text: Backgroud Dysregulation of claudin-6 (CLDN6) manifestation in cancers continues to be widely documented. development, migration and invasion skills of HLC-1Bs, cell counting package-8 (CCK-8) assay (24, 48, 72 and 96 hours post-transfection), clone test, and migration and invasion assays were conducted. Through traditional western blotting evaluation, CLDN6-mediated phosphatidylinositol 3-kinase (PI3K) pathway was examined. Results Predicated on the info of TCGA data source, scientific cell and sufferers series HEC-1B, CLDN6 was up-regulated in EC weighed against normal. Univariate aswell simply because multivariate COX evaluation indicated that CLDN6 manifestation can act AZD5363 manufacturer as an independent prognostic element for overall survival of EC. Further, knockdown of CLDN6 significantly inhibited HEC-1B cell proliferation, suppressed the colony numbers of HEC-1-B cells, and restrained the invasive and migratory ability of HEC-1-B cells. Importantly, through western blot analysis, we found that inhibition of CLDN6 amazingly decreased p-AKT, p-PI3K, and mTOR manifestation level in EC HEC-1B cell collection. Summary Our data underscore the significance of CLDN6 in EC progression, and CLDN6 is definitely a new candidate oncogene in EC. Our findings propose that focusing on CLDN6 might present long term medical energy in EC. strong class=”kwd-title” Keywords: endometrial carcinoma, CLDN6, knockdown, proliferation, PI3K/AKT pathway, prognostic, invasion Intro Endometrial carcinoma (EC) is one of the 3 most common gynecologic cancers, with about 200,000 fresh diagnoses worldwide yearly.1 With the AZD5363 manufacturer increase in obesity and the reduction in physical activity, the occurrence of EC is definitely rising and exhibits a pattern in younger women.2 Currently, surgery, chemotherapy, and radiotherapy are the main therapeutic strategies for EC. However, only a minority of EC individuals are sensitive to these treatments.3 Moreover, type II EC individuals have a poor prognosis with 5-yr survival rate 35%.4 Thus, recognition of novel therapeutic targets and further elucidation of the molecular mechanisms underlying the tumorigenesis and progression of EC may have a major impact on the health of ladies. Claudins (CLDNs) are essential transmembrane proteins in limited junction, which function primarily like a barrier against paracellular transport between epithelial cells and the CLDN family. These proteins perform important tasks in cellular adhesion, polarity, permeability, and glandular differentiation.5,6 Abnormal expression of CLDNs has been considered as a molecular mechanism of the progression of malignancy, for example, breast cancer, prostate malignancy, and ovarian malignancy.7C10 CLDN6, a member of CLDN family, is located on 16p13.3 and AZD5363 manufacturer maintains cell-cell junctions in epithelial cell bedding, and the manifestation of this gene is mainly observed in mouse embryonic stem cells and primitive germ cell tumors.11 CLDN6 has been demonstrated to suppress malignancy cell development and induce cell apoptosis.12,13 Within a former research, CLDN6 continues to be proven to work as a tumor suppressor in breasts cancer tumor, inhibiting the breasts cancer cell development, migration, aswell as invasion through p38/mitogen-activated proteins kinase (MAPK) pathway.14 Moreover, another research has recommended that silencing of CLDN6 improves migration ability from the individual breasts epithelium cell series HBL-100.12 Zavala-Zendejas et al15 have implicated that increased appearance of CLDN6 can promote the tumorigenic properties of the gastric adenocarcinoma cell line. Furthermore, CLDN6 is normally a biomarker for pediatric tumors.16 However, up to now, there is absolutely no released report over the CLDN6 expression in EC tissue, and the precise mechanism underlying CLDN6 in EC continues to be unclear. Therefore, inside our research, we made to investigate the appearance of CLDN6 and its own clinical-pathological features in EC. As cancers is seen as a increased migratory/intrusive capacity, we analyzed the migratory/intrusive capability of HEC-1-B cells with CLDN6 knockdown in today’s research. Transwell assay outcomes demonstrated that knockdown of CLDN6 triggered significant suppression of migratory/intrusive capacity. Our outcomes demonstrated that CLDN6 might serve as a potential therapeutic focus on for EC. Materials and strategies Patient examples This research was accepted by the study Ethics Committee of Danyang Individuals Medical center of Jiangsu Province, China. Specimens had been gathered after obtaining written informed consents of all individuals. The EC cells and their matched adjacent non-tumorous (ANT) cells were collected from 82 instances of EC individuals and 82 ANT samples through medical resection at Danyang Peoples Hospital of Jiangsu Province between March 2009 and January 2013, and were confirmed by histopathological evaluation. AZD5363 manufacturer Mouse monoclonal to CDC2 These samples had been iced and kept at instantly ?80C until use. All EC sufferers received no preoperative treatment, for instance, chemotherapy or radiotherapy. The overall success (Operating-system) was thought as the period between the procedure AZD5363 manufacturer as well as the time of loss of life or the finish of follow-up. CLDN6 appearance in The Cancers Genome Atlas (TCGA) data source TCGA addresses the scientific data from 552 examples of EC and 35 regular tissue samples. The difference of CLDN6 expression level between normal EC and tissues samples was analyzed using limma.


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domain: finance


How does Honda replace the powertrain without upsetting the bike’s low weight and beloved handling characteristics? What the carmaker did is place the heavy battery in a low and central position, lowering the center of gravity. This also makes it easier to mount and dismount the bike. The battery is detachable, so the rider can take it inside their home and charge it from a standard wall socket.
The Super Cub concepts employ a more scooter-like stance than current production models. The colors hearken back to older examples, but the ten-spoke cast wheels are new. Y-shaped handlebars are integrated with the bodywork, and the instrument cluster features a blue digital display.
The current Honda Super Cub has sold 87 million units as of March 2014, making it the bestselling motor vehicle in history. That is more than the next three bestselling vehicles — the Toyota Corolla, Volkswagen Beetle and Ford Model T — combined. The Super Cub began production in 1958, and is currently manufactured in 15 factories in 14 countries. It is marketed in 160 countries.
Honda’s 1960s Super Cub ad campaign, featuring the slogan “You meet the nicest people on a Honda,” was so popular that it became a case study for students and advertisers alike.
In 2014, the Japanese government issued its first three-dimensional vehicle trademark registration to the Super Cub. That’s right, the actual shape of the bike is now its own brand.
The Tokyo Motor Show will run from October 29 to November 8. We will be bringing you more motoring news as the event approaches.
- E-tron GT concept is the latest volley in Audi’s electrified offensive
- Kia completes its green-car hat trick with the all-electric 2019 Niro EV
- 2020 Kia Soul and Soul EV continue to think inside the box
- Startup Rivian exits stealth mode with a bold promise to electrify off-roaders
- Austrian e-car drivers get Go-Faster card, raising the speed limit by 30 percent


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The top-ranked middle to high-range hotels near Logan Airport are Boston Park Plaza, Omni Boston Hotel at the Seaport, and The Westin Boston Waterfront. When traveling on a budget, the best hostels near Logan Airport are Hostelling International Boston, YMCA of Greater Boston, and Boston Fenway Inn.
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About Logan Airport
Logan Airport is the primary international airport that serves the Boston metropolitan area. Located in East Boston, just three miles north of Downtown Boston, the airport is one of the main gateways for the Northeast. The airport, officially known as the Edward Lawrence Logan International Airport, is named after a Boston local and Harvard graduate who served in the First World War. With more than 20 million travelers departing out of Logan Airport every year, it is one of the United States’ busiest airports.
Fun Fact: Boston’s Logan Airport saw the nation’s shortest security wait time in Summer 2018 with a quick 9.58 minutes!
The Logan International Airport is easily accessible by public transportation from Downtown Boston
- Logan Express: Offered by the airport, the bus runs between to and from downtown Boston’s Back Bay station
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domain: travel


text: Hailed for his revelatory account of Bach s Well-Tempered Clavier (The New York Times), Richard Egarr turns to one of the least-known and most entrancing collections in the repertory for solo harpsichord. This complete recording of the works for solo keyboard by Louis Couperin (c.1626-1661) revels in the music s rich harmonic and contrapuntal textures, which are marked by a poignant use of dissonance. None of Couperin s music was published during his lifetime, but manuscript copies of some 200 pieces survive, some of them only rediscovered in the mid-20th century. The first historically important member of the Couperin family, Louis Couperin made seminal contributions to the development of both the French organ school and French harpsichord school. His innovations included composing organ pieces for specific registrations and inventing the genre of the unmeasured prelude for harpsichord, for which he devised a special type of notation.

domain: history


text:
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domain: artistic


text:
By BRENT MARTIN
St. Joseph Post
St. Joseph health officials report 123 new cases of the coronavirus since last reporting on Thursday.
The St. Joseph Health Department reports 39 new COVID-19 cases on Friday and 84 over the three days from Saturday to Monday.
Buchanan County’s positivity rate has jumped by more than three percent to 10.68%, according to the health department.
Mosaic Life Care reports it is treating 33 COVID-19 patients in its system with 28 hospitalized in St. Joseph and five in Maryville.

domain: medical


text:
The Single Best Strategy To Use For dog flea virus
They are very good at hiding in your Doggy’s hair. But You might even see some flea “dirt” or brown-black grit. This can be gritty, dim red-brown flea feces that is generally built up on the blood which the flea has taken from your Canine. (Of course, fleas are disgusting.) This can be a sure indicator that your dog has fleas.
When fitting your pet's collar, ensure you can slip two fingers in between the collar and your pet's neck.
When can I bathe my Pet dog after application of Seresto® for dogs? – Seresto® is drinking water-resistant^. You don’t will need to remove Seresto® whenever you give your Pet dog a bath or if they get wet. This is because:
Sensitivities may manifest right after employing ANY pesticide products for pets. If signs of sensitivity arise, eliminate collar and bathe your Puppy with mild cleaning soap and rinse with large amounts of water. If signs continue, check with a veterinarian promptly.
What can make Comfortis successful is spinosad — an component that assaults a flea’s anxious process. It kills all of the Grownup fleas in your dog. It can be done that fleas could reappear in your Pet dog following a several days of using Comfortis as these fleas are from the eggs laid ahead of the treatment. Because Comfortis incorporates a cycle of 30 days, it sooner or later kicks in and eliminates the remaining fleas.
While some individual dogs might have a bad reaction, most dogs don’t dog has fleas yahoo have problems with these products as long as you carefully follow the directions to be used.
So why are working with this product that may be this costly? When, you will get a better collar at a low cost. So I think you are just squandering your funds.
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PetLock II is actually a once-a-month topical flea treatment for dogs 7 weeks of age or more mature. PetLock II kills and controls all flea life ...stages. study extra
But you ought to ensure to proper collar for your Canine. Otherwise, it may be unsafe to your pet, mainly because your Pet or A further Pet can chew or licking that collar. Should you don’t pick the ideal collar, then your Pet dog will suffer from flea collar.
Flea medication remains successful & provides protection regardless of whether pet will get soaked. Advecta II is actually a effortless, quick-to-implement topical Alternative for the prevention and treatment of fleas on dogs 7 weeks of age and more mature.
No. Wetting the collar will not likely impair its success, and it is not essential to get rid of the collar In the event the Canine is out in the rain.
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domain: pet


text:
Hear ye this word which I take up against you.
The end of carnal security
Such words as these must have fallen like a thunderbolt into the midst of the corrupt and careless inhabitants of Samaria and the other cities of Israel among whom Amos prophesied. It is a dirge or lamentation, uttered by one who sees beyond the present prosperity of the land the future ruin of its proud idolaters.
I. Carnal security. Nothing about sin is more wonderful to the awakened soul than that blindness which hides from the ungodly the awful future. Noah’s generation, on the eve of that signal punishment of the deluge, saw no sign of peril (Matthew 24:39). The same spirit marked the society of Amos’s time. The sinners forgot all fear. They lived in careless ease in their winter houses and summer houses, enjoying all manner of luxury, and no fear of God or man disturbed their rest, or made them pause either in oppression or idolatry. Such is the prevailing spirit of sin. It hills the soul to sleep till suspicion of danger scarcely ever comes to darken the spirit; like the little sailor lads who fell asleep on deck during the roar of the cannon in the great battle of the Nile, none of the dangers rouse them to seek safety (Philippians 3:19).
II. God’s way of breaking this security is by revealing its end. At every turn of this prophecy our wonder at the tact and resource of the prophet seems to grow. His Master took him aside to show him the future, and then, with those awful sights before his eyes, sent him forth to utter his solemn dirge over the vanished glories of the nation. What an effect such revelations must have had on all who were willing to understand their meaning. “The virgin of Israel is fallen”--she who was now adorned with tabrets and joined in the dances of those that made merry (Jeremiah 31:4), should soon lie prostrate, not to rise again, forsaken of all her friends, and without any to lift her up or comfort her--none of her sons left to guide her, or take her by the hand in this day of calamity (Isaiah 51:18). Her glory gone, her pride humbled, her resources cut off. This is the picture of the end of that false security. It is accompanied by God’s message (verse 3), which give added terror to this revelation. A general decay similar to that mentioned in chap. 2:14-16 should fall upon the cities of the land. Application. Remember that sin blinds men’s eyes. The god of this world has no hope of retaining his power save by blinding the eyes of them that believe not. Remember that warning voices are God’s messengers. (J. Telford, B. A.)

domain: literature


The death core metal band hailing from France known as STENGAH formed back in 2013 have revealed their debut single “Above Inhumanity” and you can view the in your face melting track here. STENGAH bring the riffs along with the face melting vibe I speak of that you expect from a true hardcore metal band and fans from around the world are taking note. The single “Above Inhumanity” released via Mascot Records / Mascot Label Group is a fragment of a full set we called ‘The Mosaic Session’ Founded by drummer Eliott Williame, STENGAH have the sound, the smarts and the ambition to push heavy music ever further into the future. After years of steady evolution and meticulous attention to detail, the band – completed by bassist Benoit Creteur, lead guitarist Maxime Delassus, rhythm guitarist Alex Orta and powerhouse frontman Nicolas Queste – have honed their sound to a state of cutting-edge perfection.
With the world in chaos, exhilarating new music has become more important than ever before. As a result, the emergence of tech-metal mavericks STENGAH could hardly be better timed. One of the most exciting new bands on the planet, the French quintet have spent the last few years in a state of perpetual evolution, armed with some of the most visceral and forward-thinking riffs and refrains in recent memory. “The music is about (re)connecting with yourself,” says Eliott. “It’s about people, their fears, their faiths and their philosophies. How sometimes those things can guide them, and how sometimes they can blind them. It asks, with no judgement, about how odd and how strange the social and emotional behaviours of human beings are. It’s all about the power to believe, in creativity, and in consciousness.”
The video for “Above Inhumanity” acts out the story of a young woman haunted by the childish depiction of a ghost – herself in a parallel dimension. Trapped in a time loop, she awakes again to find a filmstrip containing a disturbing video of a ghost following her. The video projector turns out to be a gateway between both realms. The foreboding tale sees her awake where everything appears as it really is. They add, “It’s a dreamlike narrative that makes spiritual and physical realms collapse. A story where a hunter may be a prey, and the prey a monster…” With this project we wanted to go further than just a live performance. We wanted the venue to be part of the show. The improbable fusion of a room entirely made of mosaic with our own musical mosaic ; the wide diversity of our tones and the myriad of musical genres that influence the band.
This one of a kind session was an awesome and very challenging capture made possible thanks to our epic team directed by Samuel Petit for the video and Thomas Jankowski for the acoustical engineering. The result offers a unique intimate and immersive live show with a very massive sound carried by the breathtaking echo of the room and the band in a state of trance. The band has opened many eyes across the globe and the response is overwhelming. This is a must see band once they head out on tour until then you can preorder the heart penetrating music here.
To view live performance video of Above Inhumanity click here:


Alameda County supervisors have whittled down the list of candidates to fill the District 2 seat. But not by much. Instead of eight there are now five after a brief board vote during a surprisingly short and empty special meeting Tuesday afternoon.
Newark Councilmember Ana Apodaca garnered the most votes -- one each from the board's four sitting members. The tally qualified her to move to the interview phase of the process.
The supervisors could vote for more than one candidate and decided to interview the runners-up. Those included Union City Mayor Mark Green, who is also running for state Assembly and did not appear at Tuesday's meeting. He received one vote from District 1 Supervisor Scott Haggerty. Haggerty, District 4 Supervisor Nate Miley and District 3 Supervisor Wilma Chan each gave former Union City councilman and mayoral hopeful Richard Valle a vote.
Political newcomer Sheryl Grant, a technology sales executive and community volunteer, received votes from District 5 Supervisor Keith Carson and Miley.
Carson also voted in favor of retired District 2 Supervisor Gail Steele, who has pledged not to seek election to the seat in November. Steele, a Hayward resident, held the seat from 1992 through 2010, with electoral victories over both Valle and Green.
She said she decided to compete for the appointment to "level the playing field" in November and restore confidence in the supervisor representing Hayward, Union City, Newark,
"Our community has had a lot to deal with," Steele said Tuesday.
She was referring to the resignation of Nadia Lockyer last month amid scandalous revelations about drug abuse and an affair with a meth addict.
The caretaker supervisor will serve through the November general election, when District 2 voters will elect a new supervisor to serve out the remaining two years of Lockyer's term.
The appointment could give the caretaker supervisor an inside track to winning the November election for District 2.
This time, Miley predicted, "The voters of District 2 are going to be very on their toes with who they elect."
In addition, candidates can no longer accept donations larger than $20,000 total from any one donor. That measure was taken after Lockyer's election, which was largely bankrolled by her husband, State Treasurer Bill Lockyer.
The next step is the May 29 interview, with supervisors scheduled to make the appointment June 5 and swear in their choice June 12.
"Next week we ask the questions," Miley said. "Today was not about who we're going to select."
Staff writer Matt Artz contributed to this report.


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Opium is one of the world’s oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many of their undesirable side effects (sedation, apnea and dependence) by binding to and activating the G-protein-coupled μ-opioid receptor (μOR) in the central nervous system. Here we describe the 2.8 Å crystal structure of the μOR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most GPCRs published to date, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the μOR crystallizes as a two-fold symmetric dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.
Opium extracts from the plant Papaver somniferum have been used for therapeutic and recreational purposes for thousands of years. Opioid alkaloids and related pharmaceuticals are the most effective analgesics for the treatment of acute and chronic pain. They also represent one of the largest components of the illicit drug market world-wide, generating revenue of approximately $70 billion in 2009, much of which supports crime, wars and terrorism (UNODC World Drug Report 2011). Intravenous use of opioid drugs is a leading cause of death by overdose in Europe and North America, and a major contributing factor to the worldwide AIDS epidemic.
Morphine and codeine are the main active opioid alkaloids in opium. In humans, they act on the central nervous system to produce a wide range of effects including analgesia, euphoria, sedation, respiratory depression, and cough suppression, and have peripheral effects such as constipation1. Gene disruption studies in mice show that the target for the majority of the effects of opioid alkaloids, whether beneficial or adverse, is the μ-opioid receptor (μOR)2. The μOR is a rhodopsin-like family A a G protein-coupled receptor having two closely related family members known as the δ and κ opioid receptors3. Hence, the μOR constitutes the main opioid target for the management of pain, acute pulmonary edema, cough, diarrhea and shivering1. However, opioid drugs are highly addictive, with the acetylated form of morphine, heroin, being the best-known example. Because of this, the clinical efficacy of opioid drugs is often limited by the development of tolerance and dependence.
While both beneficial and adverse effects are attributable to activation of the μOR, they appear to be mediated by different down-stream signaling and regulatory pathways. The μOR couples predominantly to Gi, the inhibitory G protein for adenylyl cyclase. μOR signaling through Gi is responsible for its analgesic properties4. Following activation, the μOR undergoes phosphorylation and subsequently couples to arrestins, which have both regulatory and signaling functions5. Studies suggest that ligands with the greatest addictive potential, such as morphine, promote interactions with Gi more strongly than they promote interactions with arrestins6. These studies suggest that it may be possible to develop safer and more effective therapeutics targeting the μOR.
To better understand the structural basis for μOR function we pursued a crystallographic study of this receptor using the T4 lysozyme (T4L) fusion protein strategy developed by Rosenbaum et al.7 (Supplementary Fig. 1). Using the in meso crystallization method, we obtained crystals and collected diffraction data from 25 crystals of Mus musculus μOR-T4L protein bound to the irreversible morphinan antagonist β-funaltrexamine (β-FNA). The structure was solved by molecular replacement from a 2.8 Å data set.
The lattice for the μOR receptor shows alternating aqueous and lipidic layers with receptors arranged in parallel dimers tightly associated through transmembrane (TM) helices 5 and 6. More limited parallel interdimeric contacts through TM1, TM2 and helix eight are observed between adjacent dimers (Supplementary Fig. 2).
As in other GPCRs, the structure of the μOR consists of seven TM alpha-helices that are connected by three extracellular loops (ECLs 1–3) and three intracellular loops (ICLs 1–3) (Fig. 1a). TM3 is connected to the ECL2 by a conserved disulfide bridge between C1403.25 (superscripts indicate Ballesteros-Weinstein numbers8) and C217. The morphinan ligand β-FNA (Fig. 1b, 1c) makes contacts with TMs 3, 5, 6, and 7 (Fig. 1a), and the electron density observed in the structure confirms previous data identifying the K2335.39 side chain as the site of covalent attachment9 (Fig. 1c, Supplementary Fig. 3).
The intracellular face of the μOR closely resembles rhodopsin with respect to the relative positions of TM3, TM5 and TM6 (Supplementary Fig. 4). Nevertheless, like the β2-adrenergic receptor (β2AR), there is no ionic bridge between the DRY sequence in TM3 and the cytoplasmic end of TM6. As with the β2AR, R1653.50 forms a salt-bridge with the adjacent D1643.49 of the DRY sequence. D1643.49 also engages in a polar interaction with R179 in ICL2, a feature that is similar to an interaction between observed between D1303.49 and S143 in ICL2 of the β2AR (Supplementary Fig. 4). In μOR, it has been shown that the mutation of T2796.34 to a lysine results in a constitutively active receptor10. This may be explained by a polar interaction observed in the crystal structure of μOR between T2796.34 and R1653.50 (Supplementary Fig. 4). This interaction may stabilize the receptor in an inactive state.
In most available GPCR structures, the ligand is partially buried within the helical bundle by more superficial residues in TM segments and ECL2. The most extreme examples are the M2 and M3 muscarinic receptors11,12, in which the ligand is covered with a layer of tyrosines (Fig. 2). This provides a structural basis for the very slow dissociation kinetics of muscarinic antagonists. For example, the dissociation half-life of the clinically used drug tiotropium at the M3R is 34.7 h while its dissociation constant (Kd) is 40 pM13. By contrast, the binding pocket for β-FNA in the μOR is largely exposed to the extracellular surface (Fig. 2a). This may explain why extremely potent opioids such as buprenorphine (Ki 740 pM), diprenorphine (Ki 72 pM), alvimopan (Ki 350 pM), and etorphine (Ki 230 pM) present rapid dissociation half-lives of 44 min, 36 min, 30 min14, and less than one minute15, respectively. Therefore, although the affinity of high affinity opioid ligands is comparable to tiotropium, the dissociation kinetics are considerably different. This feature of opioid ligands may explain why heroin overdoses are rapidly reversible by naloxone16. In addition, the extremely high potency and fast kinetics of etorphine agonism and diprenorphine antagonism allows for a system that is capable of rapid anesthesia and prompt reversal in veterinary use. As a result, etorphine is a preferred anesthetic (dose in the range of 5 to 20 μg/kg) for valuable racehorses and for captive and free ranging mammals17.
The μOR belongs to a subgroup of peptide GPCRs, and the closest published structure is that of the CXCR4 chemokine receptor18 (RMSD value of 1.35 Å). In the μOR the morphinan ligand β-FNA binds much more deeply than the small molecule CXCR4 antagonist IT1t and occupies a similar position as agonists and antagonists for the β2-AR (RMSD value of 1.52 Å) and other monoamine receptors (Fig. 2c).
There are 14 residues within 4 Å of β-FNA. Nine of these have more direct interactions with the ligand (Fig. 3a, b and c), and are conserved in κOR and δOR. D1473.32 engages in a charge-charge interaction with the amine moiety of the ligand and hydrogen bonds with Y3267.43 (both residues are strictly conserved in all the opioid receptor subtypes). While D1473.32 occupies the same position as the counter ion in aminergic receptors, a sequence comparison shows that it is not conserved in other peptide receptors. H2976.52 interacts with the aromatic ring of the morphinan group, but does not directly hydrogen-bond with β-FNA as has been previously suggested19. However, the electron density suggests the presence of two water molecules that are well positioned to form a hydrogen bonding network between H2976.52 and the phenolic hydroxyl of the morphinan group (Fig. 3b and 3c).
A direct comparison with the δOR sequence also shows that of the 14 residues within 4Å of the ligand, 11 are identical between μOR and δOR. The three differences are at μOR positions E229ECL2, K3036.58, and W3187.35, which are Asp, Trp, and Leu in the δOR, respectively. The substitution of leucine in δOR for W3187.35 is highlighted in Fig. 3d. W3187.35 was shown to be responsible for the binding selectivity of naltrindole, a δOR selective antagonist and of DPDPE ([D-Pen2,D-Pen5]Enkephalin), a δOR selective peptide agonist20. In particular, the point mutation W318L dramatically increases the affinity of both these ligands at the μOR. Positioning naltrindole (represented in Fig. 3d) into the μOR binding pocket by superimposition of its morphinan group on that of β-FNA shows that naltrindole would clash with the W318 side chain in μOR (Fig. 3d), while the leucine in this position of δOR would likely accommodate naltrindole without requiring structural rearrangement.
Endomorphins 1 and 2 are small peptides isolated from brain that were shown to have the highest affinity (low nM range) and the highest selectivity profile for the μOR receptor21. For instance, endomorphin 1 exhibits 4,000 and 15,000 fold selectivity for μOR over δOR and κOR, respectively21. Although little is known about the determinants of endomorphin binding, mutagenesis studies suggest that the μOR-selective synthetic peptide agonist DAMGO ([D-Ala2, N- MePhe4 ,Gly-ol5 ]enkephalin) occupies a space that overlaps with the β-FNA binding pocket but also extends beyond this site22. Sites of mutations that impair DAMGO binding include H2976.52 positioned near the bottom of the β-FNA pocket as well as K3036.58, W3187.35 and H3197.36 positioned above the β-FNA binding pocket (Supplementary Fig. 5). Given the residues involved in DAMGO binding to μOR, opioid peptides likely make both polar and non-polar contacts within the μOR binding pocket. This feature of opioid peptide binding is also reflected in the lack of a highly charged surface within the μOR binding pocket compared with that of the CXCR4 receptor18.
The structure of μOR shows receptor molecules intimately associated into pairs along the crystallographic two-fold axis through two different interfaces (Fig. 4a, b). The first interface is a more limited parallel association mediated by TM1, TM2 and helix eight with a buried surface area of 615 Å2 (Fig. 4d, Supplementary Fig. 6). The second and more prominent interface observed in the μOR crystal structure is comprised of TMs 5 and 6 (Fig. 4c). In this case, within each μOR-μOR pair, the buried surface area for a single protomer is 1492 Å2. This represents 92 % of the total buried surface between μOR-T4L molecules, indicating that the comparatively small 114 Å2 buried surface contributed by T4L is unlikely to drive the contact (Supplementary Fig. 7). This suggests that the pairwise association of receptor monomers may represent a physiological opioid receptor dimer or higher order oligomer, the existence of which is supported by previous biochemical, pharmacological and cell biological studies23.
Recent computational and biochemical studies have suggested the potential role of TM4 and TM5 in the interaction between δOR receptors24. More generally, oligomers have been observed for a large number of GPCRs (recently reviewed in 25). Some of these studies have shown that TM5 and TM6 peptides can disrupt dimers of the β2AR and V2 vasopressin receptor26,27, and recent crosslinking experiments with the M3 muscarinic receptor suggest a direct dimeric contact mediated by TM5 of each monomer28. The potential involvement of the alternative TM1-TM2-H8 interface in GPCR oligomerization has previously been suggested by several different biochemical studies (reviewed in 25) and, more recently, by the structure of opsin (3CAP)29. In the case of opioid receptors, it has been shown that a μOR-TM1 domain fused to a polybasic TAT sequence could disrupt the μOR/δOR interaction in the mouse spinal cord, resulting in an enhancement of morphine analgesia and a reduction in morphine tolerance30.
The more prominent interface observed in the μOR crystal structure is comprised of TMs 5 and 6 of each protomer arranged in a four-helix bundle motif (Fig. 5a). This interface is formed by an extensive network of interactions involving 28 residues in TM5 and TM6 (Fig. 5c, Supplementary Fig. 8). These surface packing interactions are highly complementary and are maintained all along the receptor membrane plane from the extracellular to the intracellular side of the μOR (Fig. 5 c, d). The T2796.34 residue described earlier as playing a role in maintaining the receptor in an inactive state is also part of the dimer interface, with the methyl of the threonine contacting I2565.62 of the adjacent protomer. It is thus tempting to speculate that dimerization of the μOR could have a role in regulating receptor signaling.
The observed dimer is of interest because of existing evidence for both homo- and heterodimers (or oligomers) involving the μOR31. It has been suggested that opioid agonists such as DAMGO and methadone reduce tolerance to morphine in vivo by facilitating morphine-induced endocytosis through μOR oligomerization32,33. These studies implicate allosteric interactions between a protomer bound to DAMGO or methadone and an adjacent protomer bound to morphine. Co-expressing μOR and δOR in cells results in pharmacologic profiles distinct from either receptor expressed alone34. Of interest, morphine is more efficacious in cells expressing both μOR and δOR in the presence of a δOR-selective antagonist, suggesting an allosteric interaction between μOR and δOR protomers35. Hetero-oligomerization between μOR and non-opioid receptors has also been reported23. For example, the α2a adrenergic receptor was shown to modulate receptor μOR structure and signaling36.
Consistent with a role for oligomerization in μOR function, we observed that the amino acids involved in the dimer interface display a high degree of homology with the δOR (Supplementary Fig. 9, 10). Replacing the residues of μOR with the corresponding residues from δOR would not be predicted to interfere with dimer formation (Supplementary Fig. 9, 10). This analysis also suggests that a μOR-δOR dimer could share the same interface. Interestingly, in the μOR TM5/TM6 dimer, the two binding sites are coupled through a network of packing interactions at the dimeric interface (Fig. 5b). This network could provide a structural explanation for the distinct pharmacological profiles obtained for μOR heterodimers and for the allosteric effects of one protomer on the pharmacological properties of the other. This dimeric interface thus provides potential insights into the mechanism of allosteric regulation of one GPCR protomer by the other.
Parallel dimers have also been observed in other GPCR crystal structures, most notably of CXCR4-T4L18. Interestingly, the CXCR4 dimer is also related by a two-fold rotational symmetry axis with a receptor arrangement similar but not identical to that seen in μOR (Supplementary Fig. 8). However, for the five different CXCR4-T4L crystal structures, the largest calculated contact area between the two CXCR4 protomers is smaller (1077 Å2 for 3OE0) than in the μOR structure (Supplementary Fig. 7) and it presents a comparatively less extensive network of interactions (Supplementary Fig. 8).
The dimeric arrangement o f μOR across the TM5-TM6 interface observed in the crystal structure would likely preclude either protomer from coupling to G proteins. This is based on structural changes in TM5 and TM6 observed in the recent crystal structure of the β2AR-Gs complex37. This is also consistent with the observation that inverse agonists stabilize β2AR oligomers, while the G protein Gs reduced the extent of oligomerization38. However, we were able to model an active structure of μOR in complex with G protein based on the crystal structure of the β2AR-Gs complex. Here, we observed that a tetramer formed by the association of two dimers through a TM5/TM6 interface would accommodate two G proteins in interaction with the two distal protomers (Supplementary Fig. 11). This model of an activated μOR-G protein oligomeric complex is highly speculative but is compatible with results from a recent biophysical study suggesting that the G-protein Gi remains associated with a μOR tetramer stabilized by the agonist morphine 39.
The μOR is perhaps the most economically important GPCR in terms of the combined legal and illicit drug market. While there are a number of effective drugs targeting the μOR on the market, the ideal agonist has yet to be developed. The structure of the μOR presented here provides the first high-resolution insight into a peptide receptor that can also be activated by small molecule agonist ligands, some of which are the oldest used drugs in human history. This structure will enable the application of structure-based approaches to complement more conventional drug discovery programs. In addition, it may provide novel insight into the role of oligomerization in GPCR function.
Previously crystallized GPCRs show little density for the poorly ordered amino and carboxy terminal domains. Although these domains are not critical for maintaining high ligand affinity, these flexible regions may inhibit crystallogenesis7. We therefore removed these regions in the receptor construct used for crystallography. Specifically, a TEV protease recognition site was introduced after reside G51 in the amino-terminus and the carboxy terminus was truncated after Q360. The short third intracellular loop of μOR, consisting of residues 264–269 was replaced with T4 lysozyme residues 1–161 in a manner described previously7. In order to facilitate receptor purification, a FLAG M1 tag was added to the amino-terminus and an octa-histidine tag was appended to the carboxy terminus. Finally, a proline residue was introduced N-terminal to the octahistidine tag to allow efficient removal of C-terminal histidines by carboxypeptidase A. For these studies, we utilized the Mus musculus μOR sequence because it expressed at higher levels. The mouse and human μOR share 94% sequence identity and there are only four residues in the resolved part of the structure that differ between mouse and human μOR. These include residues 66, 137, 187, and 306, which are all in the extracellular or intracellular loops of μOR and do not make contacts in the ligand-binding pocket. The final crystallization construct (μOR-T4L) is shown in a representative snake diagram in Supplementary Fig. 1a.
We compared the pharmacological properties of μOR-T4L to those of the wild-type receptor (Supplementary Fig. 1b; see below for methods details). Both constructs showed identical affinity for the radiolabeled antagonist [3H]-diprenorphine ([3H]DPN).
The μOR-T4L construct was expressed in Sf9 cells using the baculovirus system. Culture media was supplemented with 10 μM naloxone to stabilize the receptor during expression. Cells were infected at a density of 4×106 cells per mL and culture flasks were shaken at 27 °C for 48 hr. After harvesting, cells were lysed by osmotic shock in a buffer comprised of 10mM Tris-HCl pH 7.5, 1mM EDTA, 100 µM TCEP, 1 µM naloxone, and 2 mg/ml iodoacetamide to block reactive cysteines. Extraction of μOR-T4L from Sf9 membranes was done with a Dounce homogenizer in a solubilization buffer comprised of 0.5% dodecyl maltoside (DDM), 0.3% 3-[(3-Cholamidopropyl) dimethylammonio]-1-propanesulfonate (CHAPS), 0.03% cholesterol hemisuccinate (CHS), 20 mM HEPES pH 7.5, 0.5 M NaCl, 30% v/v glycerol, 2 mg/ml iodoacetamide, 100 μM TCEP, and 1 µM naloxone. After centrifugation, nickel-NTA agarose was added to the supernatant, stirred for two hours, and then washed in batch with 100 × g spins for 5 min each with a washing buffer of 0.1% DDM, 0.03% CHAPS, 0.01% CHS, 20 mM HEPES pH 7.5 and 0.5 M NaCl. The resin was poured into a glass column and bound receptor was eluted in washing buffer supplemented with 300 mM imidazole.
We utilized anti-FLAG M1 affinity resin to further purify μOR-T4L and to exchange the ligand to the covalent antagonist β-funaltrexamine (β-FNA). Nickel-resin eluate was loaded onto anti-FLAG M1 resin and washed extensively in the presence of 10 µM β-FNA. The detergent DDM was then gradually exchanged over 1 hr into a buffer with 0.01% lauryl maltose neopentyl glycol (MNG) and the NaCl concentration was lowered to 100 mM. Receptor was eluted from the anti-FLAG M1 affinity resin with 0.2 mg/mL FLAG peptide and 5 mM EDTA in the presence of 1 µM β-FNA. To remove the amino terminus of μOR-T4L, TEV protease was added at 1:3 w/w (TEV:μOR-T4L) and incubated at room temperature for 1 hr. Receptor was then treated with carboxypeptidase A (1:100 w/w) and incubated overnight at 4°C to remove the octa-histidine tag. The final purification step separated TEV and carboxypeptidase A from receptor by size exclusion chromatography (SEC) on a Sephadex S200 column (GE Healthcare) in a buffer of 0.01% MNG, 0.001% CHS, 100 mM NaCl, 20 mM HEPES pH 7.5, and 1 µM β-FNA. After size exclusion, β-FNA was added to a final concentration of 10 µM. The resulting receptor preparation was pure and monodisperse (Supplementary Fig. 12).
Purified μOR-T4L receptor was concentrated to 30 mg/mL using a Vivaspin sample concentrator with a 50 kDa molecular weight cut off (GE Healthcare) and crystallization was performed using the in meso method41. Concentrated μOR-T4L was reconstituted into 10:1 monoolein:cholesterol (Sigma) in a ratio of 1:1.5 parts by weight receptor:lipid mixture. Reconstitution was done by the two-syringe method41. The resulting mesophase was dispensed onto glass plates in 80 nL drops and overlaid with 700 nL precipitant solution by a Gryphon LCP robot (Art Robbins Instruments). Crystals grew in precipitant solution consisting of 30 – 38% PEG 400, 100 mM HEPES pH 7.0, 7.5% DMSO, and 300 mM lithium sulfate. Crystals were observed after 24 hours and grew to full size after 5 days. Typical crystals prior to harvesting are shown in Supplementary Fig. 2. Diffraction data were collected at Advanced Photon Source GM/CA-CAT beamline 23ID-D using a beam size of 10 µm. Due to radiation damage, the diffraction quality decayed during exposure. Wedges of 10–20 degrees were collected and merged from 25 crystals using HKL200042. Diffraction quality ranged from 2.4–3.5 Å in most cases. The structure of the μOR was solved by molecular replacement in Phaser43 using the CXCR4 receptor as a search model. We improved the initial model by iteratively building regions of the receptor in Coot44 and refining in Phenix45. We utilized translation libration screw-motion (TLS) refinement with groups generated within Phenix. Electron density suggested the presence of a cholesterol molecule and a monoolein lipid within the lipidic layer. These were subsequently incorporated into the model. To assess the overall quality of the final structure, we used MolProbity46. The resulting statistics for data collection and refinement are shown in Supplementary table 1. Figures were prepared in PyMOL47.
Membrane homogenates were prepared from Sf9 cells expressing either wild-type μOR or μOR-T4L. Membranes containing μOR or μOR-T4L were incubated with the opioid antagonist, [3H]DPN, for 1 h at 22 °C in 0.5 mL of binding buffer containing 75 mM Tris-HCl pH 7.4, 1 mM EDTA, 5 mM MgCl2, 100 mM NaCl. To determine the affinity for diprenorphine, we utilized [3H]DPN concentrations ranging from 0.1 to 13.5 nM. High concentrations of un-labeled naloxone (1 µM) were used to determine non-specific binding. To separate unbound [3H]-ligand, binding reactions were rapidly filtered over GF/C Brandel filters. The filters were then washed three times with 5 mL ice-cold binding buffer. Radioactivity was assayed by liquid scintillation counting. The resulting data were analyzed using Prism 5.0 (GraphPad Software Inc., San Diego, CA). [3H]-diprenorphine ([3H]DPN; specific activity: 55.0 Ci/mmol) was obtained from PerkinElmer Life Sciences (Waltham, MA).
We acknowledge support from INSERM (S.G.), from the Stanford Medical Scientist Training Program (A.M.), from the National Science Foundation (A.C.K.), from the Lundbeck Foundation (J.M.M), from the National Institutes of Health Grants NS028471 (B.K.K) and DA031418 (B.K.K and R.K.S), and from the Mathers Foundation (B.K.K. and W.I.W.).
Supplementary Information is linked to the online version of the paper at www.nature.com/nature.
Author Contributions A.M., A.C.K., and S.G. designed experiments, performed research and analyzed data. T.S.K. and F.S.T expressed and purified receptor. J.M.M. performed preliminary biochemical experiments with wild-type μOR. R.K.S. contributed to the effort of μOR crystallization and writing of the manuscript. W.I.W supervised diffraction data analysis and model refinement. L.P. built the tetramer model and helped with the analysis of the dimer interfaces. A.M., A.C.K., S.G., and B.K.K prepared the manuscript. S.G. and B.K.K supervised the research.
Coordinates and structure factors for μOR-T4L are deposited in the Protein Data Bank (accession code 4DKL).
The authors declare no competing financial interests.

domain: biology


text: Onychomycosis is a nail disease that causes at least half of all nail disorders. Onychomycosis is more likely to affect men than women and those over 60 years of age. People with diabetes or leukemia are also more likely to develop onychomycosis than the rest of the population due to poor blood circulation and a weakened immune system. Onychomycosis is a hard disease to treat. That is because the onychomycosis infection penetrates deep into the nails, making it difficult for topical treatments to reach them.


text:
Warning to workers: Your productivity tools may also be tracking your workplace productivity, and your bosses may not even know it. But as more workplace surveillance capabilities appear, legal experts warn that organizations must ensure their tools do not violate employees' privacy rights.
Glen Hymers, CISO and head of data protection at the U.K.-based charity Save the Children International, says adapting to a cloud-first environment requires extensive security measures, including automated monitoring.
Two vulnerabilities in Tesla's keyless entry system allowed researchers to clone a key fob and drive away with a Model X. The electric vehicle manufacturer is issuing over-the-air updates to fix the flaws, which allegedly center on a failure to validate firmware updates and a faulty Bluetooth pairing protocol.
With digital transformation come new applications and efficiencies in the cloud. But governance, visibility and access challenges also emerge. Ron Bennetan of Imperva shares strategies for improving data governance and security in the cloud.
The FBI has sent out a private industry alert warning about an increase in attacks using Ragnar Locker ransomware. The operators behind this crypto-locking malware have recently targeted companies that include EDP, Campari and Capcom, researchers note.
Google removed two Android apps made by Baidu, a Chinese company, from its Google Play store after security researchers found they were collecting and possibly leaking data that could have been used to track individuals.
What are the critical components of a strong enterprise cyber risk management program for healthcare entities? Bob Chaput, founder of security and privacy consulting firm Clearwater, outlines key factors in an interview about his new book on the topic.
The gang operating Trickbot is continuing its activities despite recent takedown efforts, rolling out two updates that make the malware more difficult to kill, according to the security firm Bitdefender.
Cybersecurity leaders are not immune to the forces of digital transformation. In fact, Nicolas Casimir, CISO EMEA with Zscaler, says the role is forever changed by the business and technologies evolutions we have seen in 2020.
The Telecommunications Security Bill introduced by the British government aims to set enforceable, minimum security standards for the nation's telecommunications providers, backed by penalties, including for any company that opted to use equipment from high-risk providers such as China's Huawei.

domain: news


text:
ASUS Republic of Gamers (ROG) has announced Zephyrus M (GU502), a laptop that blends style, portability, performance and value to create a device that’s equal parts gaming laptop and work machine. The slim‑bezel PANTONE® Validated display is available with a 240Hz refresh rate that is fit for esports champions, and exceptional colour accuracy for creators. NVIDIA® Optimus™ technology dynamically switches between integrated and discrete graphics to balance speed and battery life, while Intelligent Cooling combines hardware and software to optimize performance and acoustics.
Light and strong
At 1.9 kg, Zephyrus M is about 45% lighter than the average 15‑inch laptop, making it extremely portable. Its profile slims down to 18.9 mm, and ultraslim bezels around the display keep the footprint as compact as possible, so it slips easily into backpacks and bags.
The durable chassis incorporates magnesium alloy, which is lighter than aluminum but just as strong. A combination of die-casting and machining molds molten metal into the palm rests, which are reinforced by a honeycomb of hexagonal cells that increases strength and rigidity with minimal material. This hidden structure helps make the laptop feel more solid than its slim profile suggests.
Its black lid features a brushed finish, reflecting a distinctive Zephyrus design that combines perfectly with the understated exterior. A soft-touch coating on the palm rest adds comfort and is highly resistant to fingerprints and smudges, helping the laptop always look its best.
Zephyrus M features up to GeForce® RTX™ 2060 GPUs, and effective cooling allows the GPU to be clocked to up to 1435MHz at 90W with ROG Boost in Turbo Mode, ensuring fluid frame rates with detailed graphics across a wide range of genres. The GPU is based on the new NVIDIA Turing™ architecture, which combines upgraded CUDA cores for programmable shading with new RT cores for ray tracing and Tensor cores for AI acceleration. Together, they enable real-time reflections, shadows, and lighting effects that are more realistic than ever before. The powerful GPU can also speed up other tasks, like 3D modeling, video rendering, and other forms of content creation.
The display on Zephyrus M is calibrated at the factory to guarantee the PANTONE Validated colour accuracy required for serious creative work. The IPS-level display covers the full sRGB colour space over wide viewing angles that simplify sharing the screen with coworkers and friends. When it’s time to play, high refresh-rate options up to 240Hz enable insanely fast frame rates and silky-smooth gameplay, while a 3ms grey-to-grey response time keeps the picture crisp and devoid of unsightly motion blur.
The 15.6‑inch panel is neatly framed with slim 6.2 mm bezels on either side, and the narrow border works in tandem with the smooth visuals for a more immersive experience overall. Whether at home or the office, the HDMI 2.0b output and DisplayPort (via USB-C™) offer easy connections to external 4K UHD displays.
Pedal to the metal
Zephyrus M is powered by an Intel Core i7-9750H processor with six cores and 12 threads capable of running at clock speeds as high as 4GHz. With so many available parallel threads, it’s not a problem to game and simultaneously broadcast a high-quality stream, or run video rendering in the background while surfing the web or creating a presentation.
In addition, Zephyrus M comes with up to 32GB of DDR4-2666 memory, and has dual NVMe SSDs in a RAID 0 configuration for superfast storage.
Intricate cooling system
ROG adopted an Intelligent Cooling philosophy for Zephyrus M to keep clock speeds high and temperatures low whether in the middle of an epic gaming marathon or processor‑intensive rendering.
Inside the chassis, an intricate thermal module draws heat away from key components. The CPU and GPU each have their own dedicated heatsinks and pipes on either side of the machine, and dual heatsinks at the back that are shared by both chips and the circuitry feeding them power. The heatsink fins measure just 0.1 mm thick, so more of them can be stacked to increase the surface area available to dissipate heat. Even at higher densities, the fins are thin enough to lower resistance to airflow generated by dual n-blade fans. The n-Blade fans pack 83 razor-thin blades apiece. Each blade is 33% thinner than conventional designs, and in order to survive spinning at the required speed they are made from an exceptionally strong liquid-crystal polymer.
To prevent dust from building up in the heatsinks and fans, the housings have a self-cleaning design. Anti-dust tunnels use centrifugal force to collect and expel particles out the back, which helps to maintain consistent cooling that enables top performance and reliable stability over time.
Performance and cooling requirements often change based on the task at hand, so Zephyrus M offers Silent, Balanced and Turbo modes tuned for different needs, adjustable with a convenient keyboard shortcut or with the ROG Armoury Crate software.
Charge into battle
Away from the gaming arena, Zephyrus M has the battery life to get users through the work day. One key is Optimus, a switching technology that reverts to the integrated Intel GPU when the need for graphics power is low, allowing the system to conserve power by shutting down the discrete GeForce GPU completely. Using the processor’s integrated graphics for lighter workloads lets Zephyrus M maximize its 76Wh battery.
Zephyrus M has a 230W power adapter, but when out and about and only engaged in lighter work like everyday productivity, mobility can be maximized by leaving the bigger adapter at home and carrying a standard USB-C charger up to 65W. USB-C chargers are lighter and more compact, and can be used to charge other USB-C devices like the ROG Phone.
Zephyrus M can also be charged from compatible USB power packs like the ZenPower Pro PD. USB Power Delivery also works for charging devices from the laptop, so users can quickly top up their phone without carrying a separate adapter.
In addition to USB-C, three USB Type-A ports offer ample connectivity for external storage or a gaming mouse.
An unforgettable sound
Audio is a crucial element of the entertainment experience that’s so often overlooked by laptops. But backed by an ESS SABRE Hi‑Fi DAC, Zephyrus M delivers impressive sound, even via headphones. This setup lowers total harmonic distortion, so sound remains clear as the volume is turned up. The DAC’s signal-to-noise ratio and dynamic range far surpass those of common codecs, granting extra clarity even when explosions are booming and bullets are flying. Activating the 7.1-channel virtual surround-sound heightens immersion by putting the user right into the middle of the action.
Zephyrus M provides multiple options for getting online. Gigabit Ethernet delivers the low-latency wired connection needed for competitive play, while ROG RangeBoost technology bolsters the wireless link when roaming freely. It evaluates the signal strength of four internal antennas and uses the best pair based on the environment, an on-the-fly adjustment that can help extend range by up to 30%. The gigabit-class Intel 2×2 Wi-Fi 5 (802.11ac) boasts a peak theoretical bandwidth of 1.7Gbps[i], allowing for easy large files transfers at speed.
Key in on victory
The keyboard on Zephyrus M has RGB lighting compatible ASUS Aura Sync peripherals. Distinctive colours and effects can flag important bindings for games and shortcuts for workflows. If desired, the look can be incredibly subtle, while 10 preprogrammed effects quickly get a light show going.
The keyboard features a familiar desktop-style layout, grouping the F-keys in smaller sets and then spacing those out to make it easier to quickly find shortcuts. A distinct arrow key block speeds up navigation, while dedicated hotkeys make vital volume and microphone mute controls easy to reach. N-key rollover registers every key press, no matter how many keys are simultaneously mashed, so inputs are precise. Key presses even trigger slightly quicker thanks to ROG Overstroke technology that actuates early in the key travel.
The definition of equilibrium
Lightweight and powerful, Zephyrus M GU502 teams the latest Core i7 CPU and GeForce graphics with amazingly fast and accurate displays to create an incredibly formidable crossover laptop. Slim and serious enough to stow away in a work bag, it still has the graphics prowess for high frame rates. Whether for work or play, Zephyrus M is more than ready for the challenge.
AVAILABILITY & PRICING
ROG Zephyrus M GU502 will be available in Q2 2019. Please check with your local representative for details on pricing and configurations.

domain: design


text:
Marriage equality advocates have called for LGBTI representation on the review of religious freedom in Australia announced by Prime Minister Malcolm Turnbull.
On Wednesday, Turnbull likely cleared the way for same-sex marriage legislation to be passed by Christmas with the separate review into “whether Australian law adequately protects the human right to religious freedom”.
The review will report by March 2018 and will be headed by former Howard Government minister Phillip Ruddock, who introduced the amendment that explicitly banned the recognition of same-sex marriages from the Marriage Act in 2004.
Turnbull said “a variety of proposals for legislative reform to protect freedom of religion” had emerged during the same-sex marriage postal survey.
He said many of the proposals went beyond the “immediate issue of marriage” and any reforms to “protect religious freedom at large should be undertaken carefully.”
“There is a high risk of unintended consequences when Parliament attempts to legislate protections for basic rights and freedoms, such as freedom of religion,” he said.
“The Government is particularly concerned to prevent uncertainties caused by generally worded Bill of Rights-style declarations.”
Ruddock will conduct the review with an expert panel consisting of Australian Human Rights Commission president Rosalind Croucher, retired federal court judge Annabelle Bennett and Jesuit priest Frank Brennan.
“There are broad human rights that we protect — and are very committed to — and one wouldn’t expect that endorsing freedom of religion would endorse a breach of other human rights,” Ruddock told the ABC.
Just.equal spokesperson Rodney Croome said religious freedom is “too often used as an excuse for discriminating against LGBTI people” and LGBTI representation on the review was “vital”.
“The panel members who were announced today include human rights experts, but they are not necessarily familiar with the concerns of LGBTI Australians when it comes to how ‘religious freedom’ is used to undermine our equal rights and dignity,” Mr Croome said.
“The context of this review is the myth that marriage equality is at odds with religious freedom, and the subsequent push to roll back laws protecting LGBTI people from discrimination, so it’s vital there is an LGBTI panel member to ensure our community’s concerns are heeded.
“Genuine religious freedom must be respected and protected but it must never become a weapon to be wielded against vulnerable minorities.”
Liberal senator Dean Smith, whose same-sex marriage bill will be debated in the Senate in the coming weeks, said he “fully endorsed” the review.
“It is a well-considered pathway to guaranteeing a comprehensive discussion about the proper place for religious freedom in our legal architecture,” he tweeted.
His same-sex marriage bill includes exemptions to allow religious organisations and existing civil celebrants to refuse same-sex marriages.
Opposition leader Bill Shorten told the ABC Labor would consider the detail of the review but the party is “not interested in delaying tactics or extending discrimination”.
“If there is a way that we can deal with legitimate concerns about religious freedom in the new year, Labor has already said we will be highly constructive and respectful,” he said.

domain: sociology


Xiaomi’s Redmi brand just announced the Redmi K30 5G and 4G versions at an event in China, as it had promised. It packs a 6.67-inch Full HD+ 120Hz LCD screen with 4.38mm, dual-punch-hole screen with 91% screen-to-body ratio, thanks to 4.25mm ultra-narrow bottom frame. The K30 5G is the world’s first phone to be powered by the latest Snapdragon 765G with support for built-in 5G stand alone and non-stand alone (SA/NSA) sub-6GHz networks. The Redmi K30 4G is powered by Snapdragon 730G instead of Snapdragon 765G and lacks 5G support.
It has 5mm copper tube liquid cooling to the temperature of the phone by up to 7 degrees, and runs Android 10 with MIUI 11 on top. The K30 is also the world’s first smartphone to pack Sony IMX686 64-megapixel 1/1.7″ sensor, and it has an 8-megapixel ultra-wide-angle lens, 5-megapixel (2-megapixel in K30) 2cm super macro and a 2-megapixel camera for portrait shots. On the front there is a 20-megapixel camera along with a secondary 2-megapixel camera for portait shots.
The phone has a 3D curved frosted glass body with Corning Gorilla Glass 5 protection, side-mounted fingerprint scanner and packs a 4500mAh battery with 30W Flash Charge fast charging with new charging architecture with charging conversion efficiency of up to 97% that can charge the phone in 1 hour, while the K30 4G comes with 27W fast charging.
Redmi K30 4G / 5G specifications
- 6.67-inch (1080 × 2400 pixels) Full HD+ 20:9 LCD screen with 120Hz refresh rate, HDR 10, Corning Gorilla Glass 5 protection
- K30 5G — Octa Core (1 x 2.4GHz + 1 x 2.2GHz + 6 x 1.8GHz Kryo 475 CPUs) Snapdragon 765G 7nm EUV Mobile Platform with Adreno 620 GPU
- K30 4G — Octa Core (2.2GHz Dual + 1.8GHz Hexa) Snapdragon 730G 8nm Mobile Platform with Adreno 618 GPU
- 6GB LPDDR4X RAM with 64GB / 128GB (UFS 2.1) storage, 8GB LPDDR4X RAM with 128GB / 256GB (UFS 2.1) storage expandable memory up to 512GB
- Android 10 with MIUI 11
- Hybrid Dual SIM (nano + nano / microSD)
- 64MP rear camera with LED Flash, Sony IMX686 sensor, 0.8μm, f/1.89 aperture, 8MP 120° ultra-wide sensor with 1.12μm, f/2.2 aperture, 2MP depth and 5MP (2MP in K30) macro sensors with 1.75μm, f/2.4 aperture, 4K 30fps, 960 fps at 720p
- 20MP front-facing camera, 2MP secondary camera with 1.75μm for portrait
- Side-mounted fingerprint sensor, IR sensor
- 3.5mm audio jack, FM Radio, 1217 Linear Speaker, Smart PA
- Dimensions: 165.3×76.6×8.79mm; Weight: 208g
- 5G SA/ NSA (Optional) / Dual 4G VoLTE, WiFi 802.11 ac (2.4GHz + 5GHz), Bluetooth 5, Dual-frequency (L1+L5) (K30 5G), GPS/GLONASS/Beidou, NFC, USB Type-C
- 4500mAh (Typical) / 4400mAh (Minimum) battery with 30W (K30 5G) flash / 27W (K30) fast charging
The Redmi K30 comes in White, Blue Red and Purple colors. The Redmi K30 4G version will be available in China from December 12th and the Redmi K30 5G will go on sale from January 2020. Pricing as follows.
- Redmi K30 4G 6GB + 64GB — 1599 yuan (US$ 227 / Rs. 16,100 approx.)
- Redmi K30 4G 6GB + 128GB — 1699 yuan (US$ 241 / Rs. 17,120 approx.)
- Redmi K30 4G 8GB + 128GB — 1899 yuan (US$ 269 / Rs. 19,120 approx.)
- Redmi K30 4G 8GB + 256GB — 2199 yuan (US$ 312 / Rs. 22,140 approx.)
- Redmi K30 5G 6GB + 64GB — 1999 yuan (US$ 284 / Rs. 20,125 approx.)
- Redmi K30 5G 6GB + 128GB — 2299 yuan (US$ 326 / Rs. 23,145 approx.)
- Redmi K30 5G 8GB + 128GB — 2599 yuan (US$ 369 / Rs. 26,165 approx.)
- Redmi K30 5G 8GB + 256GB — 2899 yuan (US$ 227 / Rs. 29,200 approx.)


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Darksiders II14 Aug 2012
Thane's Side Quests: The Maker's Warrior - Part 1
Thane has a bone to pick with a few creatures in the world of Darksiders II. After losing a friendly battle with Death, Thane asks Death to put an end to certain foul creatures that plague the worlds. Gorewood, Bheithir, Achidna, and the Deposed king are his targets. Take them down and Thane will forever see Death as a true warrior. NOTE: Achidna is part of the main story line and will be a mandatory boss fight.

domain: entertainment


Fujisan Station in July 2011
|Location||2-5-1 Kamiyoshida, Fujiyoshida, Yamanashi
|Operated by||Fuji Kyuko|
|Distance||23.6 km from Ōtsuki|
|Opened||19 June 1929|
|Previous names||Fuji-yoshida (until 2011)|
|Passengers (FY1998)||1,693 daily|
Fujisan Station (富士山駅 Fujisan-eki?) is a railway station on the Fujikyuko Line in Fujiyoshida, Yamanashi, Japan, operated by the private railway operator Fuji Kyuko (Fujikyu). The station is located at an altitude of 809 metres (2,654 ft). This is one of the gateway stations to Mount Fuji and Fuji Five Lakes, including Lake Kawaguchi and Lake Yamanaka.
|1||■ Fujikyuko Line||(not used)|
|2||■ Fujikyuko Line||for Kawaguchiko|
|3||■ Fujikyuko Line||for Ōtsuki|
|Shimoyoshida||Fuji Tozan Densha||Fujikyu-Highland|
In fiscal 1998, the station was used by an average of 1,693 passengers daily.
- Hibarigaoka High School
- Yoshida Junior High School
- Yoshida Elementary School
- National Route 137
- National Route 139
- Chūō Kōsoku Bus; For Shinjuku Station
- For Tokyo Station
- For Shibuya Station (Shibuya Mark City)
- Chūō Kōsoku Bus; For Seiseki-sakuragaoka Station, Tama-Center Station, and Minami-ōsawa Station
- For Ikebukuro Station, Kawagoe Station, and Ōmiya Station
- Airport Limousine; For Shinagawa Station and Haneda Airport
- Airport Limousine; For Akihabara Station and Narita International Airport
- Resort Express; For Nagoya Station
- For Nyūkawa and Takayama Station
- For Fukui Station (Fukui), Komatsu Station and Kanazawa Station
- Fujiyama Liner; For Kyoto Station, Osaka Station, Namba Station (OCAT), and Ōsaka Abenobashi Station
- Hakata-Fujiyama Express; For Kokura Station, Nishitetsu Fukuoka Station (Tenjin), and Hakata Station
- 各駅のご案内 [Station information] (in Japanese). Japan: Fujikyuko. 30 June 2011. Retrieved 2 March 2012.
- Terada, Hirokazu (July 2002). データブック日本の私鉄 [Databook: Japan's Private Railways]. Japan: Neko Publishing. p. 220. ISBN 4-87366-874-3.
- 水戸岡鋭治氏、次は富士吉田の市街地をリニューアル!? - 富士山駅誕生式典 [Fujisan Station Opening Ceremony - Eiji Mitooka: Next plan is to renovate the town of Fujiyoshida?]. Mynavi News (in Japanese). Japan: Mynavi Corporation. 2 July 2011. Retrieved 22 August 2012.
- 富士山を発着する高速バス - 富士急行バス [Highwaybuses from Fujisan - Fuji Kyuko Bus] (in Japanese). Japan. Retrieved 15 January 2016.
|Wikimedia Commons has media related to Fujisan Station.|


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Hello! I wanted to share some great projects shared at our Stampin' Smile group meeting last night. There were some great swaps and MaryAnn taught us how to make some really neat things that I will surely make again in the future! Thanks, Mary Ann!
Here's Heid's flip-flop card. I'm really not sure if that's the "official" name, but that's what it does, so that's what I'm calling it... :)
Reina made this card perfect for Father's Day using the spotlight technique. There's even a slot to put a gift card from Dad's favorite place!
Here's mine, I cased it from the new catalog...It uses the new "Petal Prints" stamp set that was part of our pillow gift while on the Caribbean Cruise! Stampin' Up! sure knows how to spoil us!
And here is a cute holder that MaryAnn taught us how to make. It can be used to hold note paper, cards, Post-Its...It's very versatile as it can be decorated for any theme. She also made a collection of cards to put in it using the Level I Hostess Set "It's the Thought". Receive this set FREE when you host a workshop of $150 or more. Here's the holder:
And here are close up photos of the cards...very simple and clean. These cards were colored with the Aqua Painter and re-inkers and dusted with a little bit of dazzling diamonds for that perfect touch!
We also used the watercolor technique to make pansies that we used as a focal point for our Fancy Favor Box and a beautiful flower to adorn a elegant card!
MaryAnn also taught us how to make this tea bag holder/dispenser made with the new Designer Series Paper Greenhouse Gala. As a demonstrator, we are able to order certain sneak peek items...It's wonderful! :) Do you know how much more onolicious ('ono' is yummy in Hawaiian) your tea will taste coming from such a beautiful dispenser? Unless you're like me and forever keep everything in tact as a "sample" in "The Collection". Hee, hee! Those of you who know what I'm talking about...Aren't we funny?! Oh, here's the photo... This box also uses our new Marina Mist 1/8" taffeta ribbon and Mini Vintage Tags.
I look forward to our monthly Stampin' Smile get-together where we swap, talk about Stampin' Up!, share a project--in this case several--and have a super time! If this sounds like something you would enjoy, we would love to have you in our Stampin' Smile group too! Now is a perfect time to join with the $99 special Stampin' Up is offering! Please contact me for details and/or visit my Stampin' Up! website.
If you would like to learn how to make any of the projects here, please let me know. If you would like to order any of the supplies to make these projects, I am happy to help you!


There is a growing need for ultra- low damage specimens below 40 nm thickness as researchers surpass boundaries of HR imaging and elemental analysis with transmission electron microscopes (TEM).
Image Credit: Shutterstock/anil Evskyi
While studying preparation techniques for these thin lamellae, factors to be considered include the class of the material being polished, and whether the technique is repeatable when applied across a range of samples. In this article, broad argon beam milling and focused ion beam milling (FIB) are discussed.
Techniques for Preparation of TEM Specimens
These two common methods are used to prepare electron transport specimens for a range of materials including metals, semiconductors and ceramics.
FIB is feasible in cases when there is a need for specific sample orientation or site specific positional accuracy. However, amorphization, implantation and vacancies due to application of high energy gallium ions, selective abrasion, surface roughness and sample alteration due to beam heating together with re-deposition, are certain damages that this technique causes.
Since FIB-induced surface amorphization reduces the signal-to-noise ratio, it is highly limiting and extensive. In order to avoid geometrical blurring for high resolution transmission electron microcopy (HRTEM) applications, sample thickness must be reduced by the square root of the feature size. A 25 KeV Ga+ FIB column can generate ~20 nm per specimen side damage in silicon (Si). In modern Si-based semiconductor devices, this can be limiting in cases where feature size is below 20 nm.
Approaches to Reduce Damage in TEM Samples
The depth of te FIB induced amorphous layer is based on beam angle, beam energy and material being milled. Some of the techniques used to limit this damage in TEM samples are:
- Gas-assisted etching - This method enhances the milling rate, however, it increases the roughness of crystalline-amorphous interface, which further damages TEM images.
- Low-energy FIB – Beam energy reduction brings down damage depth, though etching rate and positional resolution are also affected at these energies.
- Wet etching – Single-layered materials profit considerably when used with the right solution, but due to a varying etching rates, this technique cannot be used for multi-layer semiconductor devices.
- Argon ion milling – This is a highly promising technique for multi-layer materials, as none of the drawbacks mentioned are present. The original FIB damage layer is substituted by a newly formed Ar ion-induced damage layer. This layer thickness is based on the milling energy, angle and time, which are all parameters controlled by the user in the Gatan PIPS™ II System.
Practical Aspects of Argon Ion Polishing of FIB Specimens in PIPS II System
In order to optimize new layer thickness formed during Ar polishing of FIB-induced amorphous layer, while preventing re-deposition or specimen contamination, a number of parameters need to be considered:
- Beam energy – Low energy ions have a very shallow penetration depth, which reduces ion-induced surface damage. Beam energies lesser than 300 eV are recommended.
- Milling time – Since the Ar ion beam is well focussed at low energies in the PIPS II system (~ 1 mm FWHM), current density at the milling area is high, hence material removal rate is also high. Milling time needs to be optimized in order to remove enough material to enhance sample quality, but the specimen should not be over-thinned. The specimen must be milled for a few tens of seconds (<60 s), then checked in a microscope and milled further if needed.
- Milling angle: Even though it is known that a higher beam angle improves the ion induced surface damage, at low beam energies commonly used for this specific application (<0.5 keV), stopping and range of ions in matter (SRIM) models show that the sputtering yields are almost the same at high and low angles. Higher angles are more appropriate for post-FIB polishing in PIPS II System, in case of constraints from the mounting grid geometry. The chances of the thin areas causing lamella bending are reduced by milling from top and bottom.
- Sample temperature – For the prevention of heat-induced damage caused by ion bombardment, the stage (specimen) temperature is brought down to make sure that the milling area remains close to ambient temperature during milling.
- Ion milling mode – It has been observed that keeping the sample stationary and milling with just one gun at a time offers ideal results and the minimum amount of re-deposition (PIPS II Stationary milling mode).
- Type of supporting grid – Molybdenum (Mo) and Copper (Cu) are typical grid materials. The sputtering rate of Mo is low, reducing the chance of re-deposition from grid onto the FIB lamella.
- Position of FIB thinned area with respect to the milling gun – FIB specimens are either H-bars, or lift-out type (mounted on a grid fingertip or side wall). The sample is positioned at the PIPS II home position (Figure 1c) after mounting in the DuoPost™.
The thin lamella is brought to the center of rotation with the touch screen alignment page and X-Y stage movement available on the PIPS II System. The stage orientation angle is arranged such that the ion beam passes above the lamella prior to milling the grid or the substrate in order to minimise re-deposition. The PIPS II stage is rotated about 5° offset from the pre-set positions in the alignment page (Figure 2) for lift-out specimens placed on the side wall of the grid finger. While choosing this offset angle, remember that the Ar beam is 1 mm wide and not as small as the lamella.
Figure 1. PIPS II optical images of: (a) FIB H-bar sample and (b) FIB lift-out specimen mounted on the side wall of a Cu grid. (c) Top view cartoons show samples in home position as they are inserted in PIPS II System for post FIB polish.
Figure 2. Cartoons show how FIB H-bar and lift-out specimens are oriented with respect to the left and right guns. When lamella is mounted on the side wall of a grid finger, it is better to rotate the specimen at least 5° offset, so the beam does not deposit grid/substrate or weld material on the specimen thin area. Note that as shown in images on the right, the thickness of the lamella is much less than the grid, as a result the lamella can be welded at different positions on the finger.
It can be inferred from these examples that there was an improvement in the quality of FIB-prepared TEM samples and the FIB induced amorphous layer thickness reduced by applying low energy (<300 eV), broad beam ion milling in the PIPS II system. Lift- out samples were mounted on Mo or Cu OmniProbe grids. Imaging of specimens was performed before polishing in the PIPS II System as reference of the sample condition after FIB preparation.
Using low energy Ar ion guns in stages with sequential TEM observation, the samples were polished. Milling was carried out at incident angles >7° from either top or bottom. Using the PIPS II X-Y stage, the lamellae were centered and aligned with regards to each gun then milled with stationary milling mode. Samples were cooled during polishing in order to minimise heat induced damage (-80 °C). Figure 3 shows micrographs depicting removal of FIB produced amorphous surface layers in a Niobium sample.
Figure 3. Removal of FIB produced amorphous surface layers in a Niobium (Nb) sample can be readily seen in these micrographs. The right image shows changes after 30 seconds of milling at 300 eV. During this time, the amorphous layer was reduced from approximately 5.6 nm to 3.5 nm (~40% reduction). [FIB prepared specimen provided by University of Chicago, Illinois.]
Figure 4 shows TEM micrographs of a multi-layer sample as prepared in FIB.
Figure 4. TEM micrographs of a multi-layer sample as prepared in FIB (left), after polishing in PIPS II System at 300 eV for 60 seconds (center), after polishing in PIPS II System for additional 40 seconds (right). Due to FIB-induced amorphization, the second layer in the middle is not visible in the first two images (left and center), but after sufficient Ar ion polishing it is clearly visible in the last one (right). [FIB prepared specimen provided by Texas Instruments, Dallas Texas.]
Figure 5. Color images (left) show sample thickness maps* in the device, captured after milling in FIB (H-bar) and low energy milling in PIPS II System (300 eV beam, stationary milling mode, 130 seconds). Sample thickness is compared in these two images using profile lines averaged along the graph arrows shown below. TEM micrographs (right) show high resolution images taken before and after low energy ion milling in PIPS II System (taken from yellow square areas shown on the thickness maps). By reducing sample thickness, parts of FIB-induced sample surface damage have been removed. [FIB prepared specimen provided by Texas Instruments, Dallas Texas.]
Figure 6. TEM micrographs of a multi-layer sample. The left image was captured as prepared in FIB. The right image was taken after polishing in PIPS II System for 90 seconds. Due to FIB-induced amorphization, and sample thickness, layers are not clearly visible in the first image, however after Ar ion polishing they are clearly visible. The EELS data (right) shows no sign of re- deposition of grid material (Mo) on the sample.
FIB samples were effeciently polished at below 300 eV. This enhanced the sample quality without redepositing the holder material or the grid. This was possible due to innovative features such as the optical camera along with DigitalMicrograph™ Imaging Software, focused ion beams at low energies (~ 1 mm in diameter), X-Y alignment stage and custom milling angles in PIPS II System.
This information has been sourced, reviewed and adapted from materials provided by Gatan Inc.
For more information on this source, please visit Gatan Inc.


A world leader in marine water purification systems needed a next generation control unit with new LCD display and cloud application to monitor the status of their units.
Technologies Used: C, C++, Sqlite DB
Gadgeon team analyzed the flow diagrams supplied by customer for control application and developed the embedded Linux application C++ with following features
Web based control of the controller board including all functionalities provided by Linux application for monitoring and control. Included remote firmware upgrade feature.


by Ivanka Barzashka and Ivan Oelrich
A much anticipated IAEA report on Iran’s nuclear activities was leaked today. The report indicates that, among other things, Iran has conceded to additional safeguard at Natanz. This is a welcome development but occurring amidst a contested Iranian election, European threats of increased sanctions, continuing oblique hints of Israeli military action, and US talk of cutting off Iranian gasoline imports if nuclear talks are rejected. How important are these increased safeguards? Do they represent a change of course for Iran? Continue reading
|A high-security weapons storage area northwest of Karachi appears to be a potential nuclear weapons storage site. (click image to download larger version)
By Hans M. Kristensen
Pakistan’s nuclear weapons stockpile now includes an estimated 70-90 nuclear warheads, according to the latest Nuclear Notebook published in the Bulletin of the Atomic Scientists. The estimate is an increase compared with the previous estimate of approximately 60 warheads due to Pakistan’s pending introduction of a new ballistic missile and cruise missiles.
The increase in the warhead estimate does not mean Pakistan is thought to be sprinting ahead of India, which is also increasing its stockpile. Continue reading
By Matt Schroeder
The recent discovery of Swedish AT-4 anti-tank rockets sold to Venezuela in a Colombian rebel arms cache raises serious questions about Venezuela’s ability to safeguard its arsenal of modern weaponry, including dozens of advanced SA-24 shoulder-fired, surface-to-air missiles. Given the potential threat posed by these missiles and other weapons in Venezuela’s rapidly growing arsenal, the international community should take immediate steps to identify and close the gaps in Venezuela’s stockpile security and to ensure that the end-use monitoring conducted by states that export weapons to Venezuela is sufficiently robust.
According to Colombian authorities, Swedish anti-tank rocket launchers were found in October 2008 in an arms cache allegedly linked to the FARC. On July 27th, Colombian Vice President Francisco Santos asserted that “[i]n several operations in which we have recovered weapons from the FARC, we have found powerful munitions and powerful equipment, including anti-tank weapons, from a European country that sold them to Venezuela and that turned up in the hands of the FARC.” Thomas Samuelsson of the Swedish firm Saab Bofors Dynamics confirmed that the AT-4 rockets were manufactured and sold to Venezuela by his firm. The Venezuelan government responded harshly to Colombia’s revelation, calling it “laughable” and recalling the Venezuelan ambassador to Colombia.
This is not the first time that Colombian authorities have discovered Venezuelan weapons in rebel arms caches. In 2006, the Federation of American Scientists called attention to several reports of Venezuelan firearms acquired by the FARC, sometimes “…in lots of 50,” according to a demobilized guerrilla interviewed by Jane’s Information Group. In most of these cases, it is not clear what role, if any, that Venezuelan government officials played in the diversion. There is much speculation about the regime’s support of the FARC and its role in arms trafficking to the embattled rebel group, but verifying accusations of high-level complicity by the Venezuelan government based on information in the public domain is nearly impossible and, at one level, it doesn’t matter. The Venezuelan government is responsible for safeguarding the military’s arsenal and should be held accountable for any diverted weapons, regardless of the circumstances surrounding their diversion. The focus, therefore, should shift from the fruitless back-and-forth with Chavez over his regime’s alleged support for the FARC to identifying the specific sources of diverted weapons, bolstering Venezuelan stockpile security, and calling on states that arm Venezuela to closely monitor their exported weapons. Continue reading


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Bexhill College students questioned Sir Richard Jolly, Honorary Professor and Research Associate at the University of Sussex, on Wednesday 16th November.
The 82-year-old shared his wealth of knowledge and experience with the students, most of which who study social sciences and economics. Speaking about his achievements during the time he directed projects with UNICEF, Sir Richard recalled being part of an effort to prevent children dying from smallpox and measles in 1983.
He said: “I still smile at night thinking about that. It cost $300,000,000 but smallpox was eradicated in 11 years.”
Sir Richard was asked by students about current and future challenges the organisation faces. He added:
“One of the toughest challenges for the UN is in countries like Syria where my old colleague is working as a Preventive Diplomat.”
He referred to the Sustainable Development Goals which he's written about in his books. They are a series of targets set out by the UN to deal with global issues and meet human needs.
For students wishing to work for the United Nations in the future Sir Richard said it may be more difficult joining as a British male as they make up a large majority of workers but they offer a rewarding work experience and internship programme.
If you wish to apply for 2019-2020 academic year, please complete the online application form.