically those that are designed to correct for familywise error (FWE), are validated against real-world, resting-state fMRI data from healthy controls. FWE-correction is important in experiments where multiple measurements are taken in parallel and combined to infer a statistical signal, as the statistical error is amplified leading to a higher overall false positive rate. Eklund et al. compare the FWE rates for three standard fMRI analysis software packages (SPM, FSL and AFNI), using a variety of commonly-employed methods and parameters, and identified up to 70 % false positive rates. Importantly, the paper concludes by recommending that the fMRI community focuses on validating existing statistical analysis methods and highlights the importance of real-world data sharing in efforts to do this; these are considerations that apply in many areas of the life-sciences.
Cluster failure: Why fMRI inferences for spatial extent have inflated false-positive rates.
PNAS, 2016, 113(28), 7900-7905
BucketListPapers 98/100: Walking with Purpose
A drug discovery project has various twist and turns in its iterative design and optimisation process that can cover various areas of chemical space. Understanding how these projects evolve overtime could be crucial in the development of new projects. It is also important to understand why projects fail and the parameters set that could effect the drug discovery projects and understanding the end-goal of the project. #BucketListPapers
Delaney created a model that attempts to replicate the process through a self-avoiding walk (SAW). As overall researchers are a lot better at documenting successes rather than failures it makes it difficult to understand the difference in projects that work and don't. The parameters of the modelled project can be adapted and explored. The model trajectories can be modelled on Sammon plots and these are similar to real life projects. The figure below is an example of a random walk generated by Delaney. The green circle is the starting point and the red circle is the end point, in this instance after 1000 steps. The start of the sequence is green, the mid section is blue and the end steps of the sequence is in red. Delaney analysed the number of successes and failures of each SAW project, where a success is a project that reaches it's specific target and a failure is one where the SAW terminates before reaching the projects target. This analysis showed that allowing projects to run for longer increases the number of successes per project. Additionally, when altering the departmental parameters they have little effect on the number of success per project but did have an impact on the number of projects per step. Self-avoiding walks can, therefore, be used to predict how a drug-discovery project would react with certain constraints to understand how potentially success or not it maybe.
Delaney: Modelling Iterative Compound Optimisation using a Self-Avoiding Walk
Drug Discov Today. 2009 Feb;14(3-4):198-207
BucketListPapers 97/100: Still relevant today…
From the title of this #BucketListPapers you would think it was just out. Given the resurgence of deep learning methods to devises synthetic routes you might expect this, but it was published in 1969; a couple of months after the Moon landings! The work is famous in organic chemistry, and E.J.Corey won a Nobel prize. Although you may have been taught the methods (and read the books) you may not have read the paper 'Computer-Assisted Design of Complex Organic Synthese'** The paper is long and describes in detail many of the chem-infomatics issues that come around when writing a piece of software for use by chemists. All through the paper you will keep saying to yourself 'this was 1969!'. The process of automating the retro-synthetic analysis of an organic molecule is hard. Like a game of chess once a few moves have been made the possible combinations multiply.
One important facet of the design of this software was the continued input of the chemist to 'guide' the algorithm through the process – this also saves computational effect and memory. The descriptions of a chemical structure drawing package***, mapping the structure into a graph, and perceiving the chemical functionality are still relevant today, and the methods, for the most part, unchanged. The description of the SSSR (Smallest Set of Smallest Ring problem) is in here too!
We picked out Figure 2, one of many describing the algorithm, because it starts with 'Chemists enters target molecule' and ends with 'Chemist satisfied?'. The essential principles of devising a computer program to design synthetic routes is still current. The approach taken in the program is supervised; the chemical disconnections / forward reactions need to be encoded and as such it is hard to keep it up-to-date and modern.
Computer-Assisted Design of Complex Organic Syntheses
Science 10 Oct 1969: Vol. 166, Issue 3902, pp. 178-192
A mention must be made to the current approaches using Deep Learning to effectively extract the chemical reactions from the data and provide the body of knowledge in an unsupervised and updatable manner.
Planning chemical syntheses with deep neural networks and symbolic AI
Nature 2018, 555(7698), 604-610.
** – of additional note: The modern availability of journals on-line means we miss that trip to library and the discovery of 'the paper after the one we were looking for' moment. For this paper (when you download the pdf) just read the start of the following paper…. still relevant today….
*** – and they basically look the same today…
BucketListPapers 96/100: Automating Structure-Activity Evaluation
The main principles of the drug discovery process rely on a correlation existing between a chemical structure and it's activity. This #BucketListPapers integrates two methods of finding these. Several different promising methods have arose that attempt to find the relationship between structure and biological activity. These are quantitative structure-activity relationship (QSAR), pattern recognition methods (PR) and discriminant analysis (DA). Klopmann introduced a new method that combines the latter two. The method fragments a molecule into varying size fragments, from 3 to 12 interconnecting atoms. The hydrogens are retained along with information about the multiplicity of the bonds and whether an atom is connected to a terminal functionality group. Statistical analysis is then performed on each of the fragments to indicate whether it is an important feature in an active or inactive molecule, where the active fragments are known as biophores and the inactive fragments are biophobes.
Three studies were carried out in order to understand how useful this method was. Two of the studies already had existing information and the biophores and biophobes that were extracted were reasonable and aligned with previous studies. Additionally, the models correctly identifying 35/43 and 41/43 respectively. The image below demonstrates three fragments, two activating and on deactivating. The two activating fragments show a bay region that had previously, in a different study, been considered to be important in the binding, which the deactivating fragment does not possess. The last study there was no known information about what caused molecules to be active or inactive. There were 10 identified statistically relevant biophores/ biophobes. When using these biophores and biophobes the model was able to correctly predict 33/39.
Klopmann, therefore, showed that this approach had the potential to automatically extract information and turn them into useful biophores and biophobes. This method paved the way in applying artificial intelligence approaches to structure-activity studies.
Klopmann: Artificial intelligence approach to structure-activity studies. Computer automated structure evaluation of biological activity of organic molecules
J. Am. Chem. Soc. 1984, 106, 24, 7315–7321
BucketListPapers 95/100: Automated workflow for multiobjective de novo design
De novo drug design involves the enumeration of new molecules with the aim of satisfying multiple activity and pharmacokinetic objectives. The combination of multiparameter optimisation, along with the vast area of chemical search space, makes enumeration and ranking a significant challenge for any de novo design project. This #BucketListPapers introduces MOARF (MultiObjective Automated Replacement of Fragments), a workflow for the multiobjective design of synthetically-accessible small molecules. Specifically, the protocol involves the implementation of SynDiR, a fragmentation algorithm that uses retrosynthetic rule-based cuts, to an input molecule. Replacement fragments are then identified from a large dataset of predefined fragments, generated by using SynDiR on molecule libraries, based on their physicochemical properties, similarity to the original fragment and alignment using Rapid Alignment Searching (RATS). The reconstructed molecules are then filtered and scored using a combined scoring function assembled from a range of user-defined functions, such as activity prediction and shape similarity models.
Importantly, the MOARF workflow was tested on a historical project from the Institute of Cancer Research (ICR), in which a CDK2 inhibitor was optimised for potency and metabolic stability. The results showed that MOARF generated a diverse dataset of suggestions within relevant areas of chemical space, and optimising against shape similarity (using ROCS), atom pair similarity, CDK2 activity prediction and CLogP resulted in the synthesis of several molecules with CDK2 activity and improved metabolic stability. This demonstrates the value of using computational enumeration and scoring methods to guide de novo design and multiparameter optimisation.
MOARF, an Integrated Workflow for Multiobjective Optimization: Implementation, Synthesis, and Biological Evaluation
J. Chem. Inf. Model. 2015, 55, 1169−1180
BucketListPapers 94/100 It is more than physical properties alone…
We learn at degree level that the enantiomeric compounds have properties which are exactly the same, but for measurements like polarised light. However, when enantiomers are measured in common assays used in drug hunting, what effects to we see, and by how much do they vary? In this #BucketListPapers, Leach et al looked at enantiomeric matched pairs and found that, for the likes of aqueous solubility, that there was no difference, as expected, but for some measured properties, like Cytochrome P450 inhibition there were significant differences. Perhaps most surprisingly were the absorption measurements, these showed no difference for both A-B, and for efflux ratio.
Enantiomeric pairs reveal that key medicinal chemistry parameters vary more than simple physical property based models can explain.
Med. Chem. Commun., 2012, 3, 528
BucketListPapers 93/100: More Matched Pairs Papers!
A critical part of Matched Molecular Pair Analysis is the includsion of the chemical environment information with the chemical change. Scientists at GSK were the first to publish this finding and quantify the importance. Hence this is second selection for a #BucketListPapers on MMPA.
Lead Optimization Using Matched Molecular Pairs: Inclusion of Contextual Information for Enhanced Prediction of hERG Inhibition, Solubility, and Lipophilicity
J. Chem. Inf. Model. 2010, 50, 1872–1886
More honourable mentions:
In 2006, Abbott Laboratories published Drug-Guru, a medicinal chemistry "expert system" that contained a collection of molecular transformations compiled from the literature and medicinal chemists' experience. When this was published, we had started work on a similar idea but using MMPA to 'find' all of the significant molecular transformations for med chem, thus saving the bother of manual cataloguing, and thus operating in an un-biased way.
A computer software program for drug design using medicinal chemistry rules.
Bioorg. Med. Chem. 2006, 14, 7011-7022.
For the statistical analysis of MMPA and the establishment of 'med chem rules' see:
Turbocharging Matched Molecular Pair Analysis: Optimizing the Identification and Analysis of Pairs.
Coming back to the good people at GSK and Sheffield Uni, recently they examined the output drug design algorithms, compared to human output… an excellent read,..
A Turing test for molecular generators
J. Med. Chem. 2020, 63, 20, 11964–11971
BucketListPapers 92/100: Here Come the Matched Pair Papers!
Presenters at medicinal chemistry conference now use the phrases 'matched pairs' and 'matched pair analysis', showing the technique has become a 'must-have' part of the analysis toolbox. Choosing which matched pair papers to feature in #BucketListPapers was surprisingly difficult, given this is our area of expertise. We have chosen one of the first papers in the area:
J. Med. Chem., 2006, 49 (23), 6672-6682
For a review of the techniques and the literature, a book chapter is now available:
Matched Molecular Pair Analysis. Andrew Leach
Comprehensive Medicinal Chemistry III, Volume 3 page 221.
The field has advanced due to efficient and reproducible algorithms being published. Here are two key references:
Computationally Efficient Algorithm to Identify Matched Molecular Pairs (MMPs) in Large Data Sets
J. Chem. Inf. Model. 2010, 50, 339–348
WizePairZ: A Novel Algorithm to Identify, Encode, and Exploit Matched Molecular
Pairs with Unspecified Cores in Medicinal Chemistry
Matched Molecular Pair Analysis can be used to share knowledge between organisations without sharing the original chemical structures and data.
J. Med. Chem. 2018, 61, 3277−3292
..and it can be combined with Machine Learning…
Coupling Matched Molecular Pairs with Machine Learning for Virtual Compound Optimization.
J. Chem. Inf. Model. 2017, 57, 12, 3079–3085
BucketListPapers 91/100 – How to Assess Uncertainty in a Given Data Set.
As the abstract says "The maximum achievable accuracy of in silico models depends on the quality of the experimental data." The paper describes beautifully, methods to examine a given dataset and so "defines a natural upper limit to the predictive performance possible." This #BucketListPapers uses publicly available data from ChEMBL and Figure 5 illustrates the spread in the data for pairs for measurements for a given molecule – the 2.5 log lines really show how much measurements can vary. An appreciation of this degree in variation is important when building ML models for drug discovery.
Kramer : The Experimental Uncertainty of Heterogeneous Public Ki Data.
J. Med. Chem. 2012, 55, 5165-5173
A great follow up, by the same author, is the impact of uncertainty on Matched Molecular Pair Analyis.
Matched Molecular Pair Analysis: Significance and the Impact of Experimental Uncertainty.
J.Med. Chem. 2014, 57, 9, 3786–3802.
BucketListPapers 90/100 – Identification of pharmacophores and who is the best?
This bucket list paper draws comparisons between three commercially available pharmacophore generation programs. All three programs are extensively described. The programs are then compared on their ability to identify the target pharmacophore which was a known pharmacophore, from Relibase+ and the literature, for five different proteins that had a vast collection of crystallographic data. The pharmacophoric features that were of interest include hydrogen-bond acceptors and donors, positive and negatively charged groups and hydrophobic centres. Two separate evaluations were performed, the first was using a rigid search and the second a flexible search. It is difficult to evaluate how good each of this methods were at generating the target pharmacophores, therefore, two criteria were used to judge. Firstly, the RMSD between the found pharmacophores and the target pharmacophore was calculated. The second method was to identify the number of "misses" that occurred, either a feature was missing or a wrong functional group was assigned to the pharmacophore. The generate pharmacophores can then be scored and ranked according to these two criteria. For all five datasets each of the results generated by each method are discussed in detail. These results indicated that Catalyst and GASP outperformed DISCO for all five datasets. GASP ranked first in three out of five cases and Catalyst ranked first in the other two cases. Both of these methodologies identified the target pharmacophore quickly as they were found within the first ten solutions.
A comparison of the pharmacophore identification programs:
Catalyst, DISCO and GASP. Journal of Computer-Aided Molecular Design, 16 (8-9). 653 – 681.
BucketListPapers 89/100: How do we find binding pockets in proteins?
Goodford describes, in 1985, a method for probing proteins computationally to find putative binding sites. For budding computational chemists this is a must read. For medicinal chemists, the understanding of the techniques and an ability to evaluate the results is highly useful. The method applies a grid over the protein and then probes with 'spheres' that represent a small number of chemical groups [NH3+, =O, O-, OH, CH3, H2O]. Using a consideration of the molecular physics, Lennard-Jones potentials and electrostatic interactions were calculated and a model for hydrogen bonding applied for each of these groups, hence the energy of binding is estimated. The paper has several examples of the algorithm probing phospholipase-A2 structures.
We think every methodology paper should start a 'Discussion' session with the phrase – "Before assessing the findings, it is necessary to consider the shortcomings of the method." It is worth reading the paper for this section alone and the detailed self-assessment of the method.
Methods for determining binding sites within proteins is an area of continuous development and exciting for AI drug discovery. The combination of protein folding algorithms, binding pocket determination and directed screening to select small sets of compounds to screen offers a genuine opportunity to reduce the cost and time to drug discovery research.
A computational procedure for determining energetically favorable binding sites on biologically important macromolecules
J. Med. Chem. 1985, 28, 7, 849–857
BucketListPapers 88/100 : Energising QSAR Models
Comparative Molecular Field Analysis (CoMFA). 1. Effect of Shape on Binding of Steroids to Carrier Proteins.
J. Am. Chem. Soc. 1988, 110, 5959-5967.
Comparative molecular field analysis (CoMFA) is a method that was created for three-dimensional quantitative structure analysis (3D-QSAR). The work Cramer et al. did was an extension of work that had been done several years prior.1 The CoMFA analysis is performed by placing molecules into on 10-degree grid and the minimising the structures to aligning structures within the lattice. A QSAR table is then generated by calculating energy at several points within the grid. This energy value incorporates electrostatic and steric properties of the molecule. These energies can then be used as descriptors in QSAR models. The CoMFA method was then applied to two sets of steroid structures, the first contains 21 molecules and the latter contains 10 molecules, the descriptors were for both were used in a partial least squares (PLS) model. The results highlighted that the CoMFA method as a promising QSAR method.
Wise, M., Cramer, R.D., Smith, D. and Exman, I. (1983) Progress in three-dimensional drug design: the use of realtime colour graphics and computer postulation of bioactive molecules in dylomms. In Quantitive Approaches to Drug Design (Proceedings of the 4th European Symposium on Chemical Structure-Biological Activity: Quantitative Approaches) pp. 145-146. Elsevier, Amsterdam
BucketListPapers 87/100: The Ramachandran Plot
A protein's function is inherently linked to its secondary and tertiary structure, which is determined by its amino acid sequence. Understanding the structures of various disease-linked proteins is, therefore, a crucial step towards designing modulators that can influence protein function. When considering the conformational propensity of a polypeptide, given that the CO-NH peptide bond atoms have a very stable planar conformation, it is apparent that the secondary structure -determining coordinates are the two backbone dihedral angles that occur between atoms CO-NH-C(α)-CO (Φ) and NH-C(α)-CO-NH (Ψ). This idea was first introduced by Ramachandran et al. in the 1960s, who hypothesised that only certain regions of Φ / Ψ space are energetically feasible given the minimum contact distances permitted by the van der Waals interactions between atoms in adjacent residues (https://doi.org/10.1016/S0022-2836(63)80023-6). Indeed, when Ramachandran et al. analysed structural data from di-, tri- and poly-peptides, they found that all of the structures resided within the theoretically permitted regions of Φ / Ψ space, and that the space occupied was characteristic of the secondary structure present in the polypeptide chain.
Stereochemistry of polypeptide chain configurations.
J. Mol. Biol. 1963. 7. 95-99.
Today, Ramachandran analysis remains a staple for protein structure validation and secondary structure analysis/ parameterisation of molecular models and simulations:
Structural biology data archiving – where we are and what lies ahead.
FEBS Letters. 2018. 592(12). 2153-2167.
A New Generation of Crystallographic Validation Tools for the Protein Data Bank.
Structure. 2011. 19(10). 1395-1412.
Combining Ramachandran plot and molecular dynamics simulation for structural-based variant classification: Using TP53 variants as model.
CSBJ. 2020. 18. 4033-4039.
BucketListPapers 86/100: A Step Closer to Unlocking the Potential of FEP for Drug Discovery
Free energy perturbation (FEP), a molecular dynamics (MD) simulation technique that involves transforming a model system between two states to calculate the free energy difference between the states, has been well used and developed within academia for decades. In the context of drug discovery, this methodology has promised the ability to calculate relative protein binding energies of similar compounds (e.g matched molecular pairs) by performing alchemical transformation simulations between the compounds in solution and embedded in the protein pocket. However, the challenges that are associated with many MD simulation methodologies also apply here and have prevented the efficient use of FEP within industrial projects to guide lead optimisation. Namely, these challenges include the limited accuracy of molecular mechanics force fields, the computational cost involved in sampling the conformational and configurational landscape of the system and the technical barrier for users to implement specialist MD methods.
In this publication by Wang et al., researchers at Schrodinger present their extensive work towards resolving some of these issues. Importantly, the paper highlights efforts to generate a more transferable small molecule force field (OPLS2.1) that is parameterised using 10,000 drug-like compounds, an implementation of a sophisticated enhanced sampling approach (replica exchange with solute tempering (REST)) within the FEP simulation protocol, and the automation of missing parameter calculations and simulation setups, making the approach accessible for industrial medicinal chemists. The results presented show a significant improvement in force field accuracy compared to a previous OPLS model and the commonly used MMFF force field, along with promising false negative and true positive rates when the method was tested on a retrospective project, and a 6-fold enrichment in compound selection for synthesis within a prospective drug discovery project. The ability to improve the accuracy of relative binding affinity predictions and the usability of FEP technologies through user-friendly interfaces brings us a step closer to allowing industrial medicinal chemists to fully utilise FEP to benefit their projects.
Accurate and Reliable Prediction of Relative Ligand Binding Potency in Prospective Drug Discovery by Way of a Modern Free-Energy Calculation Protocol and Force Field.
Journal of the American Chem. Soc. 2015. 137(7). 2695-2703.
BucketListPapers 85/100: Amber: The force (field) is strong with this one!
Following on from our previous bucket list release on the CHARMM MD package and force fields, we now choose to introduce Amber, another MD simulation package and force field family that are frequently employed for biomolecular simulations in drug discovery. Like CHARMM, the Amber MD software originated in the late 1970s and has been maintained and expanded throughout the years. Following over a decade of model refinement and optimisation, the modern family of Amber force fields began with the development of the Cornell et al. force field in 1995 (commonly referred to as ff94), with the potential energy equation including bonded and non-bonded terms and parameters for amino acids and nucleic acids. Importantly, Cornell et al. established a general parameterisation procedure to ensure continuity and additivity for future iterations of molecule parameterisation. The procedure involves the derivation of partial atomic charges from an electrostatic potential, determined using QM calculations with the 6-31G* basis set, followed by two-stage restrained electrostatic potential (RESP) fitting. Since ff94, many refinements, corrections and additions to the Amber force field have been published, including ff14SB and LIPID14, that include parameters for amino acids, nucleic acids, carbohydrates and lipids. There is also a general amber force field (GAFF) that, like CGenFF, allows anyone to parameterise small molecules in a consistent way to the biomolecular force fields, allowing the interactions between drug molecules and their targets to be explored using simulation.
The Amber biomolecular simulation programs.
J Comp Chem. 2005. 26(16) 1668-1688
A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules.
JACS. 1995. 117(19). 5179-5197.
ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB.
J. Chem. Theory Comput. 2015. 11(8). 3696-3713.
Lipid14: The Amber Lipid Force Field.
J. Chem. Theory Comput. 2014. 10(2). 865-879.
Development and testing of a general amber force field.
J. Comput. Chem. 2004. 25(9). 1157-1174.
BucketListPapers 84/100: CHARMM: may the force (field) be with you!
First conceived in the 1950s and advanced through the latter half of the 20th century, molecular dynamics simulations have become a key branch of computer aided drug discovery. The ability to calculate the evolution of atomic positions through time, based on an underlying molecular mechanic energy function, brought with it the potential to explore dynamic ensembles of biomolecular drug targets, and to gain mechanistic understanding of drug interactions at an atomic level. Significant contributions to the field have been made by Karplus and MacKerell, who have been responsible for the development of the popular CHARMM MD software and force fields (the potential energy function and parameters used as the underlying model) (https://doi.org/10.1002/jcc.540040211). The first CHARMM force field (CHARMM19) was developed in the 1980s and used an united-atom representation (where implicit hydrogens were treated as part of the attached heavy atom) (https://doi.org/10.1063/1.472061). Since then, multiple re-parameterisations, corrections and additions, where parameters were fitted to experimental structure and ab inito data, have been released (https://doi.org/10.1021/jp973084f). Today, the CHARMM force fields utilises an all-atom model that incorporates bonded and non-bonded potential energy terms and parameters for the basic biochemical building blocks; e.g the standard amino acids, phospholipids, and nucleic acids (https://doi.org/10.1038/nmeth.4067). In addition, the CHARMM general force field (CGenFF) allows users to fit parameters to a wide range of small molecules based on the chemical groups and atom types present in the structure, which crucially allows researchers to model the interactions of small molecules with biomolecular targets (https://doi.org/10.1002/jcc.21367).
CHARMM: A program for macromolecular energy, minimization, and dynamics calculations
Journal of Computational Chemistry, 1983, 4, 187-217.
Simulation of activation free energies in molecular systems
J. Chem. Phys. 105, 1902 (1996)
CHARMM36m: an improved force field for folded and intrinsically disordered proteins
Nature Methods volume 14, 2016, pages 71–73
CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields
Journal of Computational Chemistry, 2010, 31, 671-690.
BucketListPapers 83/100: The amazing Ames test – avoiding mutagens
For a long time, I had assumed that the AMES test was an abbreviation and that it was one of the most brilliant transformations of a surprising insight into something useful. I was delighted and envious when I discovered that this clever trick was actually named after its inventor, Bruce Ames. In this test for mutagenicity, a range of bacterial strains that have naturally occurring mutations preventing them from synthesising a specific amino acid (usually histidine) are grown in media lacking that amino acid. Exposure to certain types of mutagen cause reversion to a form that is able to synthesise the amino acid and hence the bacteria can grow and reproduce leading to the appearance of colonies on the plates (Figure). The details of the test, including some of its history, are described in this article by Mortelmans and Zeiger. The paper is a veritable manual for those wishing to run the test with troubleshooting and detailed instructions for all procedures provided. One of the key challenges is that many compounds are not mutagenic until they are metabolised and so the test requires the inclusion of some form of metabolic system and the choice of this can be critical. There remains much debate about the reproducibility and relevance of the Ames test but it has been a crucial defence in pre-clinical screening.
The Salmonella (Ames) test for mutagenicity
K Mortelmans, E Zeiger
Current protocols in toxicology Curr Protoc Toxicol. 2001 May;Chapter 3:Unit3.1.
Among many others, I've shown how results in the Ames test for aromatic amines (a common mutagen class) can be correlated with simple chemical descriptors and that this can be used to design safer compounds (doi: 10.1021/jm3001295), McCarren and colleagues and Novartis have shown that this approach likely has a dependence on the size of the molecule (doi: 10.1016/j.bmc.2011.03.066) and Shamovsky and colleagues at Astrazeneca (doi: 10.1021/acs.jmedchem.1c00514) have probed the metabolic process and this may relate to the molecular weight limit already mentioned. The beauty of this area is that unlike much that is utterly mysterious about biology when looked at by chemists, mutagenicity often has a strong chemical component that be rationalised and predicted.
BucketListPapers 82/100: Hydrogen Bonds – not all the same!
Although Lipinski's rules and related approaches demand that we count any hydrogen bond donor or acceptor (defined in a rather limited way) as equivalent, there is a significant strand of experimental and computational work that has sought to quantify the differences between the acceptor and donor ability of different functional groups. I was first introduced to these ideas in one of the series Hydrogen Bonding, Parts 1 to at least 9. In part 9, Abraham et al. introduced an overview of their measurements made by using a standard donor (4-nitrophenol) or a standard acceptor (N-methylpyrollidinone) in 1,1,1-trichloroethane. A large array of functional group types were studied. Subsequently, these data were found to correlate well with electrostatic potential computed in quantum mechanical calculations by Kenny in two important publications (Acceptors: and Donors:). This work was extended to show how hydrogen bonding strength could be related to differences between partitioning coefficients measured in 1-octanol and partitioning coefficients measured in hexadecane.
In parallel with this activity, mostly undertaken at Astrazeneca, Hunter was using similar considerations to build a unifying model of the nature of interactions between molecules that led to the map shown below in which blue regions represent acceptors (across the top) and donors (down the side) that are able to form attractive interactions in water. The red regions represent those interaction types that involve loss of so much solvation by the more polar partner that the new interaction is unable to compensate for it.
Quantifying Intermolecular Interactions: Guidelines for the Molecular Recognition Toolbox
BucketListPapers 81/100: Pair up your atoms….
The concept of using pairs of atoms and how far apart they are as a way to encode structures underpins many of the grouping techniques that are particularly popular in HTS analysis and other large collections of biochemical data. Here, Carhart, Smith and Venkataraghavan introduce atom pairs and describe how the shortest path between two atoms can be identified by crawling through a molecule starting at each atom in turn to identify the shortest distance to every other atom. This way to encode the structure of molecules is illustrated for acetone and isobutylene and allows for a very compact and general representation that allows connections between molecules to be made that are usefully surprising.
Atom pairs as molecular features in structure-activity studies: definition and applications
J. Chem. Inf. Comput. Sci. 1985, 25, 2, 64–73
BucketListPapers 80/100: Polar exploration complements non-polar exploration
By investigating the correlation of a variety of group descriptors, Craig established that there are a group of non-polar descriptors such as π, molecular volume, parachor, ES and group refractivity that all correlate to a significant extent. By contrast, the various polar descriptors considered did not show appreciable correlations either with the non-polar set or among themselves (confirming earlier findings). By establishing independence of these two types of descriptor, it follows that choosing groups that span a range of π and s would be an effective way to explore SAR. The distribution of substituents by values appropriate for the para position are shown and selection of groups from each quadrant should be considered.
Interdependence between physical parameters and selection of substituent groups for correlation studies. Craig, Paul N.
J. Med. Chem. 1971, 14, 680–684.
BucketListPapers 79/100: Designing CNS penetrant drugs….maybe the hardest thing?
Perhaps the hardest medicinal chemistry challenge is taking a series of compounds, and modifying them, so they pass through the blood brain barrier. Such drug discovery projects have enlarged testing cascades, and usually require an early in-vitro absorption assay, and secondary rodent pharmacokinetics experiments to measure concentration of drug in the brain compartment. As such the cycle times around the Design-Make-Test-Analyse are protracted. The need for clear understanding of the processes involved, and the properties required in molecules, to reduce the number of cycles is paramount. We selected the review "Demystifying brain penetration…" as this gives a broad summary of the understanding so far.
Demystifying brain penetration in central nervous system drug discovery.
J. Med. Chem. 2013, 56, 2−12.
In recent years the "CNS MPO" score, which can be calculated at the point of design, has gained popularity, so it is worth referencing this paper too.
Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach To Enable Alignment of Druglike Properties
ACS Chem. Neurosci. 2010, 1, 435–449
However, the CNS MPO score might become dated, as further understanding of the transporters involve rises. It might be that the count of number of Hydrogen Bond Donor (HBD) might be the key predictor.
How hydrogen bonds impact P-glycoprotein transport and permeability.
Bioorg. Med. Chem. Lett. 2012, 22, 6540−6548.
And lastly a couple of medchem papers on series that were optimised for CNS penetration:
The design and identification of brain penetrant inhibitors of phosphoinositide 3- kinase α.
J. Med. Chem. 2012, 55, 8007−8020.
J. Med. Chem. 2014, 57, 970−986
A couple of more papers suggested by Pete Kenny.
CNS Drug Design: Balancing Physicochemical Properties for Optimal Brain Exposure
J. Med. Chem. 2015, 58, 2584–2608
Structural Modifications that Alter the P-Glycoprotein Efflux Properties of Compounds
BucketListPapers 78/100: Improving on existing drugs, covalent binders and the late LO medicinal chemistry
A successful drug in the clinic is the final proof that modulation of a protein target yields benefits. The drug in question may have limitations, such as side-effects from off-target toxicity, dose limited efficacy and the such like. As such drug discovery program 'restart' with the aim of making a 'gold-standard' treatment, armed with a wealth of data and understanding from the clinic. These programs can be difficult and have protracted testing cascades as a large quantity of measurements are required to demonstrate superiority.
This paper is one of host of recent examples with the aim optimising for a specific mutation of the protein target and off-target effects. The selectivity is gained using the covalent binding group and off-target selectivity (IGFR) is achieved by a combination of groups, shown by some excellent matched pair analysis. This in itself is great medicinal chemistry, but the paper also describes some of the trials and tribulations of late LO and early pre-clinical, including a small amount of human PK data.
Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor
J. Med. Chem. 2014, 57, 20, 8249–8267
BucketListPapers 77/100: The first tyrosine kinase inhibitor…
Perhaps this paper is showing its age, but at the time BMCL papers were basic, with just a table of two of measurements and simple synthesis. Non the less, this is the paper describing the discovery of a candidate drug (1) that went on to become the product Gleevec (Imatinib); this first tyrosine kinase inhibitor (the Wikipedia page has more data). The drug made quite an impact on many patients lives. Looking back, with experienced eyes, we can see the structural features now present in ATP binding pocket kinase inhibitors. The research process was rational and screened multiple kinases, leading by careful SAR analysis to 1. Tne compound, which is quite selective, in part due to the methyl group on the central ring. Of note is the 'pan' kinase inhibitor 9 – this compound might be worth adding to your compound collections, such that early screening could yield a tool compound?
Imatinib – Potent and selective inhibitors of the Abl-kinase: phenylamino-pyrimidine (PAP) derivatives
Bioorg. & Med. Chem. Lett. 1997, 7, 187-192
BucketListPapers 76/100: Macrocyclisation as the route to success?
The story of Lorlatinib started with an existing inihibitor and used macrocyclization to improve properties. Macrocyclisation has been a recent approach to improving small molecules, and is usually performed as part of a structure-based design program. The ideal starting point is a high quality x-ray structure determination of the small molecule bound to protein, thats shows the molecule is folded, in such a way, that groups in the molecules are close enough together to 'join up', thus forming a large ring. The difference in entropy on the binding can be significant and can yield highly potent compounds. In addition, these macrocycles present different shapes and have been demonstrated to have improved absorption and reduced efflux. Although the approved drug Crizotinib has robust efficacy in ALK-positive tumors, patients eventually develop resistance, and metastases to the brain can occur. Many cancer drugs have poor penetration across the Blood Brain Barrier (BBB), so a new suite of kinase inhibitors with high brain blood concentration is highly desirable. The authors in this paper started from Crizothinib and initially made acyclic compounds, focussing on efficient small molecules (low LipE) to improve brain penetration (see references within). Co-crystallisation of these inhibitors in ALK showed the compounds were folded in the U-shape, positioning two aryl groups close together (see Figure 3). The idea for macrocyclic compounds was born, but this was not without difficulties. The paper describes in great detail the medicinal chemistry and synthetic chemistry challenges and is rich in data and analysis.
Lorlatinib.
Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations.

redpajama_set_name: RedPajamaCommonCrawl


text:
Home / Blog • Info • News / EurekAlert!: Invaluable to the …
July 6, 2018 Blog, Info, News
The following press release originally appeared July 4, 2018 on EurekAlert!, the online global science news source operated by the American Association for the Advancement of Science. The original public release can be seen at this link: https://www.eurekalert.org/pub_releases/2018-07/f-itt070418.php
Invaluable to the medical industry, the horseshoe crab is under threat
The unique properties of horseshoe crab blood make it invaluable for drug and safety testing -- but this commercial demand threatens these 'living fossils,' along with climate change, habitat destruction and use as bait
Blood from horseshoe crabs is essential for many drug, implant and environmental safety tests - but blood harvesting, together with capture for bait and impacts from climate change and habitat destruction, is threatening populations of these "living fossils." A review published in Frontiers in Marine Science highlights that these continuing threats will detrimentally affect the surrounding ecosystem, including migratory shorebirds who rely on horseshoe crab eggs for food. To enable a sustainable harvest of their blood for the biomedical industry --which currently is entirely dependent on these creatures for drug and environmental safety testing -- alternative tests should be explored in conjunction with better harvesting and conservation strategies.
"The horseshoe crab has survived every period of mass extinction in the last 450-million years, but now faces its greatest threats: wild capture for biomedical testing and exploitation as whelk and eel bait," says lead author Jordan Krisfalusi-Gannon, an intern at Kepley BioSystems Incorporated, USA, and a student at High Point University. "This keystone species, which plays a unique and crucial role in the ecosystem around it, is also threatened by climate change and habitat destruction."
More closely related to scorpions and spiders than to crabs, the horseshoe crab is commonly referred to as a "living fossil," having remained unchanged for millions of years. They are an important part of the ecosystem, found along the East Coat of America and Gulf of Mexico. Migratory shorebirds arrive to feed on horseshoe crab eggs during the spawning season, before continuing to northern breeding grounds.
The unique properties of horseshoe crab blood makes it invaluable for the biomedical industry. The blood is also increasingly used for air and water quality testing.
Krisfalusi-Gannon explains, "Cells in horseshoe crab blood are uniquely very sensitive to certain bacteria, such as E. coli and Salmonella, so they have been used to ensure the safety of injectable drugs and implantable medical devices for millions of patients worldwide."
Dr. Anthony Dellinger, co-author, President of Kepley BioSystems, continues, "The gradual extinction of this once-abundant important species is alarming, and evidence shows many migrating bird populations have been declining in tandem with diminishing horseshoe crab populations. We wanted to find out the scope of the problem and begin to assess alternatives to current harvesting procedures."
The researchers found several threats to horseshoe crab populations. Along with climate change and habitat destruction, they are a popular bait for whelks and eels, although new regulations hope to minimize over-harvesting. The commercial demand for their blood is also a problem; while the crabs are returned to the water after their blood has been harvested, there are issues surrounding this process.
"There are unintended impacts on horseshoe crab spawning and health from biomedical capture, bleeding and release. The harvest often takes place during the spawning season, when the crabs are easily accessible on the beach. The stress of transportation, being out of water and blood loss pose significant risks to their ongoing health," explains Waleed Ali, co-author and intern at Kepley BioSystems.
The review highlights alternatives to the current harvesting process, such as tighter restrictions on the process of blood harvesting, the development of new biomedical tests and alternative baits for the fishing industry, as well as investigating the potential for aquaculture.
"Sepsis is projected to cause up to 300-million deaths in the next 30 years due to antibiotic microbial resistance. If a sustainable, robust supply of horseshoe crabs could also be successfully cultivated in captivity, we believe important clinical applications could be employed to detect and treat septicemia to save millions of lives," concludes Dellinger.
About EurekAlert!:
EurekAlert! is an online, global news service operated by AAAS, the science society. EurekAlert! provides a central place through which universities, medical centers, journals, government agencies, corporations and other organizations engaged in research can bring their news to the media. EurekAlert! also offers its news and resources to the public. EurekAlert! features news and resources focused on all areas of science, medicine and technology.
Read the Eurekalert! release here


text:
BBC Board
Commercial Holdings Board
John Shield
John Shield, Director of Communications
John leads the Communications Group
He is responsible for devising and implementing the BBC's communications strategy
Last updated September 2020
John Shield joined the BBC as Director of Communications in November 2013. He is responsible for all of the BBC's communications activity.
Prior to this John was Director of Communications at the Department for Work and Pensions - John headed up all the communications activity for the department, including press, marketing and internal communications.
John has both private and public sector experience, having been a Director at one of Britain's largest transport businesses and the Head of Communications for news, current affairs and sport at the BBC. He was also Director of Communications at the Department for Communications and Local Government, and Head of News at the Department for Education and Skills. He has also worked at the Foreign Office and No. 10.
Annual remuneration (as at April 2020)
Expenses and central bookings
Expenses are costs incurred by BBC staff on behalf of the BBC and claimed through the BBC's expenses system.
Central bookings are costs incurred on behalf of the BBC and booked through the BBC's central bookings system. Both expenses and central bookings are published every three months.
John Shield had no expenses paid in Q4 2019-20
John Shield's central bookings Q4 2019-20
John Shield's central bookings Q4 2018-19
John Shield's expenses Q3 2017-18
John Shield had no central bookings in Q1 2016-17
Gifts and Hospitality Register
Gifts and hospitality may only be accepted in line with BBC policy. Information about gifts and hospitality is published every three months.
John Shield had no gifts or hospitality to declare in Q4 2019-20
John Shield had no gifts or hospitality to declare in 2018-19
John Shield's Gifts and Hospitality Register Q4 2013-14
Declaration of personal interests
Staff must make a declaration of their personal and business interests, including any memberships or directorships of public or industry bodies, and any shareholdings, as well as any interests that their immediate families may also have.
A summary is published where there is something to declare and where there is nothing to declare. Occasionally an individual will have something to declare but due to the personal nature of the declaration we do not publish details as to do so would breach the General Data Protection Regulation.
This information is published annually, although if any amendments are made during the year an updated summary will be published if necessary as soon as it is available.
John Shield's Declaration of Personal Interests


text:
The Opening Bell 8/01/17: The Elephant in The Room for Venture Capitalism…
The Opening Bell
by: Bennett Wakenight
Posted: Aug 1, 2017 / 06:21 AM CDT / Updated: Aug 1, 2017 / 06:20 AM CDT
(AP Photo/Kamran Jebreili)
If you've been noticing a drop in the amount in your paycheck, that is the 32% Illinois income tax hike hard at work. Steve reminded listeners about the change for Illinois residents with the help of Martin Wojtulewicz (Founder of CPA Advisors Group). Steve then turned to where there is plenty of money, the world of venture capitalism. Clare O'Connor (Staff Writer at Forbes) detailed how VC firms are four times more likely to fund all male startups than those with even one woman leader.
by BERENICE BAUTISTA, Associated Press / Jan 28, 2022
MEXICO CITY (AP) — Argentine singer-songwriter Diego Verdaguer, whose romantic hits such as "Corazón de papel," "Yo te amo" and "Volveré" sold almost 50 million copies, has died of complications from COVID-19, his family said Friday. He was 70.
The naturalized Mexican-Argentine musician, who was married to singer Amanda Miguel, died Thursday afternoon in Los Angeles, his daughter Ana Victoria said in a statement released by Diam Music, Verdaguer's record company.
by MATTHEW LEE, Associated Press / Jan 28, 2022
WASHINGTON (AP) — The Biden administration said Friday it is cancelling $130 million in military aid to Egypt over human rights concerns. The announcement comes just days after the administration approved a massive $2.5 billion arms sale to the country.
The State Department said Friday that Egypt had not met the conditions to receive the $130 million in foreign military financing that has been on hold since September. It said the money would be shifted to other programs. It did not elaborate.
NEW YORK (AP) — Just days after the banning of "Maus" by a Tennessee school district made national news, two editions of Art Spiegelman's Pulitzer Prize winning graphic novel about the Holocaust have reached the top 20 on Amazon.com and are in limited supply.
"Maus" was No. 12 on Amazon as of early Friday evening, and was not available for delivery until mid-February. "The Complete Maus," which includes a second volume, was No. 9 and out of stock.
Warm up this winter with a cup of coffee from McDonald's
Bill Snyder addresses Chicago's latest snow storm


Trouble with the mapping, and Process Flow (PF) applets don't open in Firefox (FF) on a new Windows 2012 server. When I click on the 'Data Mapper' button, a black window flashes open and shut, and the startMapper.jsp file downloads, but nothing happens.
The security level of your Java installation is blocking the Adeptia Applet from opening. An initial pop up, similar to below may have initially appeared, but the user chose not to launch the app.
5) Now try to launch the applet again, and select Run from the Security Warning above.


1. Download this file or right click and "Save As". Do not fill out in browser.
2. Go to download folder and open Suppliers Directory Registration Form. File should open in pdf format that you can edit. If not, download Adobe Reader DC.
2. Download Adobe Fill & Sign app.
3. Open file in app.
4. Tap with finger and fill in form.
5. Tap share, and email to directory@wireropenews.com.


text:
Union, Connecticut
Town in Connecticut, United States
Location in Tolland County, Connecticut
Coordinates: 41°59′17″N 72°09′41″W / 41.98806°N 72.16139°W / 41.98806; -72.16139Coordinates: 41°59′17″N 72°09′41″W / 41.98806°N 72.16139°W / 41.98806; -72.16139
Selectman-town meeting
• First selectman
David D. Eaton (R)
• Selectman
Mary Huda (R)
David Heck (D)
• State Senator
Dan Champaigne
(R-35th District)
• State Rep.
Pat Boyd
(D-50th District)
29.8 sq mi (77.2 km2)
1.1 sq mi (2.9 km2)
28.7/sq mi (11.5/km2)
06076 (Stafford Springs) and 06242 (Eastford)
www.unionconnecticut.org
Union is a town located in the northeastern part of Tolland County, Connecticut, United States and is part of the Quinebaug and Shetucket Rivers Valley National Heritage Corridor. The population was 854 at the 2010 census, making it the least populous town and municipality in Connecticut. Union includes the village of Mashapaug located in the Eastern Uplands at the Massachusetts state line. Also, Union is located 33 miles (53 kilometers) northeast of the state capital, Hartford and 67 mi (108 km) southwest of Boston as well as 153 mi (246 km) northeast of New York City.
2 Civic associations
6 Tourism
6.1 Recreation
6.2 Landmarks
7 Notable people
The first European Settlement in Union was in 1727, making Union the last Connecticut town east of the Connecticut River to be settled. The first settler was James McNall of Ireland.[1] He was closely followed by his brother William.[2] The town was incorporated in October 1734.[3] The name Union designates "union of lands".[4]
There were 500 people in the town in 1756. The population grew to 767 by 1800, but declined thereafter. There were just 431 people in Union in 1890.[5]
Civic associations[edit]
Union is home to Venturing Crew 83 of the Connecticut Rivers Council. They are a member of the Nipmuck District and chartered by the Union Volunteer Fire Department.
According to the United States Census Bureau, the town has a total area of 29.8 square miles (77 km2), of which 28.7 square miles (74 km2) is land and 1.1 square miles (2.8 km2) (3.75%) is water.
Union has the highest town center in eastern Connecticut at 1,015 feet (309 m) and the 4th highest in the state.[6] The highest elevation in eastern Connecticut is 1,315 feet (401 m) Burley Hill in the northwest part of town.[7] In addition, I-84 reaches its highest elevation in Connecticut (1,002 feet (305 m)) in Union.
Approximately one-third of the town is state park land, including Bigelow Hollow State Park, Nipmuck State Forest and the Mountain Laurel Sanctuary. A portion of the Yale-Myers Forest and Hull Foresters[8] are located in Union. All combined, there are nearly 34,000 acres of forestland in Union.[9]
Mashapaug Lake is a large lake in Union. The lake is used for fishing, boating, and swimming.
1800 767 21.6%
1810 752 −2.0%
1820 757 0.7%
1870 627 −14.3%
Est. 2014 846 [10] −0.9%
See also: List of Connecticut locations by per capita income
At the census[12] of 2000, there were 693 people, 285 households, and 200 families residing in the town. The population density was 24.1 people per square mile (9.3/km²). There were 332 housing units at an average density of 11.6 per square mile (4.5/km²). The racial makeup of the town was 98.56% White, 0.14% Asian, and 1.30% from two or more races.
There were 285 households out of which 27.4% had children under the age of 18 living with them, 64.6% were married couples living together, 4.6% had a female householder with no husband present, and 29.5% were non-families. 22.5% of all households were made up of individuals and 4.9% had someone living alone who was 65 years of age or older. The average household size was 2.43 and the average family size was 2.87.
In the town, the population was spread out with 21.5% under the age of 18, 3.3% from 18 to 24, 34.6% from 25 to 44, 28.7% from 45 to 64, and 11.8% who were 65 years of age or older. The median age was 40 years. For every 100 females, there were 103.2 males. For every 100 females age 18 and over, there were 103.0 males.
The median income for a household in the town was $58,214, and the median income for a family was $65,417. Males had a median income of $48,021 versus $35,469 for females. The per capita income for the town was $27,900. About 2.0% of families and 3.5% of the population were below the poverty line, including 5.9% of those under age 18 and none of those age 65 or over.
Union residents are zoned to the Union School District for grades Kindergarten through 8. The only school in the district is Union Elementary School.
High Schoolers have the option of attending Stafford High School, Rockville Vocational-Agricultural School, Windham Regional Technical Vocational School or Woodstock Academy.
Tourism[edit]
Recreation[edit]
With over 40,000 acres of forestland in and around town and a major interstate going through it, Union is known for outdoor recreation such as hunting, fishing, hiking, camping and picnicking.[6] The area's elevation and dominance of evergreen trees makes the area cooler than surrounding places.[13] Most activity is centered on Bigelow Hollow State Park, and especially at Mashapaug Lake.
Snowmobiling is also enjoyed in the area.[14]
Landmarks[edit]
The village of Mashapaug in Union is the site of the Traveler Restaurant, a unique eating establishment that gives away used books to its patrons.[15][16]
Camp Pomperaug, a Boy Scout camp operated by the Connecticut Yankee Council, BSA, is situated within Union, and borders the state forest. It was originally property of the Wells family, for whom Wells Pond is named. The camp was originally situated on Lake Zoar in Monroe, but was relocated to the Union property when the original camp's dining hall was destroyed by a severe winter storm.
The camp includes old stone foundations of the buildings once comprising Well's Mill, and also includes a small Revolutionary War cemetery where, among other soldiers interred, lies a brother-in-law of Benedict Arnold. The burial site is thought by some to be haunted.
The Union Free Public Library is housed in one of the town's few public buildings. The library was established by a town meeting in November 1894, and opened March 25, 1895 in a private home. In 1912 it moved into a newly built building, which it still occupies.[17]
Union Green Historic District
Notable people[edit]
Alonzo Horton, considered the second founder of the city of San Diego, California, and the founder of Hortonville, Wisconsin, was born in Union on October 24, 1813. His family moved away from the area in 1815.[18]
Moses G. Leonard (1809–1899), a United States Representative from New York, grew up in Union but was born in nearby Stafford.[19]
Ebenezer Stoddard (1785–1847), a United States Representative from Connecticut and Lieutenant Governor of Connecticut, was born in Union.[19]
^ Rivero, Nicolas (25 August 2017). "The Smallest Town in Each of the 50 States". Mental Floss. Retrieved 25 June 2018.
^ Charles Hammond and Harvey Merrill Lawson (1893) The History of Union, Conn, Price, Lee, & Adkins Co., New Haven, Connecticut. Pages 36 and 43.
^ Charles Hammond and Harvey Merrill Lawson (1893) The History of Union, Conn, Price, Lee, & Adkins Co., New Haven, Connecticut. Pages 48-50.
^ The Connecticut Magazine: An Illustrated Monthly. Connecticut Magazine Company. 1903. p. 335.
^ Charles Hammond and Harvey Merrill Lawson (1893) The History of Union, Conn, Price, Lee, & Adkins Co., New Haven, Connecticut. Page 506.
^ a b http://www.unionconnecticut.org/about.php
^ http://docs.unh.edu/MA/wale52sw.jpg
^ http://www.hullforest.com/forestry/forest_conservation.html
^ http://www.nature.org/ourinitiatives/regions/northamerica/unitedstates/connecticut/placesweprotect/quinebaug-highlands.xml
^ "Annual Estimates of the Resident Population for Incorporated Places: April 1, 2010 to July 1, 2014". Archived from the original on May 23, 2015. Retrieved June 4, 2015.
^ "Census of Population and Housing". Census.gov. Retrieved June 4, 2015.
^ "American FactFinder". United States Census Bureau. Retrieved 2008-01-31.
^ http://www.wunderground.com/cgi-bin/findweather/getForecast?query=06076&sp=MD8905
^ http://www.nipmucktrailriders.com/index.html
^ http://www.hiddenboston.com/TravelerRestaurant.html
^ http://www.visitingnewengland.com/traveler-restaurant.html
^ Union Free Public Library website, accessed June 25, 2009
^ Charles Hammond and Harvey Merrill Lawson (1893) The History of Union, Conn, Price, Lee, & Adkins Co., New Haven, Connecticut. Pages 368-369.
^ a b Charles Hammond and Harvey Merrill Lawson (1893) The History of Union, Conn, Price, Lee, & Adkins Co., New Haven, Connecticut. Pages 469-470.
Connecticut portal
Town of Union Website
Union Elementry School Website
Municipalities and communities of Tolland County, Connecticut, United States
County seat: Rockville
Coventry Lake
South Coventry
Hydeville
Stafford Hollow
Connecticut portal United States portal
Hartford (capital)
Party strength
Councils of governments
Connecticut panhandle
Coastal Connecticut
Greater Bridgeport
Greater Hartford
Lower Connecticut River Valley
Central Naugatuck Valley
Naugatuck River Valley
Southeastern Connecticut
Bozrah
Ledyard
North Canaan
Voluntown
≤10k
Hartford-Springfield metropolitan area
Retrieved from "https://en.wikipedia.org/w/index.php?title=Union,_Connecticut&oldid=917762367"
Towns in Tolland County, Connecticut
Towns in Connecticut


see v. 见, 明白 see you. see you late. you see? I see.
- How are you doing? - What's up?
What's Tom like? He's very fat.
slim 苗条的 That woman is slim. The man is realy heavyset.
hot adj. 热的,辣的,性感的 hot fish 水煮鱼 hot pot 火锅 That girl is hot.