Dear Readers, As we embark on a new year, I want to take a moment to thank you for reading and to look back at the highlights of 2014.

Nearly 50 years after Congress passed Title IX, female athletes are still scrambling for a fair shot in the male-dominated world of sport. In hockey, top Americans and Canadians train with their national teams part-time; the rest of the season, they have only a small pro league that offers twice-a-week practices, weekend games and thin salaries.

Fashion designer turned lifestyle guru Jenni Kayne renovated a property she calls "The Lake House," an all-white, three-level cabin tucked away in the mountains in Lake Arrowhead. We got a peek inside.

Could this be the 'Amazon Prime moment' for cannabis deliveries?

Schools have been told they must provide equal learning opportunities to students with disabilities, but the schools and parents say that's not happening during the coronavirus crisis.

Join the watch party for Ballet Hispánico's 'Con Brazos Abiertos' and catch a Q&A with choreographer Michelle Manzanales.

Mitch McConnell has promised that the next coronavirus bill would protect business owners from lawsuits related to COVID-19.

The Cannabis Cafe is selling weed and food through a new drive-thru operation.

These are extraordinary times, and Joe Biden has a number of legislators, mayors and governors who could fill an entire Cabinet.

Goldberg, the grandson of Romanian and Russian immigrants, had his bar mitzvah in his native Tulsa, Oklahoma.

'It's really hard for your mental health,' says crew member

Kalvin Phillips is destined to play in the Premier League but that may not be with Leeds United after all.

LYING flat out on a hot stone table, wearing nothing but the skimpiest of briefs, I suddenly felt incredibly uneasy. A Turkish man, topless and muscular, entered the room, threw freezing water over me then rubbed my stomach with abrasive mittens… and this was meant to be a holiday!

PIONEERING new research has indicated life can thrive on planets with hydrogen-rich atmospheres, opening up a whole new area of exploration for astrobiologists.

CRUISE holidays are currently on hold, but new plans to implement safety regulations means that travellers must fit certain health criteria in order to sail. What will the new measures entail?

This year, I am currently making over $12,000 less a year then I was supposed to when I was hired in 2004, a letter to the editor says.

Belatedly, I've got round to looking at the Treasury's recent decision to change how it calculates the necessary contributions that have to be made to cover the future costs of unfunded public service pensions.

My interest was sparked by a letter sent to the chancellor by 23 pension experts, organised by the consultant John Ralfe. They argue that the Treasury has made a mistake in its choice of a new so-called discount rate.

If you think this is tedious abstruse stuff that has no relevance to you, think again. The aggregate public-sector net liability for pensions is so huge - perhaps £1 trillion - that it matters to all of us as taxpayers, especially those likely to be paying tax in 10 and 20 years time, that the government has a reliable and accurate valuation of pension promises.

Pensions represent, to coin the phrase, a massive off-balance-sheet debt. And as we've all learned to our cost from the financial crisis of 2007-8, it is a bad idea to carry on blithely pretending off-balance-sheet liabilities don't exist.

So what is this blessed discount rate? Well in the private sector it can be seen as the number used to translate into today's money a commitment to pay £650 a week pension (for example) for 30 years or so to a retired employee (till he or she dies), so that we can see whether there's enough money in the pension fund to pay that employee (and all the other employees) during his or her long retirement.

The point of the discount rate is to assess whether there's enough money in the pension fund - or whether it needs to be topped up.

Which is all very well, except that for most of the public sector, there are no funds or pots of money to pay for future pensions. Most of the pension promises are unfunded, payable out of employees' current contributions and out of general taxation.

That said, since public sector workers are increasingly expected to make a contribution to the costs of their own pensions, it would presumably be sensible for that contribution to be set at a level that is rationally related to the value of promised pensions.

So what is the best way of measuring the cost today of new pension promises?

Well the government has decided to "discount" those promises by the rate at which the economy is expected to grow.

Now there is some logic to that: the growth rate of the economy should determine the growth rate of tax revenues; and the growth rate of tax revenues will have a direct bearing on whether future pension promises will bankrupt us all or not.

But here's the thing. Any private sector chief executive might well be sent to prison if he or she decided to use the equivalent discount rate for a company, which would be the expected growth rate of that company's revenues or profits.

The reason is that although it might be possible to remove subjectivity (or in a worst case, manipulation) from any long-term forecast of the growth of GDP or of a company's turnover, it is not possible to remove considerable uncertainty.

To illustrate, the Treasury has chosen a GDP growth rate of 3% per annum as the discount rate for public sector pensions, which is considerably above the rate at which the UK economy has grown for years or indeed may grow for many years.

If we were growing at 3%, we would in practice be less worried about the off-balance-sheet liabilities of public-sector pensions, because the on-balance-sheet debt of the government would not be growing at an unsustainably fast rate.

To put it another way, in choosing its view of the long term growth rate of GDP as the discount rate, the Treasury is arguably understating the burden of future pensions to a considerable extent.

So what discount rate do companies use?

Well they are obliged to discount the liabilities at the yield or interest rate on AA rated corporate bonds.

Which may not be ideal, but has some advantages: there is a market price for AA corporate bonds, so the yield or discount rate is difficult to manipulate by unscrupulous employers; and it tells the company how much money would need to be in the pension pot, on the basis that all the money were invested in relatively safe investments (AA corporate bonds).

Now Ralfe and his chums believe that the discount rate for public sector promises should be the yield on long-term index linked gilts (gilts are bonds or debts of the British government) - partly because this too has a difficult-to-manipulate market price and because an index-linked government bond is a very similar liability to a public sector pension promise (both are protected against inflation, both are in effect debts of the government).

They point out that gilt interest and principal payments are paid out of future tax revenues, just as future pensions are. So if the value today of future pensions should be discounted at the GDP rate, that's how index linked gilts should be value on the government's balance sheet - which would be bonkers.

Anyway, if you've read this far (and many congratulations to you if you have), you may take the view that it would not be rational to impose a tougher discount rate on the government than on private-sector companies - which is what Ralfe et al seem to want, in that the yield on index linked gilts will always be lower than the yield on AA corporate bonds (because HMG, even with all its debts, is deemed to be more creditworthy than any British business).

But for a government and for a chancellor who have made it a badge of honour to bring transparency and prudence to public-sector finances, prospective GDP growth does look a slightly rum discount rate for valuing those enormous pension liabilities.

In Saudi Arabia, you can try authentic apple-flavored Budweiser. (Non-alcoholic, of course.)

Mike and Carol Dale purchased the dilapidated home at 551 W. Madison St. in Franklin in 2019 and soon discovered it was an 1830s log cabin.

England's physical disability cricketers have taken on an energy-sapping challenge - they are running a collective marathon each day for 10 days.

Desperate for coronavirus help, California spending billions on no-bid coronavirus contracts, little accountability

One of the hardest tasks in Earth observation is tracking tiny changes in the shape of the ground.

Ethiopian Prime Minister Abiy Ahmed has said that opposition politicians were trying to exploit uncertainty created by the coronavirus pandemic to seize power, risking instability.

The "Megatron" rapper is set to perform in the country next week despite calls to quit the gig over the government's alleged human rights violations.

The rapper said she wanted to support women's and LGTBQ rights.

Human rights advocates have urged artists not to perform in the country because of its dismal human rights record.

Discover 12 habits and things cruisers do on a cruise that annoy other cruise passengers the most. Things I have seen on my many cruises, watch cruise fans discussing on cruising forums and reading complaints about. 12 common practices, habits and things cruise guests do that drive other passengers crazy. Are you guilty of any of these? Do some or all of these drive you crazy? Or, do you not see why they upset other cruise guests?

People often tell me their cruise cabin is not important as its just a place to sleep and get ready, until they have a bad experience of a noisy cabin that disrupts and affects enjoyment of their cruising vacation. I share 5 key steps to finding and ensuring you get a great cruise cabin on a cruise ship. Discover how to find the best cruise staterooms and exactly how to choose a cruise ship cabin. Also watch my video about cruise upgrades: https://youtu.be/id160Wqmrj0

* Subscribe to the channel: http://bit.ly/TFT_YouTube2
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Gary Bembridge's Tips For Travellers aims to help you make more of your precious travel time and money on land and when cruising the oceans or rivers of the world. To help you, in every video I draw on my first-hand tips and advice from travelling every month for over 20 years and 60+ cruises.

What are the things you should never do in your cruise cabin and stateroom? I explore the 11 big things that you should never do and why. Some of these are about being respectful of the crew and other passengers, but some could get you into trouble and even have you disembarked from the cruise. Are you guilty of any of these?

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Buying my Cruise T-shirts: http://bit.ly/TFTStoreBooking your next cruise with CRUISEDIRECT.COM: http://bit.ly/TFTBookCruise

Gary Bembridge's Tips For Travellers aims to help you make more of your precious travel time and money on land and when cruising the oceans or rivers of the world. To help you, in every video I draw on my first-hand tips and advice from travelling every month for over 20 years and 74 cruises at time of recording.

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oscon: High Availability in MySQL - how to pick a solution that best matches your use case http://t.co/PItdw0maTj @h_ingo #oscon #tutorial

In the past, we’ve all witnessed sim-jacking attacks that allow a hacker to impersonate the targeted victim to steal the phone number. Hackers can gain access to unauthorized information related to the victim using the vulnerability, ‘SimJacker’ was that vulnerability. Recently there’s a similar vulnerability that has popped up, which uses the same SMS-technology to […]

The post WIB Vulnerability: Sim-Card that Allows Hackers to Takeover Phones appeared first on ReadWrite.

Hear about travel to Krabi, Thailand as the Amateur Traveler talks to Annette Fortner from chaseforadventure.com about this tropical paradise.

Ahmad Chalabi helped lead the U.S. into war in Iraq, but if he ever had regrets about his role in the invasion, and the years of violence it unleashed, "he never voiced them to me," writes FRONTLINE correspondent Martin Smith.

In Lakeshore, it may be a little while longer before a retail cannabis store opens.

At a time when store front vacancies are growing thanks to COVID-19, a new retail cannabis store in Pillette Village is hoping to open soon.

7 April 2020

Corporate Members Event

Event participants

Dr Yu Jie, Senior Research Fellow on China, Asia-Pacific Programme, Chatham House
David Lubin, Associate Fellow, Global Economy and Finance Programme, Chatham House; Managing Director and Head of Emerging Markets Economics, Citi
Jinny Yan, Managing Director and Chief China Economist, ICBC Standard
Chair: Creon Butler, Director, Global Economy and Finance Programme, Chatham House

Myriam Ferro
May 1, 2003; 2:325-345
Research

Joris J. Benschop
Jul 1, 2007; 6:1198-1214
Research

Ignat V. Shilov
Sep 1, 2007; 6:1638-1655
Technology

SUMOylation is a posttranslational modification (PTM) at a lysine residue and is crucial for the proper functions of many proteins, particularly of transcription factors, in various biological processes. Zinc finger homeobox 3 (ZFHX3), also known as AT motif-binding factor 1 (ATBF1), is a large transcription factor that is active in multiple pathological processes, including atrial fibrillation and carcinogenesis, and in circadian regulation and development. We have previously demonstrated that ZFHX3 is SUMOylated at three or more lysine residues. Here, we investigated which enzymes regulate ZFHX3 SUMOylation and whether SUMOylation modulates ZFHX3 stability and function. We found that SUMO1, SUMO2, and SUMO3 each are conjugated to ZFHX3. Multiple lysine residues in ZFHX3 were SUMOylated, but Lys-2806 was the major SUMOylation site, and we also found that it is highly conserved among ZFHX3 orthologs from different animal species. Using molecular analyses, we identified the enzymes that mediate ZFHX3 SUMOylation; these included SUMO1-activating enzyme subunit 1 (SAE1), an E1-activating enzyme; SUMO-conjugating enzyme UBC9 (UBC9), an E2-conjugating enzyme; and protein inhibitor of activated STAT2 (PIAS2), an E3 ligase. Multiple analyses established that both SUMO-specific peptidase 1 (SENP1) and SENP2 deSUMOylate ZFHX3. SUMOylation at Lys-2806 enhanced ZFHX3 stability by interfering with its ubiquitination and proteasomal degradation. Functionally, Lys-2806 SUMOylation enabled ZFHX3-mediated cell proliferation and xenograft tumor growth of the MDA-MB-231 breast cancer cell line. These findings reveal the enzymes involved in, and the functional consequences of, ZFHX3 SUMOylation, insights that may help shed light on ZFHX3's roles in various cellular and pathophysiological processes.

Mammalian cytochrome P450 enzymes often metabolize many pharmaceuticals and other xenobiotics, a feature that is valuable in a biotechnology setting. However, extant P450 enzymes are typically relatively unstable, with T50 values of ∼30–40 °C. Reconstructed ancestral cytochrome P450 enzymes tend to have variable substrate selectivity compared with related extant forms, but they also have higher thermostability and therefore may be excellent tools for commercial biosynthesis of important intermediates, final drug molecules, or drug metabolites. The mammalian ancestor of the cytochrome P450 1B subfamily was herein characterized structurally and functionally, revealing differences from the extant human CYP1B1 in ligand binding, metabolism, and potential molecular contributors to its thermostability. Whereas extant human CYP1B1 has one molecule of α-naphthoflavone in a closed active site, we observed that subtle amino acid substitutions outside the active site in the ancestor CYP1B enzyme yielded an open active site with four ligand copies. A structure of the ancestor with 17β-estradiol revealed only one molecule in the active site, which still had the same open conformation. Detailed comparisons between the extant and ancestor forms revealed increases in electrostatic and aromatic interactions between distinct secondary structure elements in the ancestral forms that may contribute to their thermostability. To the best of our knowledge, this represents the first structural evaluation of a reconstructed ancestral cytochrome P450, revealing key features that appear to contribute to its thermostability.

7 May 2020 , Volume 96, Number 3

Dawn L. Brasaemle
Dec 1, 2007; 48:2547-2559
Thematic Reviews

S-Palmitoylation is a reversible post-translational lipid modification that dynamically regulates protein functions. Voltage-gated sodium channels are subjected to S-palmitoylation and exhibit altered functions in different S-palmitoylation states. Our aim was to investigate whether and how S-palmitoylation regulates Nav1.6 channel function and to identify S-palmitoylation sites that can potentially be pharmacologically targeted. Acyl-biotin exchange assay showed that Nav1.6 is modified by S-palmitoylation in the mouse brain and in a Nav1.6 stable HEK 293 cell line. Using whole-cell voltage clamp, we discovered that enhancing S-palmitoylation with palmitic acid increases Nav1.6 current, whereas blocking S-palmitoylation with 2-bromopalmitate reduces Nav1.6 current and shifts the steady-state inactivation in the hyperpolarizing direction. Three S-palmitoylation sites (Cys1169, Cys1170, and Cys1978) were identified. These sites differentially modulate distinct Nav1.6 properties. Interestingly, Cys1978 is exclusive to Nav1.6 among all Nav isoforms and is evolutionally conserved in Nav1.6 among most species. Cys1978 S-palmitoylation regulates current amplitude uniquely in Nav1.6. Furthermore, we showed that eliminating S-palmitoylation at specific sites alters Nav1.6-mediated excitability in dorsal root ganglion neurons. Therefore, our study reveals S-palmitoylation as a potential isoform-specific mechanism to modulate Nav activity and neuronal excitability in physiological and diseased conditions.

7 May 2020 , Volume 96, Number 3