text:
Quick Transfer USA The Royal Service Your Freight Deserves
Rate Requests
Pickup Requests
Archive | Intermodal
The Busiest Freighting Hubs in the World
By Quick Transfer on April 17, 2014 in expedited shipping, Intermodal, Trucking Services
If you're from the West and you take a trip to Hong Kong, you're going to experience a very unique kind of culture shock. Not because it's so different, but because it's so similar to where you come from. Hong Kong is the land where "East Meets West," and a history of being under both [...]
Major Freight Routes in North America
By Quick Transfer on April 7, 2014 in expedited shipping, Intermodal, LTL, Trucking Services
Major freight roadways network across the entire United States and Canada. Knowing each of these highways is part of the commitment that a quality freight transport company makes to quality, on time, and competitive shipping quotes for LTL, rail and intermodal, hazardous materials, refrigerated loads, freeze protection, and exhibit and trade show shipments. Regardless of [...]
What Is the Difference Between Highways and Parkways?
By Quick Transfer on February 26, 2014 in expedited shipping, Intermodal, Trucking Services
As we go about our daily tasks, commuting to work or school and running errands, we often take driving for granted. When going long distances, our mission is often to head out on the highway and get to our next destination as expediently as possible. In the course of your adventures, you may have received [...]
Freight Shipping: Fast & Affordable
By Quick Transfer on February 19, 2014 in expedited shipping, Intermodal, LTL, Trucking Services
Many small, medium, and large companies look for the best way to transport their materials in a timely yet cost-efficient way. One of the best methods is finding a freight broker like Quick Transfer USA. The fact is that they take the time to listen to every customer's needs in order to connect them to [...]
A Winning Relay Team: Efficient Negotiation of Intermodal Shipping
By Quick Transfer on January 8, 2014 in Intermodal, Trucking Services
Intermodal shipping is like a relay race in which a transportation team, involving a number of companies and modes of transportation working together to get products from start to finish line rapidly. To succeed, this intermodal system requires smooth, secure connections between truck and rail companies, careful shipping to avoid product damage and a reasonable [...]
Truck Routes: Blue Ridge Parkway
By Quick Transfer on December 16, 2013 in Intermodal, Trucking Services
With the exception of 1949, the Blue Ridge Parkway has been the most visited component of the National Park System every year since 1946. This stretch of road connects the Shenandoah National Park with the Great Smoky Mountains National Park. Linking these two national parks, the Blue Ridge Parkway passes through 29 counties in Virginia [...]
Best Road Trips: Route 1
By Quick Transfer on December 4, 2013 in Intermodal
Route 1: The Atlantic Highway Last week, we highlighted one of the most scenic drives in the country, Route 101, the Pacific Coast Highway. This week, we're taking a look at another beautiful trip, this time on the opposite coast: Route 1 runs the entire length of the East Coast, from Fort Keith, Maine at [...]
Tel: 800-558-8086 Fax: 646-699-3628 Email: info@quicktransferusa.com Follow us:
© 2022 Quick Transfer USA. All Rights Reserved.


Take a look below at what our amazing clients have to say about their experience working with Cabinet Gallery, then drop us a line and let us know how we can take care of you!
I am an Interior Designer from Las Vegas. I traveled with my clients to The Cabinet Gallery to design a custom 7,000+ square foot house full of cabinets. The Cabinet Gallery provided everything I needed for an efficient and productive visit. Prior to my visit I was provided with preliminary cabinet designs to study based on the floor plans. Upon our arrival April and Travis gave us a tour of their beautiful showroom with hands-on displays. We designed each area of the home using CAD, which included 3D renderings and their library of photos and design inspiration. Travis and April provided us with incredible hospitality and I'm happy to say we were able to get everything done; design, color selection and cabinet hardware in 2 days! I can't wait to see the finished product!
"We recently had Cabinet Gallery help us with a large remodel of our new home and we have an exceptional experience! From the owners of the company, to the designer, to the installers, they are all wonderful to work with. If you want quality, you will get it and then some with Cabinet Gallery!"
We recently built our first custom home and we chose to use "The Cabinet Gallery" for all our custom cabinetry. We are so happy with the results! Our designer- Andrey Savich was fantastic to work with, he was helpful, creative and patient- very patient! We love the design of our cabinetry, they look beautiful and we have received many compliments about them.
We have been very impressed with the quality of the cabinetry! We have filled up the drawers with lots of heavy dishes and other kitchen equipment and feel confident that the drawers will hold up and open smoothly for years to come!
The entire team at "The Cabinet Gallery" are helpful, kind and professional. We highly recommend this company- you will receive excellence from the people and the products!
"The Cabinet Gallery is the best custom cabinet designer. We have built three custom homes and have had the best experience with them. April and her team are great to work with. They took the time to create the perfect layout and design for every room in our house. We often get comments from people visiting about our beautiful cabinets. The installers did a professional job and made sure the cabinets were Perfect. The quality and detail are second to none. We can't thank them enough and do recommend them to anyone needing new cabinets!"
"My husband and I have been looking for the best cabinet company to design our dream kitchen. We kept falling short with finding the right person until we met Andrey from The Cabinet Gallery. He listened to what we wanted and designed our dream kitchen. He redesigned the layout to a better functioning layout that added more cabinet space and an open floor plan. He was amazing to work with and made this stressful situation to be stress-free! He over exceeded our expectations with the kitchen and made it stunning. We always get compliments on the kitchen from our guests. We would highly recommend having Andrey design your kitchen!"
"The Cabinet Gallery did an excellent job on my house. High-end cabinetry that they manufacture in house. They have so many color and finish selections. They provide great ideas and can help with the design process. They pay attention to detail and work hard on customer service. I know if I need anything April is there to assist. I wouldn't hesitate to buy from them if I build again."
"Everything the Cabinet Gallery does is done with precision and thoughtful craftsmanship. Their customer service is above and beyond and it's obvious they take pride in their work by ensuring the end result exceeds expectations."
Ready To Get In Touch? Drop us a line!


text:
Bank OZK 2Q Profit Falls By 54%
Bank OZK of Little Rock on Thursday reported second-quarter net income of $50.3 million, down 54.5% from $110.5 million it reported in the same quarter of last year.
The bank blamed the poorer performance on the sudden and severe economic downturn caused by the pandemic, implementation of the new "current expected credit losses" accounting standard and uncertain future economic projection. CECL, an order from the Financial Accounting Standards Board, changed the way large and publicly traded banks reserve for possible loan losses, and it took effect this year.
Earnings per share was 39 cents, a 54.7% decrease from 86 cents. But those earnings beat Wall Street expectations. The average estimate of 10 analysts surveyed was for earnings of 58 cents per share, according to CNN.
For the six months ended June 30, net income was $62.1 million, a 71.9% decrease from $221.2 million for the first six months of 2019. Earnings per share was 48 cents, a 71.9% decrease from $1.71.
"We have continued our long-standing focus on our team members, our customers, serving the communities in which we operate and delivering favorable returns for shareholders," Chairman and CEO George Gleason said in a news release. "Our strong credit culture and consistent discipline have been important ingredients in our success, and we believe they have positioned us well for the current economic environment."
As of June 30, total loans were $19.31 billion, up 10.4% increase from the same point last year. Non-purchased loans, which exclude loans acquired in acquisitions, were $18.25 billion, up 15.6% from last year. Purchased loans were $1.06 billion, down 37.4% from last year.
Deposits were $20.72 billion at June 30, a 14% increase from last year. Total assets were $26.38billion, up 14.9% from last year.
Arkansas Business will update this story.
Previous Another steroid is thrown into the mix of potential COVID-19 treatments
Next State Economic Development Districts Get $3.2M for COVID-19 Response

redpajama_set_name: RedPajamaCommonCrawl


text:
Category Archives: Drug Discovery
Using Biochemical Light-switches to Illuminate Ion Channel Activity
Posted on December 18, 2017 by SDDC
There's no doubting that optogenetics is an important recent development within the field of neuroscience. Channelrhodopsins, non-mammalian proteins that conduct ions in response to specific wavelengths of light, have now been inserted into various neuronal pathways to demonstrate the use of light to control modalities as diverse as vision, hearing, pain and motor control. In November 2017, The Scientist reported on progress in human clinical trials using channelrhodopsins in combination with viral vectors to restore a degree of function in damaged sensory neurons in response to light1. In a study conducted by Allergan, patients suffering from retinitis pigmentosa were injected with virus carrying the genetic signal to express channelrhodopsins specifically in retinal ganglion cells, bypassing the damaged light-detecting cells of the retina, enabling a rudimentary sense of light-detection in patients that were previously totally blind. Although primarily a safety study, it has shown promising progress in the field which may soon see developments towards treating hearing loss and chronic pain using a similar approach.
However, alongside the use of non-mammalian light-activated proteins to control neuronal activity, an alternative light-based approach has been developing which has direct and immediate usefulness as a tool in the field of drug discovery. The use of light to reversibly deliver ligand to a native protein receptor or ion channel, or 'optopharmacology', is the subject of an interesting recent mini-review by Bregestovski, Maleeva and Gorostiza2. For drug discovery, the use of these chemical photo-switches enables the rapid, and most importantly, reversible activation of ion channel function in response to light. Ligand-gated channels are the subject of this particular review, but much work with voltage-gated channels and G-protein-coupled receptors has now also been published. This approach provides a huge step forward from the previous use of caged-compounds in flash photolysis – often used, for example, to study synaptic transmission, but would leave the preparation awash with ligand that was slow to clear by re-uptake/diffusion, meaning difficult and slow 'one-hit' experimentation.
At the Ion Channel Modulation Symposium in Cambridge last year (2016), Dirk Trauner spoke about the development of these tools and demonstrated their use in research conducted both within his group and in conjunction with collaborators around the world, showing examples (see figures 1 & 2 below) of the use of photochromic ligands in both their soluble (PCL) and tethered (PTL) forms.
These two forms are defined by the nature of their interaction with target proteins – PCLs are designed to mimic the ligand of a specific receptor but are freely diffusible and may not exhibit sub-type specificity within a tissue. PTLs, as their named suggests, become covalently tethered to their target, usually via naturally-occurring or genetically modified cysteine residues, conferring a much higher degree of selectivity. On exposure to specific wavelengths of light, the molecules photoisomerize between cis-and trans- states, enabling ligand-receptor interaction that triggers either activation or deactivation of the target protein.
Of the two types, PCLs are the simplest to use. Figure 1 shows the impressive degree of temporal control of gained over the function of the capsaicin receptor TRPV1 in the presence of 1uM of a 'photolipid' PCL (here, an azobenzene combining the vanilloid head-group of capsaicin with photoswitch-containing fatty-acid chain (AZCA derivatives)) in response to simply varying light stimulation between 350 and 450 nm.
Figure 1: reproduced from Frank et al (2015)3
Having proved the principle in TRPV1-expressing HEK cells, optical switching in the presence of this PCL was applied to isolated mouse DRG neurones, and c-fibre nociceptive neurones in saphenous nerve preparations, both of which contain native TRPV1 receptors. All showed rapidly reversible non-selective cation conductance in response to the shorter wavelengths of light, translating into nerve depolarisation and action potential firing in native neurones – responses which were absent in TRPV1-/- knockout mice.
Trauner also presented work using PTLs, and show-cased developments made in collaboration with US colleagues to extend the chemical tether to reinforce its chemical stability and reduce the chance of off-target attachment. Their new 'PORTL' (photoswitchable orthogonal remotely tethered ligand), shown in figure 2a, was used to demonstrate dual optical control of mGluR2 and GluK2 expressed in the same cell, differentially responding to the specified wavelengths of light (figure 2b).
Figure 2: reproduced from Broichhagen et al (2015)4
This elegant chemistry is a powerful tool for studying ion channel-mediated physiology. Its use, for example, to selectively activate or silence particular neurones, or sub-populations of heteromeric channels containing a common tagged subunit, with a degree of spacial and temporal control unachievable with perfusion, enables more qualitative assessment of the interaction between new possible therapeutic compounds and their target proteins. And like channelrhodopsins, the use of these photochromic ligands as therapies in their own right is also possible and currently being investigated.
Blog by: Sarah Lilley
1 The Scientist Nov 16 2017 article by Shawna Williams
https://www.the-scientist.com/?articles.view/articleNo/50980/title/Optogenetic-Therapies-Move-Closer-to-Clinical-Use/
2Bregestovski, P., Maleeva, G., and Gorostiza, P. (2017) Light-induced regulation of ligand-gated channel activity. British J Pharm, doi: 10.1111/bph.14022.
3Frank, JA., Moroni, M., Moshourab, R., Sumser, M., Lewin, GR., and Trauner, D. (2015) Photoswitchable fatty acids enable optical control of TRPV1. Nature Comms 6, doi:10.1038/ncomms8118
4Broichhagen, J., Damijonaitis, A., Levitz, J., Sokol, KR., Leippe, P., Konrad, D., Isacoff, EY., and Trauner, D. (2015) Orthogonal optical control of a G protein-coupled receptor with a SNAP-tethered photochromic ligand. ACS Cent Sci 1 383-393, doi: 10.1021/acscentsci.5b00260
Posted in Drug Discovery, ion channels, Medicinal Chemistry, optogenetics, optopharmacology	| Leave a reply
The Necessary Nitrogen Atom
Posted on July 7, 2017 by SDDC
In the modern drug discovery process, medicinal chemists strive for high-impact design elements during multiparameter optimisation of lead compounds into efficacious drug candidates. One of such well-known design elements, often referred to as "the magic methyl effect", "the methyl walk" or "the methyl scan", involves a replacement of a H atom with a Me group and, as the result, can lead to profound potency improvement (>100-fold).
The authors of the recently published perspective (DOI: 10.1021/acs.jmedchem.6b01807) discuss another common design element for multiparameter optimisation: substitution of a CH group with a N atom in aromatic and heteroaromatic ring systems. Such replacement, when going from a simple benzene ring to pyridine, results in profound changes in molecular and physicochemical properties, such as distribution of electron density, polar surface area, basicity, which in turn affects lipophilicity and solubility. In more complex chemical structures, these changes can impact upon a number of intra- and intermolecular, orbital, steric, electrostatic, and hydrophobic interactions, such as lone pair, dipole−dipole, hydrogen bonding, metal coordination, van der Waals, σ-hole, σ*S−X, and π-system interactions, which in turn can translate into modified pharmacological profiles.
The authors then illustrate an extensive number of drug discovery case studies from the recent literature, where a replacement of a CH group with a N atom resulted in ≥10-fold improvement in at least one key pharmacological parameter, as shown, for example, in Figure 1. The replacement of the C7 CH group in (1) with a N atom to give (2) resulted in a 300-fold improvement in biochemical potency, Cdc7 IC50 = 2700 and 9.0 nM for (1) and (2), respectively. This potency improvement was attributed to the different conformational preferences of the two analogues. The biaryl dihedral angle of >150° in indole (1) greatly differs from that of aza-indole (2) (dihedral angle of 0°), facilitated by a steric clash of H7 and H6′ in (1) and lone pair repulsion between N7 and N2′ in (2).
Figure 1. An example of a necessary nitrogen atom on potency improvement, likely due to different conformational preferences.
The effects of such replacement on basicity, lipophilicity, polar surface area, and hydrogen bonding capacity are relatively predictable; whereas effects on aqueous solubility, passive permeability, efflux profiles, active transport, protein binding, and metabolic stability can be more whimsical and counterintuitive. In some examples, no rational explanation could be given for the observed effect.
With regards to changes in potency, as the authors are cautious to point out, there is an approximately equal probability of increasing or decreasing potency by exchanging CH groups and N atoms, based on a matched molecular pair analysis (MMPA) of available data. However, these findings are very similar to those discussed for the magic methyl effect.
This perspective is not a manual for what pharmacological improvements will be realized upon the substitution of a CH group with a N atom, but rather as an extensive exemplar of the dramatic improvements that can be achieved under certain circumstances. The systematic N atom scan (N-scan) should be exploited where appropriate, particularly in cases where the preferred binding pose of the ligand is not known.
Some recommendations for the N-scan tactics are summarised below. The newly installed N atom might:
Engage in a hydrogen bond with specific residues of the target receptor or receptor-bound water molecules that need to be satisfied
Remove unfavorable van der Waals interactions the replaced CH group made with the target receptor
Form unfavorable electrostatic interactions with an antitarget receptor
Have a positive effect on the binding conformation of the ligand
Mask a hydrogen bond donor in the ligand
Reduce the basicity or HBA strength of an existing N atom in the ligand
Evenly distribute the polar surface area of the ligand
Properly tune the lipophilicity of the ligand
Be shielded by other substituents or functionality in the ligand
Stabilize chemically labile functionality in the ligand
Replace a metabolically labile CH group in the ligand
Medicinal chemists have to constantly juggle the design of biologically active molecules with drug-like properties according to the rules of Lipinski and Veber, in order to achieve good permeability and absorption levels, which in turn lead to high oral bioavailability. These properties are particularly important when considering therapeutic targets located in the central nervous system (CNS) behind the blood−brain barrier (BBB). Keeping the number of hydrogen bond acceptors down is one of such requirements; however, in some cases, it may turn out that the introduction of one (or two) extra N atoms may be necessary.
Posted in Drug Discovery	| Leave a reply
Crystallography in Fragment-based drug discovery
Fragment-based drug discovery (FBDD) serves as a starting point for the development of drug candidates to generate high affinity ligands. X-ray crystallography, a structural method, can be used to map the interactions of small molecules with proteins, rapidly and efficiently increasing the development of drug discovery. Early FBDD projects utilizing crystallography method as primary screening methods, can directly discover truly positive fragments, although crystal structures of protein should have a high diffraction value.
The process of fragment screening based on crystallography is illustrated in Fig.1.[1, 2] The purpose of this method is to expose protein to fragments and solve the crystal structures of the complexes. It, in most cases, involves growing crystals of the target protein and soaking them in solutions of the fragments, either as single compounds or as cocktails of compounds.[2]
Figure 1.Typical flow chart for high-throughput ligand screening using crystallography. [1, 2]
Fragments are followed by "rule of three" [3], i.e. molecular weight < 300 Da; clogP ≤ 3; number of hydrogen-bond donors ≤ 3; number of hydrogen-bond acceptors ≤ 3. Compared with small molecules, fragments have a lower binding affinity, but a higher hit rate to the target protein. Because of its low binding affinity feature to the target protein, a relatively high concentration of compounds are used in crystallography, in the region of 25–100 mM.[2]
The crystal structure of a protein with a high resolution is important for this method. It must be robust, stable under soaking conditions and diffract to beyond about 2.5 Å resolution—sufficient to place fragments unambiguously in electron density.[4] Besides, it is necessary to generate crystals of a similar size and quality on a large scale for the fragment screening.
From previous researches, crystallography for fragment-based screening has been successfully used to discover inhibitors, especially some difficult targets such as b-secretase[5], as well as inhibitors of a wide range of other enzymes: hPNMT, Phosphodiesterase 4A, Hsp90, Bromodomain, Adenosine A2 receptor, etc.. (Table1) One classic example is the discovery of inhibitors of β-secretase.
Murray and co-workers[5] screened a library containing 347 fragments in cocktails containing six compounds. Two hits found to have nearly identical interactions with Beta secretase-1(BACE-1), forming hydrogen bonds with catalytic aspartate residues D32 and D228. Then, they identified further fragments to access to two important regions which were important for substrate peptide binding by molecular docking and crystallography for fragment-based screening.
Article title Target protein Primary/secondary
FBDD screening
method Binding/activity
Application of Fragment Screening by X-ray
Crystallography to the Discovery of
Aminopyridines as Inhibitors of -Secretase β-Secretase X-ray crystallography Fluorescence-based
activity assay
Missing fragments: detecting cooperative
binding in fragment-based drug design hPNMT X-ray crystallography ITC/Molecular
dynamics free energy
Fragment-based screening for inhibitors of
PDE4A using enthalpy arrays and X-ray
crystallography Phosphodiesterase
4A High-throughput
calorimetry/X-ray
crystallography High-throughput
Fragment-Based Drug Discovery Applied to
Hsp90. Discovery of Two Lead Series with
High Ligand Efficiency Hsp90 NMR/X-ray
crystallography ITC/Bioassay
Fragment-Based Discovery of Bromodomain
Inhibitors Part 1: Inhibitor binding modes and implications for lead discovery Bromodomain Fluorescence anisotropy
assay/X-ray
crystallography Fluorescence
anisotropy assay
Inhibitors Part 2: Optimization of
Phenylisoxazole Sulfonamide Bromodomain/
AcK pocket Fluorescence anisotropy
assay/Modelling X-ray
crystallography SPR/Thermal shift
Structure-based design of potent and
ligand-efficient inhibitors of CTX-M class A
β-lactamase β-lactamase
CTX-M Docking/X-ray
crystallography UV-absorbance
based bioassays/
Antibacterial activity
Discovery of 1,2,4-triaine derivatives as
adenosine A2A antagonists using structure
based drug design Adenosine A2
receptor Docking/X-ray
crystallography SPR
Discovery and Optimization of New
Benzimidazole- and Benzoxazole-Pyrimidone
Selective PI3Kβ Inhibitors for the Treatment
of Phosphatase and TENsin homologue
(PTEN)-Deficient Cancers PI3K In vitro enzyme
assay/Cell based assay
X-ray crystallography In vitro enzyme
assay/Cell-based
Synthesis, Structure–Activity Relationship
Studies, and X-ray Crystallographic Analysis
of Arylsulfonamides as Potent Carbonic
Anhydrase Inhibitor Carbonic
anhydrases Docking/X-ray
crystallography Stopped-flow kinetic
Implications of Promiscuous Pim-1 Kinase
Fragment Inhibitor Hydrophobic Interactions
for Fragment-Based Drug Design Pim-1 Kinase Docking/X-ray
crystallography Mobility shift assay
Table 1. Some examples of fragment-based screening.[4]
Blog written by Xiangrong Chen
[1] I. Tickle, A. Sharff, M. Vinkovic, J. Yon, H. Jhoti, High-throughput protein crystallography and drug discovery, Chemical Society Reviews, 33 (2004) 558-565.
[2] H. Jhoti, A. Cleasby, M. Verdonk, G. Williams, Fragment-based screening using X-ray crystallography and NMR spectroscopy, Current Opinion in Chemical Biology, 11 (2007) 485-493.
[3] M. Congreve, R. Carr, C. Murray, H. Jhoti, A 'Rule of Three' for fragment-based lead discovery?, Drug Discovery Today, 8 (2003) 876-877.
[4] Z. Chilingaryan, Z. Yin, A.J. Oakley, Fragment-Based Screening by Protein Crystallography: Successes and Pitfalls, International Journal of Molecular Sciences, 13 (2012) 12857-12879.
[5] M. Congreve, D. Aharony, J. Albert, O. Callaghan, J. Campbell, R.A.E. Carr, G. Chessari, S. Cowan, P.D. Edwards, M. Frederickson, R. McMenamin, C.W. Murray, S. Patel, N. Wallis, Application of Fragment Screening by X-ray Crystallography to the Discovery of Aminopyridines as Inhibitors of β-Secretase, Journal of Medicinal Chemistry, 50 (2007) 1124-1132.
Posted in Drug Discovery	| Tagged crystallography, rule of three	| Leave a reply
Zika virus: A neglected disease with no specifically designed drugs
Posted on June 27, 2016 by SDDC
I was shocked to see in recent weeks how a potential connection between a virus infection and pregnant women have led to a global concern for the association with a high number of babies being born with microencephaly, initially in Brazil but with other cases shown worldwide, and it has even been associated to the rare Guillain-Barré Syndrome (1). Children with these syndromes are likely to have shorter life expectancies. A recent opinion article (2) with extensive research on this particular virus is analised in this blog.
After the epidemic outbreak of the Ebola virus in 2014-2015 which killed thousands of people in Africa and risked to generate a pandemic crisis, mobilising the World Health Organisation (WHO) and Governments, we have been exposed to another case of unprepared health concern with serious global implications.
Zika virus (ZIKV) is a virus from the Flaviviridae family with genetically similarities with the ones responsible for the Dengue Fever and the Yellow Fever. ZIKV was isolated and reported over 60 years ago and since then the small number of publications, the lack of a crystal structure, the abscence of reports of molecules having been screened either in vitro or in vivo in animal models, and the lack of patents covering drugs targeting ZIK virus (although there are some focused in compounds addressing the Dengue Fever), has left it as an undoubtedly case of a "Neglected Disease".
So, despite of having some knowledge of the virus, little if not nothing seems to have been done in order to understand its risks, exposing under this circumstances, right now, its danger after the outbreak. The WHO has had to move faster than 2 years ago with the Ebola epidemic, and has issued a Public Health Emergency of International Concern (PHEIC).
Ekins and co-workers(2), after extensive research on related viruses and taking into consideration antivirals and non-related drugs, suggest to create a fast-track plan of action in order to tackle the problem with more urgency, leadership and preparation. This could be applicable to other future outbreaks and put us in a better situation to fight future epidemics.
With the information we have on other closely related virus like the Dengue, the immediately plan of action against this outbreak should have to start with the use of already FDA-approved antivirals profiled against related viruses (with a safety and efficacy profile proved) as a starting point in fighting the ZIKV, and test other drugs, non antivirals and compounds from commercial sources (eg. Libraries) in a descendent order of priority as shown in Fig 1.
Figure 1. Compounds and chemical libraries suggested to be tested against Zika virus
Without much further do, the authors propose the following Drug Discovery plan:
To develop a cell or ZIKV-target based in vitro assay, which might have to be done in special protective environments, limiting the number of companies or organisations capable of such as assays.
The immediate test of all kind of available drugs (up to 48 FDA approved known antivirals) into the previously generated and validated assay, capable to produce some results against the absence of any other treatment, as reflected in Table 1.
To study and understand the genome of the ZIKV and how a chemotherapy approach could lead to effectively target the virus.
To develop and use "homology models" showing the suggested protein sequence based in similar/ related viruses with known molecule action-modes using target prediction software, such as SWISS-MODEL.
To establish a pharmacological profile with a suitable/ ethical animal model
Table 1. List of potential compounds to tes.t
Equally important and without leaving it off the schedule, the scientific community should undertake efforts to reveal the virus structure, its function and physiology and establish the relationship between the infection and the human neurological abnormalities.
Despite of getting even better co-ordinating resources through management organisations like WHO, more should be addressed in an emergency outbreak from National Governments and Health Institutions through funding (eg. from the FDA repurposing approved drugs, from big pharmaceutical companies through the donation of chemicals to be tested, from biotechs investing in the development of ZIKV-based in vitro assays, from ground-field-experienced organisations like Medecins Sans Frontieres, etc…)
We need to retain alert against highly likely-to happen diseases lurking upon us at any time and learn from past actions to make us better prepared to fight them.
Blog written by: Jose Gascon
Oehler E, Watrin L, Larre P, Leparc-Foffart I, Lastere S, Valour F, Baudouin L, Mallet HP, Musso D, Ghawche; Zika virus infection complicated by GuillainBarre syndrome–case report, French Polynesia, December 2013. Euro Surveill. 2014; 19(9): 20720
Ekins S, Mietchen D, Coffee M, Stratton TP, Freundlich JS, Freitas-Junior L, Muratov E, Siqueira-neto J, Williams AJ, Andrade C; Open drug discovery for the Zika virus. F1000Research 2016, 5:150
Posted in Drug Discovery	| Tagged Antiviral, FDA, GuillainBarre syndrome, Microcephaly, Neglected Disease, open drug discovery, Zika virus, ZIKV	| Leave a reply
Big Pharma and their adoption of Orphan Drug Research
Posted on June 8, 2016 by SDDC
A rare disease/disorder is defined as such when it affects fewer than 200,000 (USA) or fewer than 2000 (Europe) of the population at any given time. To date, over 7000 rare diseases have been identified, affecting more than 350 million people globally. In the EU, as many as 30 million people may be affected, with the same number affected in the USA. Fifty percent of those affected are children, with approximately 52 million of these children not living to see their 5th birthday.1 Considering that only 5% of rare diseases have an FDA approved drug, how much research is being carried out by Pharmaceutical companies towards orphan diseases?
Drug discovery is an expensive and time-consuming business, with strict regulatory standards and high attrition rates. According to the Tufts Center for the Study of Drug Development, as of 2014 the cost of developing a single drug stood at approximately $2.9 billion.2 Traditionally, big Pharma focused on developing drugs aimed at "common diseases" with a large patient population to maximize the possibility of recovering research and development costs, with rare diseases pushed aside because they provided little financial incentive. These rare diseases were said to be "orphaned", and can also include common diseases that have been ignored because they are far more prevalent in developing countries than in the developed world.
In 1983, Congress passed the Orphan Drug Act which provided manufacturers with three attractive primary incentives.
Federal funding of grants and contracts to perform clinical trials of orphan products
Tax credit of 50% of clinical testing costs
An exclusive right to market the orphan drug for 7 years from the date of marketing approval
The Food and Drug Administration commissioned the Office of Orphan Products Development (OOPD) to dedicate its mission to promoting the development of products that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions. In fulfilling that task, the OOPD interacts with the medical and research communities, professional organizations, academia, governmental agencies, and the pharmaceutical industry, as well as rare disease groups. The OOPD also administers the Orphan Products Grants Program which provides funding for clinical research that tests the safety and efficacy of drugs, biologics, medical devices and medical foods in rare diseases or conditions.3 The program has successfully enabled the development and marketing of more than 400 drugs and biologic products for rare diseases since 1983. In contrast, the decade prior to 1983 saw fewer than ten such products come to market.
So, with this in mind, how has research into orphan drugs progressed?
One biotech company stands out. Genzyme was founded in 1981, producing modified enzymes to test in clinical trials. In 1991, Genzyme won FDA approval for Ceredase for the treatment of Gaucher's disease, the success of which allowed Genzyme to concentrate research into recombinant human enzymes to treat enzyme deficient conditions. To overcome supply constraints, Cerezyme quickly replaced Ceredase a few years later, and in 2010 Genzyme became the fourth largest American biopharmaceutical company with a revenue of $4 billion. In 2011 Sanofi acquired Genzyme for approximately $20 billion making Genzyme its global center for excellence in rare diseases.
The marriage between Shire and Baxalta early this year has made them the Global leaders in rare diseases, creating the number one rare diseases platform in revenue and pipeline depth.4 The combined portfolio will have over 50 programs that address rare diseases. Shire anticipates more than thirty recent and planned product launches from the combined pipeline, contributing approximately $5 billion in annual revenues by 2020.
Big pharma now wanted a slice of the pie, and drug research into rare diseases was not exclusive to Biotechs.
In 2014 Pfizer joined with the Global Medical Excellence Cluster (GMEC), a group of six leading UK universities to form a Rare Disease Consortium, focusing on exploring the human genome to treat hematologic, neuromuscular and pulmonary rare diseases.5 Professor Michael Linden (Kings College London) joined Pfizers newly formed Genetic Medicine Institute in 2015 to evaluate the viability of producing effective, clinical grade gene therapy viruses.6
In 2015, Dr. Mark Fishman, President of the Novartis Institutes for BioMedical Research (NIBR) stated that "Our focus on rare diseases flows from our desire to help patients underserved by today's medicines." Novartis scientists have investigated treatments for more than 40 rare diseases, with the US Food and Drug Administration granting Novartis dozens of "orphan drug" designations. They also have more than 15 medicines approved for these conditions.7
In 2015 Roche bought the French pharma company Trophos and its lead drug for the rare neuromuscular disease spinal muscular atrophy (SMA) for €470 million.8 They have also taken on board the genomics firm Foundation Medicine as well as a collaboration with genetic testing specialist 23andMe in Parkinson's disease.9
GSK has established its own research unit exclusively devoted to seeking cures for rare diseases. GSKs partnership with Ospedale San Raffaele Telethon Institute for Gene Therapy and Fondazione Telethon (Telethon) has resulted in a recent European approval for Strimvelis, the first ex-vivo stem cell gene therapy to treat patients with the very rare disease, ADA-SCID.10
In April this year, Astra Zeneca announced that along with MedImmune, a genomics initiative has been launched to transform drug discovery and development across its entire research and development pipeline. AstraZeneca has partnered with research institutions including the Wellcome Trust Sanger Institute (UK), Human Longevity Inc. (US), and The Institute for Molecular Medicine (Finland) in the hope to unearth rare genetic sequences that are associated with disease and with responses to treatment.11
The emergence of patient advocacy groups has improved the understanding of how debilitating these diseases can be, with the non-profit organisation Global Genes® being one of the leading rare disease patient advocacy organizations in the world, promoting the needs of the rare disease community.1 Passing of the FDA's Orphan Drug Act (and similar legislation in other countries) paved the way for biotech companies to carry out research into rare diseases, offering government incentives, shorter development timelines, and exclusive markets rights. Smaller clinical trials with a reduced patient pool and FDA fast track designation has led to an average time of 3.9 years from Phase II to launch, compared to 5.4 years for non-orphan drugs.12
Research into rare diseases by smaller companies was also made possible through funding by non-profit organisations such as the Cystic Fibrosis Foundation, operating like a venture capital firm. Big Pharma can support expensive research costs, especially when orphan drugs can bring in attractive revenues – Cerezyme has an annual treatment cost of $300,000 per patient! According to the EvaluatePharma Orphan Drug Report 2015, worldwide sales are forecast at $178 billion by 2020, with the market growing by 11% each year.13
However, with more orphan drugs coming to market and the high costs per patient, will healthcare systems be able to continue to pay/subsidise for them?
Blog written by: Kamlesh Bala
https://globalgenes.org
http://csdd.tufts.edu/news/complete_story/pr_tufts_csdd_2014_cost_study
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/ucm2005525.htm
https://www.shire.com/-/media/shire/shireglobal/shirecom/pdffiles/newsroom/2016/shire-to-combine-with-baxalta-pr-1-11-16-final.pdf?la=en
http://www.pfizer.co.uk/content/rare-disease-consortium
http://www.pfizer.co.uk/latest-news/2015-11-26-pfizer-hires-professor-michael-linden-lead-new-gene-therapy-research-centre
https://www.novartis.com/stories/education-awareness/why-research-rare-diseases-matters
http://www.roche.com/media/store/releases/med-cor-2015-01-16.htm
http://www.gsk.com/en-gb/media/press-releases/2016/gsk-receives-positive-chmp-opinion-in-europe-for-strimvelis-the-first-gene-therapy-to-treat-very-rare-disease-ada-scid/
https://www.astrazeneca.com/media-centre/press-releases/2016/AstraZeneca-launches-integrated-genomics-approach-to-transform-drug-discovery-and-development-22042016.html
Meekings KN, Williams CSM, and Arrowsmith JE. Orphan drug development: an economically viable strategy for biopharma R&D. Drug Discovery Today 2012; 17 (13/14):660-664.
http://www.evaluategroup.com/public/reports/EvaluatePharma-Orphan-Drug-Report-2015.aspx
Posted in Drug Discovery	| Tagged gene therapy, Orphan Drug Act, Orphan drugs, rare diseases	| Leave a reply
TMEM16A: A new road or a secret gate?
Posted on May 23, 2016 by SDDC
As ion channels go, TMEM16A are busy ones. As one of a number of channels responsible for chloride conduction at the cell surface, their activity has implications for both water movement and transmembrane potential. They are found in the cells of epithelial and smooth muscle tissue throughout the body, and their functional diversity encompasses secretion, cell proliferation, cardiac excitability, smooth muscle contraction and the prevention of polyspermy. With such a broad range of locations and potential functions, it stands to reason that their control mechanism might be complex. Indeed, if you look them up in the ion channel and receptor guide published by the BJP, they are not readily categorised as either 'ligand-gated' or 'voltage-gated', but languish under the heading 'other' alongside several other recent additions to the chloride channel family (ClC, CFTR and volume-regulated channels). Since their molecular identification in 2008, investigation into their gating control has generated a complex and sometimes confused picture involving both ligand and voltage mechanisms. A recent paper by Contreras-Vite and colleagues2 attempts to integrate experimental evidence gained over the last 8 years in the proposal of an updated model of TMEM16A gating.
Factors at play in TMEM16A activation
There are several well-established factors controlling the conduction of chloride ions through TMEM16A channels. Primarily:
TMEM16A is a chloride channel, activated directly by intracellular calcium
Activation by calcium is strongly influenced by membrane potential
Speed of opening/closing is influenced by the concentration and nature of the permeant anion
These first two factors are inextricably linked. Under 'resting' physiological conditions of intracellular Ca2+ concentration (0.1 uM) and membrane potential (-40 to -60 mV, for example), these channels appear to be closed despite the presence of calcium. Depolarisations above the chloride equilibrium potential begin to elicit a TMEM16A current, conduction increasing with increasing depolarisation, giving TMEM16A its classic 'outward-rectifier' profile. However, when intracellular calcium concentration increases beyond 1 uM, voltage sensitivity appears to be lost, and TMEM16A conduction is seen at negative and positive membrane potentials alike. There is also evidence to suggest that the intracellular side of the channel has the capacity to bind 2 Ca2+ ions. In terms of gating speed, both fast and slow gating kinetics have been seen (whole-cell and patch recordings) depending on the duration of membrane depolarisation. This speed also appears to be influenced by the level of extracellular chloride, with the slow component most markedly affected (slowed further) by increasing extracellular chloride levels from 30 to 140 mM. More permeant anions (SCN–, I–, NO3–) promote/accelerate opening and slow channel closure when applied extracellularly.
So how do you bring these factors together in order to model TMEM16A gating? In the present study2, Contreras-Vite and his colleagues look at their own experimental findings combined with published information, presenting for example the novel observation that in zero intracellular calcium, TMEM16A conduction is still possible, but requires strong depolarisations beyond +100 mV. They also show that reducing extracellular chloride reduces channel open probability, and any 'fast' gating kinetics are entirely lost when the channel is maximally activated by high levels of intracellular calcium, and state that intracellular chloride level appears to have no effect on channel activation.
They use these findings to calculate the open-probability of the channel under the influence of these different factors, and define the rate constants governing the transitions between discreet 'open' (O) and 'closed' (C) states when 0, 1 or 2 Ca2+ ions are bound to the channel in the presence or absence of 1 external Cl– ion. By using these to simulate steady-state activation properties and comparing these to their experimentally-derived activation and closure (tail-current) data, they came up with the following 12-state Markov chain model:
Essentially, 'open' channel states are represented in the right half of the model, 'closed' in the left, concentric levels represent calcium binding – from the outer level in which both putative Ca2+ binding sites are occupied, the centre representing the channel with no calcium bound; each state being linked by a rate constants representing parameters listed fully in the paper, most of which are voltage-dependent, some being fast and some being slow (indicated in the diagram key).
Using this model, the authors demonstrate that they can reproduce the activation and deactivation kinetics shown by their experimental data, although they themselves admit that the quality of the fit begins to decrease under extreme levels of intracellular calcium and voltage. They do, however, successfully use it to predict that calcium binding affinity does not change with varying extracellular chloride. They then show experimentally that this does appear to be the case.
The basis of this latest gating model comes from evidence which is only briefly summarised here. There are, of course, other factors which have been proposed to influence TMEM16A channel activity under physiological conditions, such as the binding of calmodulin and inhibition of activation by intracellular protons. Whether this model proves to be correct, time will tell. But in targeting drugs to this channel, knowing how stable and long-lasting some of these conformations may be under various physiological conditions might lead to more efficient, state-dependent drug pharmacology.
Blog written by Sarah Lilley
"Still round the corner there may wait, A new road or a secret gate." J R R Tolkein
Contreras-Vite JA, Cruz-Rangel S, De Jesús-Pérez JJ, Figueroa IA, Rodríguez-Menchaca AA, Pérez-Cornejo P, Hartzell HC, Arreola J. (2016) Revealing the activation pathway for TMEM16A chloride channels from macroscopic currents and kinetic models. Pflugers Arch. 2016 May 2. [Epub ahead of print]
Cruz Rangel S, De Jesús Pérez JJ, Contreras Vite JA, Pérez Cornejo P, Hartzell H, Arreola J (2015) Gating modes of calcium-activated chloride channels TMEM16A and TMEM16B. JPhysiol 24:5283–98. doi:10.1113/JP271256, PMID: 2672843
Ni YL, Kuan AS, Chen TY (2014) Activation and inhibition of TMEM16A calcium-activated chloride channels. PLoS One 9:e86734. doi:10.1371/journal.pone.0086734, PMID:24489780
Ferrera L, Caputo A, Galietta L. (2010) TMEM16A protein: A new identity for Ca2+-dependent chloride channels. Physiology. 2010, DOI: 10.1152/physiol.00030.2010, PMID: 21186280
Posted in Drug Discovery	| Tagged calcium-activated chloride channels, TEM16A gating	| Leave a reply
The remyelination dogma
The myelin sheath is a major component of the white matter of the vertebrate brain and spinal cord. It serves as an electrical insulator along nerve axons that accelerates conduction and enables higher brain function [1]. This specialised lipid-rich structure maintains axonal integrity by providing metabolic and trophic support, whilst allowing for efficient nerve conduction by minimising energy consumption [1]. However, characteristic to a number of CNS disease states is the process of demyelination [2]. For example, in Multiple Sclerosis (MS), where white and grey matter brain lesions occur throughout the brain and spinal cord, there is defective saltatory signal conduction and axonal damage, which then manifests itself in clinical symptoms such as motor weakness [3]. Interestingly though, in the adult CNS a quiescent pool of precursor cells exists which can differentiate into new oligodendrocytes capable of replacing lost myelin sheath [4]. In fact remyelination is a natural repair mechanism believed to protect against progressive axonal damage in MS. Therefore, the focus of current therapeutic research has recently shifted from preventative to reparative in respect to existing white matter lesions.
The beneficial effects of remyelination are functional recovery via the restoration of both axonal conduction and trophic axonal support [5], and the additional neuroprotective properties of reducing the cell's energy consumption. This is done via recruitment of resident precursor cells to generate new oligodendrocytes [6]. However, the extent of this regeneration is limited. Although in vivo models to study MS show efficient and extensive remyelination, myelin sheaths generated in the adult brain of MS patients are generally thinner with shorter internodes. In MS, the process of remyelination is insufficient in about 80% of lesions and fails to counteract the accumulation of permanent axonal damage [7]. Successful remyelination may require the existence of oligodendrocytes, but initially needs the necessary factors that allow for the sufficient migration and differentiation of these precursor cells [8]. It is these factors that are thought to limit its success in the MS brain, although the underlying cellular and molecular mechanisms remain poorly understood.
But even so, do therapies focusing on enhancing this remyelination process inevitably incur neuroprotection? One example which suggests they may not be so intimately related is the drug Fingolimod, approved by the FDA in 2010 to treat relapsing-remitting MS (RRMS). Although this drug has been shown to reduce brain atrophy in RRMS patients [9], The Lancet this year reported that the INFORMS study, which used this drug in primary-progressive MS (PPMS) patients, failed to show any improvement in the neurodegenerative process [10]. So, why are we failing to find treatment for PPMS? Is remyelination really the answer? There is evidence from animal studies which shows that remyelination and neuroprotection may actually occur independently of each other. After completion of remyelination the mice showed initial recovery of locomotor performance; however 6 months post completion, performance then began to decline compared to age-matched controls [11]. These studies highlighted that axonal damage continues long after remyelination, and can still accumulate over time to result in functional impairment. Remyelination alone cannot compensate for the stress that demyelination has on a neuronal cell, and therefore neuroprotective strategies that do not rely solely on restoration of myelin must be explored.
Translating both remyelinating and neuroprotective strategies from bench to bedside, however, relies on appropriate in vitro and in vivo experimental settings for the development of new drug targets. Focusing on remyelination in MS, the most commonly used animal models are toxin models, whereby a focal injection or systemic administration of a toxin, for example lysolecithin or cuprizone respectively, induces demyelination and successive remyelination [12]. A benefit of these models is that they exhibit endogenous remyelination with a predictable spatial and temporal distribution. However, because remyelination is certain in these models, they are unsuitable for accessing the ability of a pharmaceutical compound to induce remyelination and can only be used to study the acceleration of it. Additionally, the lesions in these models do not develop much, if any, autoimmune reaction, and inflammation is one reason thought to be behind the failure of remyelination in the MS brain. This may be one reason behind some of the discrepancies that are seen between lab and clinic. Having said that, remyelination in both the lysolecithin and cuprizone model is hampered in aged animals the chronic EAE model exhibits limited remyelination and a substantial input from the immune system [12]. These paradigms may provide a way of better studying the induction of remyelination in a compromised environment.
In conclusion, two factors must be addressed for research in this are to proceed: firstly the experimental setting most appropriate to study drug targets for remyelination; and secondly, the simultaneous neuroprotective strategies that should be employed to prevent the accumulation of irreversible grey matter damage.
Blog written by Victoria Miller
Morrison.B, "Oligodendroglia: metabloic supporters of axons" Trends in Cell Biology, vol. 23, pp. 644-651, 2013.
Bercury.K, "Dynamics and mechanisms of CNS myelination" Developmental cell, vol. 32, pp. 447-458, 2015.
Chang.A, "Cortical remyelination: a new target for repair therapies in multiple sclerosis" Annual of Neurology, vol. 346, pp. 165-173, 2012.
R. F.-C. C. Franklin, "Remyelination in the CNS: from biology to therapy," Nature Reviews: Neuroscience, vol. 9, pp. 839-855, 2008.
Honmou.O, "Restoration of normal conduction properties in demeylinated spinal cord axons in the adult rat by transplantation of exogenous Schwann cells" Jounral of Neuroscience, vol. 16, no. 10, pp. 3199-3208, 1996.
ElWaly.B, "Oligodrendogenesis in the normal and pathological central nervous system" Frontiers Neuroscience, vol. 8, p. 145, 2014.
Frischer.J, "Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque" Annual of Neurology, vol. 78, pp. 710-721, 2015.
Kuhlmann.T, "Differentiation block of oligodendrogial progenitor cells as a cause for remyelination failur in chronic multiple sclerosis" Brain, vol. 131, pp. 1749-1758, 2008.
Ingwersen.J, "Fingolimod in multiple sclerosis: mechanisms of action and clinical efficacy" Clinical Immunology, vol. 142, pp. 15-24, 2012.
Lublin.F, "Oral Fingolimod verus placebo in primary progressive multiple sclerosis: results of INFORMS, a large phase III, randomised, double-blind, placebo-controlled trial" Lancet, 27 January 2016.
Manrique-Hoyos.N, "Late motor decline after accomplished remyelination: impact for progressive multiple sclerosis" Annual of Neurology, vol. 19, pp. 227-244, 2012
Blakemore.W, "Remyelination in experimental models of toxin-induced demyelination" Current Topics in Microbiological Immunology, vol. 318, pp. 193-212, 2008.
Posted in Drug Discovery	| Tagged Animal models, Multiple Sclerosis, Neuroprotection, Remyelination	| Leave a reply
Smuggling drugs into the brain: old and new tricks
Figure 1. Proposed mechanisms of transport across the blood-brain barrier
Every medicinal chemist involved in neuroscience drug discovery has experienced the joys and pains of the blood brain barrier (BBB), classically defined as the system of tight junctions between the epithelial cells of the brain capillaries that strictly regiment the access of molecules into the CNS.
As medicinal chemists, we usually picture the BBB as a more impenetrable version of other biological interfaces and consequently we design our CNS-penetrant molecules applying more rigid physicochemical filters. Additionally, we use in vitro brain permeability models that tend to focus only on passive diffusion and efflux.
In reality big and polar molecules, antibodies and viruses have the ability of crossing or eluding the BBB using a number of 'side entrances'.
In the last 30 years the understanding of the BBB mechanisms has increasingly gained clarity and accordingly many new opportunities for drug delivery into the brain have been tested. These new opportunities usually exploit existing mechanisms utilised by endogenous molecules that need to gain access to the brain (e.g. nutrients, aminoacids, regulatory blood proteins) or tricks invented by pathogens. Old and new ways of crossing the BBB have been recently reviewed by William A. Bank in the April issue of Nature Reviews Drug Discovery (doi:10.1038/nrd.2015.21).
Some of the most interesting and overlooked pathways include:
Access via influx (blood-to-brain) transporters – this is an old strategy for drug delivery (e.g. L-dopa, gabapentin which use transporters for neutral aminoacids). More recently this mechanism has been considered for selective delivery to targeted areas of the brain.
'Trojan Horse strategies – where a therapeutic agent (cargo) is conjugated to a ligand (Trojan Horse) of a particular influx transporter expressed on the luminal membrane (blood-side). The complex in usually routed on the abluminal membrane (brain-side) by transcytosis.
Absorptive transcytosis – another vesicle-based pathway often used by penetrating peptides and antibodies fragments.
Extracellular pathways or functional leaks – these are anatomically defined areas of the brain that are deficient in blood brain barrier and as such allow controlled access to small amount of serum proteins including albumin and immunoglobulins. It has been suggested that antibodies – with low volume of distribution and high circulating half-life – can enter the CNS using this way.
Many small molecules and biologics that exploit these or similar tricks are being validated in the clinic.
Nevertheless, these mechanisms are quite difficult to predict and permeability models available to medicinal chemists for rational design are unfortunately still very rudimental…
Figure 1 adapted from: Smuggling Drugs into the Brain: An Overview of Ligands Targeting Transcytosis for Drug Delivery across the Blood–Brain Barrier; Julia V. Georgieva et al. Pharmaceutics 2014, 6, 557-583; doi:10.3390/pharmaceutics6040557
Blog written by Alessandro Mazzacani
Posted in Drug Discovery, Medicinal Chemistry	| Tagged BBB, blod brain barrier, CNS, drug delivery brain	| Leave a reply
The 'Pathogen Box'
Posted on April 27, 2016 by SDDC
Last year I (Ryan West) attended the ISNTD-D3 2015 conference where I saw a presentation by Julio Martin from GSK Tres Cantos. He gave an interesting talk about open source drug discovery focusing on kinetoplastid diseases. One of the highlights of the talk for me was the introduction of three 200 compound collections that have been phenotypically identified as inhibitors of trypanosoma brucei, trypanosoma cruzi or leshmania donovani.
The collections were generated by screening a 1.8 million compound library from GSK against the pathogens in question. Hits were filtered to remove cytotoxic compounds and undesired structural features. The compound collections have been made available to public and private partners to facilitate research into neglected tropical diseases. Efficacy and cytotoxicity data has been published on ChEMBL and highlighted in Nature Scientific Reports 5: 8771 doi:10.138/srep08771.
Recently there has been a move towards encouraging and facilitating research into neglected tropical diseases. Medicines Malaria Venture (MMV) released a box of 400 compounds in 2011 that were active against the blood stage form of the P. falciparum parasite. Again, these compounds were freely available to the research community for further scientific investigation. This resulted in more than 40 publications, the depositing of publicly accessible data from over 20 screens and the initiation of at least 3 medicinal chemistry programs for a range of neglected tropical diseases.
Continuing from the success of the 'Malaria Box' initiative MMV have been awarded a further grant from the Bill and Melinda Gates foundation to collate another library of compounds. This time the molecules have been identified phenotypically against a broader range of 8 unique pathogens which are responsible for a large proportion of the world's neglected tropical diseases. The collection has been available from December 2015, and as part of my project I have been able to acquire one of the kits for testing. We are interested in an enzyme target responsible for the blood stream respiration of the parasite that causes human African trypanosomiasis. We hope to publish our results in the near future.
This open source approach of sharing compound collections along with generated experimental data will boost research and aid the discovery of novel molecules for treating neglected tropical diseases. It will be interesting to see the progress of these open source endeavours and if they will be more widely adopted by other disease areas.
Blog written by Ryan West
Posted in Drug Discovery	| Tagged compound library, neglected tropical diseases, open source	| Leave a reply


THE LAST GREAT INDEPENDENT LIGHTING COMPANY!
TOURIX� LED displays find home with Burning Retina.
W Hotel Scottsdale project profiled in LED Magazine.
W Hotel install is completed.
Here's a random picture from our gallery.
©2002-2019 Burning Retina Lighting & Transport. All Rights Reserved.


Grid computing has a way to go to convince its potential customers.
Respondents even dubbed it a technology bandied about by marketing professionals and the media. Unless vendors can bridge the education gap, uptake is likely to remain small.
IDC Australia PC hardware market analyst Michael Sager admitted early adoption had been restricted to high-performance computing and there is still the big task of educating the enterprise.
"The true benefits and value proposition of the model must be pushed even further as end users from the survey are still generally confused as to the concept of grid computing," Sager said. "It takes a huge cultural shift for an organization to move towards grid computing, and there still needs to be a lot more education from vendors."
"But there are a few success stories; the IBM and Qantas [project] is the main one that comes to mind, and HP has had a few big deals," Sager said.
Europe is one part of the world where grid computing is finding mainstream success with grid server revenues likely to reach US$1.8 billion. The main driver is an interest in more efficient and lower-cost computing and, based on a study of buying behaviour and trends undertaken nationally early this year, IDC predicts Australia will be a minor player in the overall market.
IDC found that only 6.8 percent of respondents indicated they were moving to or planning to move towards grid computing model. However, more than double this number, 15.2 percent, claimed they did not know if their organization was moving towards this model.
Gartner research director Phillip Sargeant said grid computing is still at the experimental stage.
However, he said vendors are sponsoring academic projects in this area. Holden Innovation supervising engineer Winson Ng said the reason enterprises are not using grid computing on a day-to-day basis is because the infrastructure is not yet available.
Ng said the main inhibitors to enterprise grid computing include availability of expertise to manage the infrastructure including a wide network, availability of bandwidth, and operational issues like time differences between computing resources.
But he said there are real business benefits in grid computing for computer aided engineering (CAE).
"For example, CAE could run calculations overnight but it would need a smart system to look at the office hours of locations," he said. "Also, the flexibility to work across operating systems and legacy software is needed."
Ng said he sees great value in grid computing, especially in a large company with many idle CPUs. So how far away is the reality?
"It's not far away for manufacturers like us that need to use as many CPUs as are available," he said. "If General Motors [US] is interested in the technology now it could be three to five years before it becomes an IT-approved process. It's definitely the way forward and the sooner the better."


LIVING2008: The Positive Leadership Summit was the twelfth International Conference of People living with HIV, but was a first in many other things. It was the first International Conference of people living with HIV organised by a consortium of 11 agencies, known as the LIVING2008 Partnership, with GNP+ acting as the 'secretariat' for the Partnership. In addition, the LIVING2008 was the first International Conference of People living with HIV organised immediately prior to an International AIDS Conference (IAC).
To provide baseline data and observations to inform possible future collaborative work among the LIVING2008 Partnership members.
The evaluation concentrated primarily on capturing the perspective of the people who participated in the Summit. Data was collected through an online survey.


. . . But the last two times that I truned him out for a run he seems to be very weak in his back legs after a couple hours of exersize.
Visit Tripawds Start Page for Coupons!
Don't wait. Your Tripawd needs all the help he or she can get in order to stay strong and healthy. Learn more about Loving Life on Three Legs and save 30 percent on a copy from now until midnight Pacific Time on February 28th.


On Friday's show, all I could talk about was how nervous I was to ride shotgun in the General Jeff May's crash to pass car at Saratoga Speedway. Well my fears didn't go away after seeing his car. This was the beast that was supposed to last numerous laps while giving out and taking hits. Let's be honest, it's seen better days.
Enough lollygagging in the pits, it's game time!
That had to be the most fun and exciting thing I've ever done. Everything from being pinned to the right side of the seat the entire time, to the sound of the twisted and mangled frame rubbing on the ground on every corner, the smell of hot exhaust, burning rubber, and various engine fluids. My hands were sore after white knuckling it the entire time, and on top of that, I didn't get to sleep until about 3am cause of all the adrenaline. When we got home, I took the dogs out for a long run and it still wasn't enough to calm me down! I wanted to give a huge thank you to Jeff and his family and friends and whole pit crew for welcoming me with open arms. A bunch of great people and a great community over at Saratoga Speedway. So thanks again!
I'd love to hear from you! Reach out on Facebook or Twitter, or you can always send me an email: bigginger@thegoatrocks.ca!


I've been thinking a lot, in my last weeks here, about the many gifts my time as your minister have given to me. You have trusted me with your stories, your joys, your fears, your children, your suffering, and your lives. What an incredible gift it is to share all that.
One of the greatest gifts of my work here has been the opportunity to sit with people who are dying. Those who have allowed me to share in their dying have taught me so much about how to live.
One thing I've noticed is that when people talk about their lives at the end of their journey, there are some things most people say. They often say that the most important thing they did with their lives was to raise their kids and love their families. They often say that what they're most grateful for is their family, friends, community—the love they shared in their lives.
And when people express regrets, they often say they wish they had been more forgiving, or they wish they had lived more fearless lives.
So many stories of the early church are stories about learning to live fearlessly. The church was born in frightening times and faced terrible persecution.
Our faith ancestors had to teach each other how to trust God in the midst of economic hard times, political turmoil, oppression, subjugation, and their terror.
This story we heard about two unknown disciples on the road to Emmaus is a resurrection story about that. It is evening on the day of the resurrection. Two nameless nobody disciples we never heard of before and will never hear from again walk away from Jerusalem toward the village of Emmaus talking about what just happened to them.
A stranger joins them who is the Risen Jesus, but they don't know its Jesus. And so, in a surreal and comic version of preaching to the choir, they tell this Risen Jesus what just happened.
When they get to the village it is dusk and the Jesus they don't recognize seems about to leave them and walk on. It is then their self-absorption breaks, and because of their practice of hospitality and sharing, they invite the stranger to share a meal and stay with them.
And when Jesus was at the table with them, he took bread, blessed and broke it, and gave it to them. Then their eyes were opened, and they recognized him. Christ shows up at the Christic table when they do. When the world is blessed, broken open, and shared, only then, for us the fearful, is God known.
We have a funny religion that teaches a funny reality. But our faith ancestors seem to say that we can taste and see it. We can experiment with our faith and notice. We don't just blindly accept our religion.
That's quite a promise–an impossible promise. And no one else can live it true for you. Oh we can testify; we can tell our stories. But it is not true until it's true for you.
That's quite a promise, isn't it? There are churches around the world who have turned this teaching into something called the prosperity gospel—some version of "give your money to the church and you'll get rich." But Jesus, Paul, or the prophets are not talking about that. They are saying that God wants us to be generous and wants all people fed. And you can trust God with your life if you do it.
When we give away some of our money, when we choose to live generous lives and be generous people, we get to see for ourselves if these promises are true. If you want to learn if God is real then you need to live in a way that leans out on God. Start where you can, but you have to risk something; you have to risk being wrong; you have to risk being foolish. You can't discover God by choosing self-contained. You have to get yourself out there and be less self-sufficient, if you want to know if you can trust this Mystery we call God.
Mary Martin has this wonderful saying I love. She says, if you can't be a good example, be a horrible warning. Don't you want to know if you should live in faith or fear? Will you risk some percentage of your money to God and learn for yourself what is true?


Tag Archives for: "wildlife artist"
Andrew Bone continues to astonish. The African conservationist, painter and adventurer has achieved yet another benchmark in his career.
In November 2008, with generous sponsorship from Park West Gallery, wildlife artist Andrew Bone undertook a South African expedition that took him to the extremes that the continent had to offer.
Park West Gallery's wildlife artist Andrew Bone is in process of putting the finishing touches to the planning of a Southern African safari for the end of the year.


I love surprising people. Especially my husband. There is little that tickles me more than truly shocking him (pleasantly, of course) with a gift.
And I've got a pretty decent track record.
Early in our marriage, I hauled an entire weight set up the stairs (one weight at a time, of course) so I could hide it in our spare bedroom closet. I wrapped one 5-pound weight and put it under the Christmas tree. He had NO idea until he opened it.
I went in with his folks a few years ago and bought him a Kindle for Christmas. He was floored when he saw it. He had not even a clue I was considering something like that (it was out of our price range).
But yesterday may just have been one of the best surprises of all. Last Monday, the kids and I went shopping, and I picked out a new version of a computer game I remember him playing several years ago as a Father's Day gift for him. He hadn't asked for it - I just remembered him enjoying it back in the day.
Four days later, he mentioned he was getting bored with his current favorite computer game and wanted to get a different one - the very game I had bought for him. To say I was happy was an understatement. Apparently, I'd bought just what he wanted. And Father's Day was only two days away. I could keep the secret for 48 hours.
But Saturday things got a bit more complicated. He decided he wanted to bid on a copy on Ebay. Fortunately, he lets me do all the ebay stuff, so I had to do some fancy (and sneaky) talking to convince him to wait a couple days before bidding (it IS best to bid closer to the closing date. Right? ;)).
Surprising my husband has almost become a tradition around here. But still, it's tough to keep the secret (and Saturday, I have to admit, was the hardest so far).
Too often, when we have great news, we don't want to keep it in, but, for one reason or another, we might have to. And we might have to be tricky to keep that secret.
It's a good thing the best news we could possibly have does not have to be kept under wraps. Jesus Chris, the Son of God, was born, lived a sinless life, died on the cross, and rose again on the third day - and because of it, we can have eternal life.
No need to keep THAT a secret. Tell the world!
How do you like getting, or giving, surprises? Do you have any fun stories to share? Would love to see them in the comments.
Great analogy!! I love keeping secrets but love telling them more:)) I have one I have to keep now and it is killing me!
What a sweet read and great verse pairing.
Fun story, Joanne! I love Father's Day because it reminds me to make my honey feel extra special ... and to take time to remember all he does. So many things can go unnoticed--all the light bulbs he changes, garbage he carts out, gas tanks he fills.
Let us know how he enjoys his new game!


Fort Shooter Simulator is tied in with rehearsing your abilities in building structures for the mainstream, multiplayer online Fortnite diversion. Stroll around a gigantic field and begin experimenting with various types of game plans for your stages. You can likewise rehearse some shooting with various types of weapons and cooperate with different kinds of items. Mess around with Fort Shooter Simulator!


Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of 1.4912 Pipes & Tubes.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of 1.4935 Pipes & Tubes.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of X6CrNiMo17-13-2 Pipes & Tubes.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of X25CrMnNiN25-9-7 Pipes & Tubes.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of X10NiCrSi35-19 Pipes & Tubes.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of 1.4438 Pipe & Tube.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of 1.4512 Pipes & Tubes.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of X2CrNiCu19-10 Pipes & Tubes.
We Aesteiron Steels Pvt Ltd, are leading manufacture & supplierof X11CrMo9 Pipe & Tube.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of 1.4122 Pipes & Tubes.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of 1.4854 Pipes & Tubes.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of 1.4872 Pipes & Tubes.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of 1.4886 Pipes & Tubes.
Aesteiron Steels Pvt Ltd is one of the leading manufacturer, supplier and exporter of EN 10216-2/ P195GH Pipe.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of 1.4940 Pipes & Tubes.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of X3CrNiMo18-12-3 Pipes & Tubes.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of 1.4945 Pipes & Tubes.
We Aesteiron Steels Pvt Ltd, are leading manufactures & suppliers of EN 10216-3 P460NL2 Tube.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of X2CrNiMoN22-5-3 Pipes & Tubes.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of 1.4371 Pipes & Tubes.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of 1.4507 Pipes & Tubes.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of X1CrNiMoCu12-5-2 Pipes & Tubes.
Aesteiron Steels Pvt Ltd is one of the leading manufacturers & suppliers of X2CrMnNiN17-7-5 Pipes & Tubes.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturer of X2CrNiN18-10 Pipe & Tube.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers & suppliers of X4CrNiMo16-5-1 Pipes & Tubes.
We Aesteiron Steels Pvt Ltd, are leading manufacture & supplierof EN 10216-3 P690QL1 Tube.
Please contact us for more detaisl.
We Aesteiron Steels Pvt Ltd, are leading manufactures & suppliers of EN 10216-3 P275NL1 Tube.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of 1.4449 Pipes & Tubes.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of 1.4477 Pipes.
We Aesteiron Steels Pvt Ltd, are leading manufacture & supplier of EN 10216-3 P355NL1 Tube.
We Aesteiron Steels Pvt Ltd, are leading manufacture & supplier of EN 10216-3 P690QH Tube.
Aesteiron Steels Pvt Ltd, is one of the leading manufacturers of 1.4362 Pipes & Tubes.
Looking for "EN 10088-1 Pipe & Tube"?


Ruchii, The Taste is not available through our online partner for your requested time.
Been to so many Indian restaurants in Ireland, but none can be as truly said to be the best authentic Indian restaurant as Ruchi .
Being a vegetarian ,its hard to find choice. In Ruchi we have traditional Indian vegetarian dishes, so palatable and reminds you of home . All the food is so nicely presented .
Family friendly and professional service .
If you have not eaten so far in this restaurant you are definitely missing some spice and taste of India .
I would like to take this opportunity to thank you for the time you've spared to share your Ruchii The Taste Blackrock experience with us, feedback is key to us as a hospitality business as it allows us to move forward and develop so that we can create enhanced experiences for our guests.
Your excellent views regarding the Ruchii The Taste entire Ruchii team who of course expressed their sincere thanks.
We hope to welcome you once again in the near future to Ruchii The Taste in Blackrock, Co Dublin.
I have never imagined that I will be writing a review about an Indian restaurant in Dublin given all my family and friends know I never prefer to eat out Indian because it never reminds me of India and sadly my experience was always it's never authentic, more over I cook better food than many of the restaurants. But something drastically changed my thinking today after dining at Ruchi Indian restaurant in Blackrock, County Dublin.
Coming from foodie Indian family and a flair to cook I can confidently say Ruchi's food comes very close to quality home cooked authentic Indian food. Finding this restaurant was truly like finding an oasis in the desert - chefs unpretentious style is presented in every morsel of food and passion to bring tantalizing dishes from its simple menu, its excellent hosts and of course the high quality of the food - the list of superlatives are endless.
The usual 'Irish indian restaurant' that litter the streets of Dublin need to take note and replace the 100 page menu with proper food. This is the only Indian Restaurant for me now.
My wife summed up the experience very well when she said the food was obviouly lovingly cooked. We cannot wait to go back there. Highly recommend.
Visited here with family and friends and everything was fantastic. We all tried something different from the menu and no one was disappointed. Taste, presentation and portion size were all perfect. The service was second to none with us never having to wait for drinks or our food. Also with the Head chef / Owner Sateesh coming around to all the tables after was a beautiful personal touch. I wish them the very best of success. We will be back.
We are delighted to learn that your family and friends have enjoyed and relished the "Dining Experience" at Ruchii, The Taste.
At Ruchii, we endeavour to enhance the magic of Indian Cuisine by good team work - both on the front and in the kitchen.
We visited this restaurant for the first time this evening. There were 10 of us. We all had a beautiful meal , excellent staff and loved the fact that the chef sateesh came out to talk to every table and make sure everyone was enjoying their food. I would highly recommend this restaurant and we will certainly be returning.
We, at Ruchii aim to provide our guests a fine dining experience in a casual atmosphere - thereby getting the best of both worlds.
We look forward to your next visit to Ruchii, Blackrock.
Been to Ruchii, The Taste? Share your experiences!


You should work hard. Work harder and hustle harder. When you love what you do, you don't get tired. If you want to succeed, you have to work until you get exhausted.
We hear and see such messages everywhere.
Modern people are very dedicated to working, and workaholism is not considered a problem but rather a necessity for everyone who wants to succeed.
Elon Musk, the founder of Tesla and SpaceX became a productivity icon for the modern generation. On Twitter, he said that "nobody ever changed the world on 40 hours a week," and many people agree with him.
Even though everybody knows that overworking leads to stress, anxiety, and burnout, such work-related problems are perceived as signs of a dedicated and strong worker. The sad truth is that the workaholic culture, which was dubbed "hustle culture" by The New York Times, justifies stress and exhaustion.
Work gives many millennials meaning and purpose. However, in reality, the obsession with productivity often causes significant damage to it. Most people don't need to work 80 hours a week to reach their point of burnout.
Many millennials feel guilty for not working enough because they get used to the idea that they would achieve much more if they just worked more. It gets harder to meet societal expectations.
We all know that stress and anxiety kill productivity, so it becomes extremely important to see the difference between working hard and being obsessed with work.
What's the difference between working hard and being obsessed?
Although workaholics and hard-working people may look the same from the outside, they are often driven by different motivations and pursue different goals. Simply put, hard-working people work to improve the quality of their lives, while workaholics sacrifice their lives to work harder.
If your main purpose is to attain results, you can prioritize tasks and develop effective planning strategies. In contrast, if your main goal is just to be busy, you may try to fill every minute of your life with work, and the actual purpose of such an activity loses its meaning.
The hard workers properly evaluate their capabilities and know that they will achieve better results with time when their skills will develop and improve. Workaholics run after perfection.
It's hard for workaholics to prioritize different tasks. They are often unsatisfied with their own performance and depend on the external sources of validation (managers, supervisors, clients, etc.).
The last but not least difference between people who work hard and people who are obsessed with work is that the former ones prioritize themselves and the quality of their lives, while the latter prioritize their work and put their lives second.
If you want to succeed, you should focus on your objectives and use your time productively. You should work effectively instead of just working as much as you can.
How do you know when you work too much? How to understand whether working actually helps you achieve your goals or becomes a problem? Here are a few typical signs that your work loses its meaning and becomes an obsession.
Your work makes you anxious.
You try to work as hard as you can because you're afraid that you won't achieve your goals.
You think about work even when you're not working.
People say that you look like you're not being present.
You answer work calls and check emails before and after your work hours.
You have hard times delegating tasks to others.
You hate yourself for being unproductive and lazy.
You try to work harder to prove something.
You cannot enjoy activities and conversations that have nothing to do with your work.
Many of us start every morning by checking our smartphones. Instead of thinking of our goals and planning our daily activities, we immediately switch from the proactive to the reactive mode: our attention is immediately stolen by emails, messages, and notifications.
You can be more productive and work more effectively if you spend this time generating ideas and setting priorities for today.
If you like to work hard, sleeping in leads to a sense of guilt so you try to compensate these wasted hours by overworking. Wake up early and you won't feel stressed out. It will be easier for you to focus and to stay productive.
Many people see salary negotiation as a conflict so they try to avoid it at any cost. At the same time, they may realize that they need more money so they work more, justifying overworking as the only solution.
You should understand that salary negotiation is a natural conversation, and any employer expects it. There's nothing wrong with negotiating your salary, in fact, negotiation is an integral part of our everyday lives.
For example, if you want to buy a car, you likely won't agree to the first price you hear. There is a certain salary range that your boss is ready to pay, so don't be afraid to talk about it.
The main thing is to stay professional and not to approach salary negotiation as a conflict.
If you want to be productive, the first thing you should do is prioritize important tasks. Not all tasks are equally important. Some tasks require more commitment and bring more results.
Thus, we suggest that you focus on the actual value of every task instead of focusing on the number of tasks. You will be much more productive devoting a few hours to important tasks than when working for over 10 hours a day just trying to complete more tasks.
Create a daily, weekly, and monthly plan, prioritize your tasks and goals, and you will be able to actually accomplish more instead of just being busy all the time.
According to research, when we switch from one task to another, our brain needs at least 25 minutes to focus on the new task. This is a so-called "attention residue" phenomenon, and it means that every time you switch to a new task, a part of your attention is still focused on the previous task — it's just the way our brain works.
Therefore, multitasking creates numerous distractions and actually prevents you from working productively. In addition, multitasking makes you feel tired and drains your energy. To avoid it, put more effort into proper planning and prioritizing.
Is being a workaholic the only way to succeed at work? Even if it seems so, the truth is that workaholism decreases your productivity, leads to lower life satisfaction, and causes significant damage to your physical and mental health.
If you want to accomplish more, you should work productively, which means working in a smart way. Set priorities and plan your work instead of trying to complete more tasks.
Focus on your goals and the purpose of your work instead of just being busy. Such a smart approach will actually help you improve the quality of your life instead of sacrificing it in the name of work.


Get in on the superhero action with HERODRIVE DC Supefriends Speed Squad Minis! These free-wheeling PVC vehicles are fast and fun racers featuring DC icons Batman, Superman, The Flash, and The Joker. Sprint through the streets of Central City or turn the tables and escape from the good guys like the Clown Prince of Crime. This 4-pack sets the scene for the perfect chase! What adventure will you go on when YOU get to drive? Appropriate for ages 3 and up.


Migdal Ohr's day care centers were established in 1978. There are now four day care centers that care for over 200 children, from newborns to three years old, who are from underprivileged or single-parent homes.
Migdal Ohr has four day care centers--Isaacs, Batya, Simchat Ohr and Mitzpe--dispersed throughout the Migdal Ha'Emek campus. These day care centers are the daytime home to approximately 240 children. The children, from newborns to three year olds, come from families at the lower end of the socio-economic spectrum and are mostly from Migdal Ha'Emek and its environs. The centers also care for orphaned children living in our foster home village. These children are looked after by a devoted and caring staff and receive warm and fresh meals daily which are prepared in kitchens at each location. Each center has a playroom and a wide range of enriching activities such as movement, rhythmic music, a mobile petting zoo and yoga. These centers provide quality care and services for free or at a subsidized rate (depending on circumstance), whereby encouraging the parents to seek employment in an effort to increase the families' long-term financial position.


text:
Alumni Report – March 17th, 2022
by Zachary Defreitas
Springfield, Illinois – With many players' seasons having come to an end, we thought we'd switch our Alumni Report up a bit and focus on four players who have really made an impact on their teams' success this season! So buckle up, folks, here's this week's Alumni Report!
Our first spotlight is on one of our most successful Alumni in recent memory: Dryden McKay. McKay, a native of Downers Grove, IL, is in his Senior season at Minnesota State-Mankato where he's set numerous records in his tenure, including the NCAA career record for shutouts (currently at 33). But what may stand out even more than his numbers is his consistency. He has won 20 games or more in each season, his goals against average has never been over 2.00, his save percentage has never dropped below .920, and he's had 4+ shutouts in each season. On top of all of that, he earned his third Goaltender of the Year award (WCHA & CCHA) and is once again a Semifinalist for the Hobey Baker and the Mike Richter Awards. With so much spotlight on his own personal accomplishments, it'd be easy to overlook how the Mavericks are ranked #1 and have a legitimate chance at winning their first National Championship this season. McKay currently has a career stat line of: 109-19-4, 1.46 GAA, .932 SV%, and 33 shutouts in 135 appearances. He has also earned seven CCHA Goaltender of the Week honors and three CCHA Goaltender of the Month honors. To say McKay has had an impact on the Mavericks and the NCAA is an understatement, and we are proud of how much he has accomplished to this point!
We stick around the CCHA to spotlight our next Alumni: Freshman forward Bradley Marek. Marek, a native of Big Rapids, MI, is in his first season at Ferris State University and has opened a lot of people's eyes with his steady play and faceoff prowess. In 36 games this season for the Bulldogs he scored 10 goals and 9 assists to finish second on the team in scoring and tying for the most goals. For his outstanding campaign Marek earned CCHA Rookie of the Year honors, leading all rookies with four out of a possible seven votes from the CCHA's coaches. He is the first hometown kid to win Rookie of the Year for Ferris State and just the second Freshman to earn the title overall. Marek recorded the third most faceoff wins and third best faceoff percentage for a freshman in the nation. He is the only forward and only freshman in the top 20 in the CCHA in blocked shots (31). He was teammates this season with fellow alum and Captain of the Bulldogs Ethan Stewart, who was also his teammate when he played here in Springfield during the 2017-18 season. Marek has shown that perseverance through adversity can result in positive surprises and we are very proud of how well Bradley has done through one year at Ferris!
The transition from collegiate hockey to professional can be tricky, but one Jr. Blues alumni has found the right recipe for success in his third season with the Pensacola Ice Flyers of the SPHL. Brennan Blaszczak, who was named Captain before the season this past fall, has been on a tear with 26 goals and 14 assists in 35 games played. He has 7 power-play goals, 2 game-winning goals, and 6 short-handed goals as he sits third on his team in points but is first in goals. Blaszczak also sits second in goals overall in the league, just one goal behind the league leader. Brennan has now played in 72 professional hockey games, all with Pensacola, and has accumulated 32 goals and 20 assists in addition to being part of their 2020-21 Championship team. Blaszczak played two seasons here in Springfield, tallying 41 goals and 29 assists in 114 games before playing in parts of three seasons for the University of Alaska-Fairbanks. He is one of six Jr. Blues alumni to have played in the SPHL this season alongside Russell Jordan, Nathan Chasteen, Timothy Faulkner, Dylan Rauh, and Riley Doyon. Brennan has displayed the leadership qualities that contributed to his stellar play here in Springfield, in Alaska, and now in Pensacola. We are proud of the work he has put in and the accomplishments he has been able to attain!
The last spotlight this afternoon takes us all the way to Davos, Switzerland where veteran netminder Sandro Aeschlimann has proven that hard work and dedication pays off. The Zaziwil, SUI native is in his sixth professional season and his third with HC Davos of the National League (NL). Sandro has been an absolute brickwall this season, compiling a 22-10-0 record with a 1.78 GAA, .942 SV%, and 7 shutouts as he leads the NL in shutouts and goals-against average, is 2nd in save percentage, and is 5th in wins. In just his third season with Davos he has gone from 27 starts to 29 to 34 this season and was also selected to represent Switzerland at the 2022 Winter Olympics in Beijing. Sandro is no stranger to success, however, as he earned MNJHL Best Goaltender, Most Valuable Player, and League Champion during the 2014-15 season, and was a part of EV Zug's Swiss Cup Winning team in 2018. Overall in 109 career starts in the NL he has compiled a 65-30-3 record with a 2.40 GAA, .922 SV%, and 10 shutouts. He is the only alumni currently playing in the NL and although Fabio Hollenstein is playing in Switzerland, he's playing in the SL. We want to congratulate Sandro for a remarkable season and we are looking forward to seeing how he and HC Davos fare in the playoffs!
Tagged: Bradley Marek, Brennan Blaszczak, Dryden McKay, Sandro Aeschlimann
Jr. Blues Split Weekend Series with Janesville
Jr. Blues Split with Steel, Clinch Playoff Spot
2022 NAHL Entry Draft Set for Tomorrow Afternoon
Alumni Report – March 2nd, 2022
Alumni Report – February 24th, 2022


5 CPE credits are available for the successful completion of this course.
This course presents the material from the reinsurance portion of the former course, "Protecting the Captive: Predicting Risk, Reinsurance and Other Transfer Mechanisms." It will begin with an overview of predicting risk for loss reserving, ratemaking, and financial forecasting. Once the basics of predicting risk have been covered, a direct writing captive may use a number of different program structures to manage its shareholders' retained risk. Policies can be written for corporate reimbursement, aggregate excess, or primary protection. In each case, the objective is to pool the risks of operations. The financing of retained risk can also be achieved by pooling risks between different captives. In either case, the captive's operating and claims handling procedures must support the transfer of risk from the insured operating entities to accomplish the shareholders' financial objectives. Participants in this course will learn how to make sure the captive operates like a real insurance company.
This course will explore how a captive uses reinsurance to protect itself from unexpected high-severity or high-frequency losses and leverages its capital to earn underwriting income without retaining risk. Participants will learn when it makes sense for a captive to buy reinsurance.
In addition to self-paced reading and assignment work, students will be required to attend three webconference sessions, one pre-recorded lecture and complete one week of follow up assignments.


9 out of 10 based on 551 ratings. 1,939 user reviews.
Nissan Td27 Service Manual Pdf Nissan ZD30 and TD27 Engine Factory Workshop Service Repair Workshop Manual (Over 600 Pages Instant PDF Files) – Download Instant PDF NOW! Nissan Urvan Td Td23 Td25 Td27 Diesel Engines Repair Manual SERVICE DATA This is a very comprehensive manual (DOWNLOAD in PDF format).