#bte without context

[mjfass]

BTE without context - part 3

[concerningwolves]

Hi, I wanted to ask under what circumstances would a deaf/HoH person choose not to use hearing aids at all? Would be a matter of physical comfort, a political statement, or something else entirely?

Hi, and thanks for the question (*^▽^*)

Why would someone choose not to use hearing aids?

The really short answer to your question is "all of the above, and more" – which is to say there are a lot of reasons why someone might choose not to wear hearing aids, and often more than one of those reasons can be true simultaneously.

Much like cochlear implants, hearing aids can carry a lot of baggage for d/Deaf people. Although they don't require an invasive surgical procedure, similar issues of personal and medical autonomy apply to them. (Here's a post where I broke down the various issues around cochlear implants; I recommend giving it a read, especially because it will give you a wider scope of d/Deaf opinions). So, yes, there absolutely can be a political element to a person's choice not to wear HAs, just as there may be a political element in the choice not to use implants – but that political element doesn't have to be a negative one.

A big part of Deaf culture is about the joy of being Deaf, and choosing not to wear hearing aids can be an extension of that. It's a celebration of our own languages, ways of communication, ways of interacting with the world, humour, history, and perspectives. I think it's very easy to fall into the trap of only thinking of Deaf culture as a "fuck you" to hearing society, and forgetting that it has its own merits. (I've definitely fallen into this trap myself).

Personally speaking, physical comfort is probably one of the biggest reasons why I don't wear my hearing aids. Having bits of plastic in my ears is a Very Bad combination with autism-related sensory issues. The type of hearing aid plays a big part in how they feel, though, so I can only speak for the comfort level of behind-the-ear (BTE) with earmould hearing aids. Have a look through deaf-centric social media forums like r/hardofhearing or r/hearingaids to find more input. As a starting point, here's a guide which explains the different types of hearing aids.

Related to physical comfort is the mental/emotional toll that hearing aids can take. The constant barrage of auditory information can be overwhelming for some people, especially if they're used to a much quieter or (mostly) silent world. Similarly, when you're deaf/hard of hearing, you're used to not hearing things. That's why questions like "how deaf are you?" are so hard to answer outside of a clinical context. If a hearing person suddenly had their hearing levels reduced to match mine, they would think their world got very quiet, but I've never known anything different, and I've been compensating (often subconsciously!) for this my entire life. Because this is what I'm used to, hearing aids feel pretty pointless for anything except specific uses (e.g., listening to music, or in combination with other assistive tech when I was in school). The rest of the time, I like my world as it is, and don't want to spend all my time being assaulted by a terrible aura of loudness.

Cost can also be a significant barrier between someone and hearing aids. I'm in the UK and eligible for hearing aids on the NHS, which means I also get my batteries for free, as well as some basic maintenance equipment. If my hearing aids ever broke, I'd be able to get an appointment to fix them free of charge (but only if the breakage were through no fault of mine, in which case I'd have to pay a fee of about £1,000, iirc). I was lucky that the kind of hearing aids the NHS offer were suitable for me – they typically only offer BTE and receiver in the ear (RITE) types, so if you needed a more specific type you would likely have to seek private treatment or go without.

To give some idea of the cost, assuming someone is paying out of pocket, they would need to pay for:

The hearing aid – cheaper models usually fall in the range of £500 and the pricier models can cost more than £3,500 (sometimes each, sometimes for a pair, depending on the seller). Different models have different specifications, so it's unlikely a person would be able to pick a cheaper hearing aid and hope it does the job. Children will need ear moulds replaced as they grow, and some types of ear moulds (like BTE) need to be custom-made.

Batteries – smallest pack size is six batteries per pack at around £1.70–2.50 depending on brand and battery size. A battery can last anywhere between 3–22 days depending on model and amount of use (when I was using my HAs regularly for school, my left one needed a new battery roughly once a week and my right one needed a new battery about twice a week).

Maintenance equipment – hearing aids need cleaning! There’s a pretty wide range of stuff they could use at varying price points. My hearing aid kit that I took to school contained an air puffer for removing condensation from the tube that connects the ear mould to the ear hook (essential, especially during hot weather!), an earwax brush (also essential), and sachets of wipes. The air puffer lasted me forever, but cleaning wires and brushes needed replacing fairly regularly. Tubing will sometimes need replacing too.

Appointments – they’d need to meet with an audiologist to be assessed and discuss options and then be fitted for ear moulds (where applicable; not always in the same appointment), and it can sometimes take several appointments before the hearing aids are tuned correctly. There may also be regular check-ups which involve hearing tests.

Extra equipment – there’s loads of extra equipment out there, ranging from adaptors that connect your hearing aids to a phone or TV (pricing starts around £100), to hearing aid receivers (£30–50 each, roughly), and FM hearing systems (anywhere between £120–1,900). I got an FM hearing system through the funding from the education system and it was revolutionary, but that funding was only there in first school and middle school.

So, as you can see, there’s a lot to consider financially as well. Obviously, I only know the situation in England firsthand, and pricing and availability of devices and equipment will vary around the globe (e.g., I’ve read that most medical insurance providers in the US won��t cover hearing aids).

Finally, hearing aids aren't suitable for every kind of hearing loss, or for every person. Some deafness is too profound and/or is related to some underlying cause that a hearing aid can't compensate for.

If anyone wants to weigh in with their reasons for not using hearing aids, that'd be really great :D

I hope that helps! For more on hearing aids, there's a whole bunch of stuff in my hearing aids tag.

[topflights]

how do the bucks have the courage to do this shit when jeff is right fuckin there. i want that confidence

[adampage]

Do you think it's possible that the BBC took out anyone they thought would potentially come to Hangman's aid??? To like. Make it SEEM like no one cares about or loves him anymore??? I just cannot see Dark Order NOT coming out to help him 😭😭

Or maybe I'm just being delusional and Hangy really did fuck up one of the only good friendships he had 😔😔

no, i definitely think it was intentional that they did it. mox was NOT happy about the loss to hangman, which he proved in the promo after revolution. further proof is the promo he cut before one of the first 3 matches on a Road To, where he said part of the reason he always wins is because he doesn’t like to lose. i think that quote is important too in the context of the elite as a whole. you can’t forget that mox has lost to very few men in AEW, and four of them are Hangman, Kenny, Nick, and Matt.

then there’s also the fact that bryan communicated his love for his friends out loud, something the elite never does on television. sure, on BTE. but even on BTE you have them miscommunicating all to hell. it’s definitely a jab at how the elite can’t ever get on the same page, emotionally.

they hurt Stu, Mox killed Uno at one point, they hurt Alex and John, they (likely) injured the Bucks, and then they took out Hangman to get to Kenny.

Now, Hangman walks out here on his own when he says something akin to “there’s no professional wrestler left in that locker room—,” just like how mox at the end of november said “there’s nobody back there, nobody within 100 miles that has the balls to take me on.” naturally, hangman answered both these calls. because he’s a fucking idiot and i think they’ve figured him out completely. just like he told punk that he would protect the aew locker room from him, he’s constantly coming out when there are wild insults made at the expense of his locker room. he is constantly putting himself in danger without back up.

do y’all remember when brodie cut that promo on hangman? how he is constantly without back up? how he doesn’t ever realise that the odds are against him? you remember when brodie said the dark order would protect him? at a bar or in the ring? that they would never leave him alone?

the dark order has always done that. if they weren’t taken out beforehand. i wonder if they’ll ever call back to those words one day, because it was such a powerful promo at the time. and i haven’t forgotten about the bucks/dark order segment on BTE around All Out last year, where they all spoke and buried the hatchet. i’d like to see them come together for real to protect him.

but i am just worried about how many eggs are being juggled here that i’m worried they’ll drop the ball on a few of them. i hope it ends up making sense, because i THINK it Does, but there’s a few pieces missing still.

back to the question, though. I DO think that them targeting his situation with his friends is very telling of where this will go. if hangman has no friends, he’s fucked.

[ijustthinkevilunoisneat]

BTE without context

[peacehunted]

Ind | Priv | HC--Based | Vash the Stampede | Trigun

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OPERATOR: Howdy! My friends call me Lucky (she/her, 30+). I'm a bit of a scatterbrained, anxious mess, but I'm always up to making new friends! I am open to most crossovers (it helps if I'm familiar with the fandom), OCs and AUs (with an accessible 'about' page OR some names I can later research myself), and duplicates of both my muse and others. Can't really say I'm even particularly protective of my headcanons and raw and unedited screenshots and gifs, so as long as our shared mutuals can still tell our blogs apart, go nuts! Only things that does require permission are edited graphics and my own artwork that may be posted here. This blog is also low activity and low maintenance, stress-free zone that's prone to some silliness (though some dark, 18+ topics will also be present given the source material), so I hope you enjoy your stay!

[dauntlcss]

( m, 26, est )  ─  the mirrors surrounding you did as they were meant to, reflecting back a spitting image of PETER GADIOT  -  but it’s clear something is wrong from the moment that a vision of JOINING THE WEST COAST AVENGERS WITH KATE BISHOP strikes you.  perhaps it was a passing daydream in the frenzy of the funhouse. you reassure yourself  -  you’re CLINT BARTON,  a THIRTY-FIVE YEAR OLD BARISTA AND PASTRY CHEF whose virtue lies in your + CHARMING & + CUNNING, although you’ve been told that you tend to be quite - RESENTFUL & - GLOOMY,  and you’re associated with THE SMELL OF FRESHLY BREWED COFFEE IN THE MORNING, EMPTY PIZZA BOXES ON THE KITCHEN TABLE, BAND-AIDS  ALWAYS COVERING YOUR FACE by those around you.  suddenly,  however,  you’ve found YOUR S.H.I.E.L.D. ID CARD on your person - was that always there? from the moment you leave the funhouse,  memories from your life in MARVEL COMICS have begun to return - leaving whoever you had been before in the mirror’s reflection behind you.  you can almost hear VOID by SEAHAVEN following in your wake.

graphic pictured above contains art from square enix.

LIFE IN ALUCARD —

NAME: Clinton Francis Barton-Barnes NICKNAME: Clint OCCUPATION: Barista & Pastry Chef at The Cat’s Meow ETHNICITY: Mexican-American NATIONALITY: American FACECLAIM: Peter Gadiot BIRTHDAY: June 18th AGE: 35 HEIGHT: 6’3” EYE COLOR: Blue HAIR COLOR: Blond SEXUALITY: Bisexual MARITAL STATUS: Married FAMILY: Harold Barton (father, deceased), Edith Barton (mother, deceased), Barney Barton (older brother), Bucky Barnes (husband), Lucky (family dog), Alpine (family cat) LANGUAGES KNOWN: English, ASL, Spanish NOTABLE FEATURES: Wears purple BTE hearing aids

Clint is the youngest son born to Harold and Edith Barton. They have one other son named Barney who is fifteen years older, which put a significant age gap between them. Their father was an angry man who never really wanted children. He preferred drinking to doing any parenting. He didn’t raise a hand to either of the boys but verbal abuse took place and the Barton household never felt like a home. Their mother tried her hardest to make it work.

Some events appear to be constant ��� the alcoholism leading to the death of Clint’s parents. Only the events that spiraled after that are different in this new life. He was only five years old, holding onto Barney’s hand at the funeral not understanding what was going on. “Where’s mama? Papa?” He would ask but not even the older Barton had the right answer. “It’s only going to be us from now on, kiddo.” He answered after kneeling down to be Clint’s level.

His brother was twenty, having held onto the same job for several years now and it paid well. He took on the responsibility of raising his little brother the best to his ability. They moved into a smaller apartment in Alucard and for a while they were happy. This was so the two of them wouldn’t be separated.

Few years later on his way home from school some older kids jumped him. Without getting into graphic details — the injuries from the beating was so extensive that it left him with head trauma. Barney was worried about his brother and how they were going to pay for his medical expenses. The doctor informs the oldest Barton that Clint lost 80% of his hearing which only made him worry that much more.

They don’t always see eye-to-eye but they’re the only family they both have left. Maybe that’s why the blonde puts up with the anger Barney feels toward him sometimes. You can usually find them signing angrily in the kitchen or living room. They do have their moments where it’s possible to get along but it usually doesn’t last.

Clint made a life for himself. He studied at a culinary institute to become a pastry chef. He knows that it wasn’t a requirement but wanted to take the extra step. It got him away from his brother since it was apparent they couldn’t live together anymore.

Three years ago, Clint got invited to attend an engagement party. One of his friends was getting married and seemed to invite everyone she has ever spoken to — renting out one of the bars in town. He didn’t know a lot of people there but wouldn’t miss out on such a joyous occasion. A few drinks into the night Clint saw the most handsome man he has ever laid eyes on standing across the room. He tried asking the person next to him if they knew the guy. “I’ve never met him but his name is Bucky, I think?” The blond repeated the name over and over in his head while handing the beer to his friend and pushing his way through the crowd. He went over there and introduced himself. He didn’t normally do this but something was telling him to try putting himself out there.

They dated for two years, moving in together in that timeframe. Clint even got a dog named Lucky from the local shelter. He’s missing his left eye and has been there for quite some time the volunteer told him. He didn’t need to know anything else and brought him home. Lucky is a smart dog and got along well with Bucky’s cat to the point they’re inseparable at times.

A little over a year ago, Clint and Bucky got married — the blond added on his husband’s last name to the end of his own. Barton-Barnes. They don’t show a lot of public displays of affection in public but you might see them holding hands. Anything more is usually kept for closed doors. They’re happy although Bucky hates Barney so when his brother stops into town that tends to create some tension if he wants to stay at their place. Bucky will even make Clint lunch to take into work! Which is always better than eating take out again.

Clint is working at The Cat’s Meow as a barista and pastry chef. He’ll work with Marinette on creating new recipe ideas for the menu sometimes. They have a little bit of a sibling dynamic going on, looking after her and always being there when she needs a shoulder to lean on. He couldn’t have picked a better place to work and will always appreciate Adrien for taking a chance on him.

Clint is deaf. If he doesn’t have his BTE hearing aids on he will need to rely on reading your lips or sign if your character happens to know ASL. It makes him really happy when people know sign language!

Not all of Spoken English can be lip-read, some words are incomprehensible. He can figure out what you’re saying by filling in the blanks with the words that were missed while lip-reading. He’ll use outside cues to figure out the context of which word is being used. Since a lot of sounds visually look similar such as. ‘th’ and ‘f’ sounds.

He doesn’t wear his hearing aids at night. You need to let them air out and keeping them in while you sleep could damage them if they fall out into your sheets or end up on the floor where you’ll step on them. They’re expensive and can cost up to six thousand dollars just for one. Clint has two so he wants to take care of them. They’re put on a charging station at night so the batteries can charge.

His hearing will NOT be perfect just because he’s wearing hearing aids. They’re AIDS not FIXES. He will miss parts of the conversation still and ask you to repeat yourself occasionally.

CANON LIFE —

ALIAS: Hawkeye, Agent Barton AFFILIATIONS: S.H.I.E.L.D., The Avengers OCCUPATION: S.H.I.E.L.D. Agent S.H.I.E.L.D. CLEARANCE LEVEL: Seven, Blue

Clinton Barton was the youngest son of Harold and Edith Barton. He grew up helping out around his fathers butcher shop with his older brother, Barney. Their mother was a sweet woman but she couldn’t protect them from what would happen when the whiskey was brought out. Harold was abusive and continually beat both of his boys. It got so bad that the injuries Clint suffered from damaged his hearing. He remembers sitting at the doctors office not being able to understand a word the doctor was saying or his parents.

Eventually his father’s alcoholism caused him to get into a car accident while Edith was in the car, costing both of them their lives. Clint and Barney were sent to numerous foster homes until running away from one of them to join a traveling circus instead. He would adapt his archery skills to become a star carnival attraction, a master archer called Hawkeye.  He spent some time as a member of Tiboldt’s Circus until leaving to try using his skillset for fighting crime.

Nick Fury would end up hand-picking Barton to join S.H.I.E.L.D. and he quickly became one of their very best agents. In addition to this Clint would also end up joining the Avengers and West Coast Avengers. He’s one of the best archers in the world and should not be underestimated for being Human.

The rest of his biography is pretty straight forward from here, if you want to know what kind of shenanigans his teams got up to then there are plenty of marvel fandom wiki pages to check out!

[abbkineeu]

New Post has been published on Biotech Advisers

New Post has been published on http://www.bioadvisers.com/optimizing-drug-combinations-multiple-myeloma-using-quadratic-phenotypic-optimization-platform-qpop/

Optimizing drug combinations against multiple myeloma using a quadratic phenotypic optimization platform (QPOP)

Content introduction:

Optimizing drug combinations against multiple myeloma using a quadratic phenotypic optimization platform (QPOP)

Laminin 511 is a target antigen in autoimmune pancreatitis

Thy-1 (CD90) promotes bone formation and protects against obesity

Profiling the origin, dynamics, and function of traction force in B cell activation

G protein signaling–biased agonism at the κ-opioid receptor is maintained in striatal neurons

1. Optimizing drug combinations against multiple myeloma using a quadratic phenotypic optimization platform (QPOP) Multiple myeloma is an incurable hematological malignancy that relies on drug combinations for first and secondary lines of treatment. The inclusion of proteasome inhibitors, such as bortezomib, into these combination regimens has improved median survival. Resistance to bortezomib, however, is a common occurrence that ultimately contributes to treatment failure, and there remains a need to identify improved drug combinations. Masturah Bte Mohd Abdul Rashid at National University of Singapore in Singapore and his colleagues developed the quadratic phenotypic optimization platform (QPOP) to optimize treatment combinations selected from a candidate pool of 114 approved drugs. QPOP uses quadratic surfaces to model the biological effects of drug combinations to identify effective drug combinations without reference to molecular mechanisms or predetermined drug synergy data. Applying QPOP to bortezomib-resistant multiple myeloma cell lines determined the drug combinations that collectively optimized treatment efficacy. They found that these combinations acted by reversing the DNA methylation and tumor suppressor silencing that often occur after acquired bortezomib resistance in multiple myeloma. Successive application of QPOP on a xenograft mouse model further optimized the dosages of each drug within a given combination while minimizing overall toxicity in vivo, and application of QPOP to ex vivo multiple myeloma patient samples optimized drug combinations in patient-specific contexts.

Read more, please click http://stm.sciencemag.org/content/10/453/eaan0941

2. Laminin 511 is a target antigen in autoimmune pancreatitis Autoimmune pancreatitis (AIP), a major manifestation of immunoglobulin G4–related disease (IgG4-RD), is an immune-mediated disorder, but the target autoantigens are still unknown. Masahiro Shiokawa at Kyoto University Graduate School of Medicine in Kyoto, Japan and his colleagues previously reported that IgG in patients with AIP induces pancreatic injuries in mice by binding the extracellular matrix (ECM). In the current study, they identified an autoantibody against laminin 511-E8, a truncated laminin 511, one of the ECM proteins, in patients with AIP. Anti–laminin 511-E8 IgG was present in 26 of 51 AIP patients (51.0%), but only in 2 of 122 controls (1.6%), by enzyme-linked immunosorbent assay. Because truncated forms of other laminin family members in other organs have been reported, they confirmed that truncated forms of laminin 511 also exist in human and mouse pancreas. Histologic studies with patient pancreatic tissues showed colocalization of patient IgG and laminin 511. Immunization of mice with human laminin 511-E8 induced antibodies and pancreatic injury, fulfilling the pathologic criteria for human AIP. Four of 25 AIP patients without laminin 511-E8 antibodies had antibodies against integrin α6β1, a laminin 511 ligand. AIP patients with laminin 511-E8 antibodies exhibited distinctive clinical features, as the frequencies of malignancies or allergic diseases were significantly lower in patients with laminin 511-E8 antibodies than in those without. The discovery of these autoantibodies should aid in the understanding of AIP pathophysiology and possibly improve the diagnosis of AIP.

Read more, please click http://stm.sciencemag.org/content/10/453/eaaq0997

3. Thy-1 (CD90) promotes bone formation and protects against obesity Osteoporosis and obesity result from disturbed osteogenic and adipogenic differentiation and present emerging challenges for our aging society. Because of the regulatory role of Thy-1 in mesenchyme-derived fibroblasts, Ann-Kristin Picke at Technische Universität Dresden in Dresden, Germany and his colleagues investigated the impact of Thy-1 expression on mesenchymal stem cell (MSC) fate between osteogenic and adipogenic differentiation and consequences for bone formation and adipose tissue development in vivo. MSCs from Thy-1–deficient mice have decreased osteoblast differentiation and increased adipogenic differentiation compared to MSCs from wild-type mice. Consistently, Thy-1–deficient mice exhibited decreased bone volume and bone formation rate with elevated cortical porosity, resulting in lower bone strength. In parallel, body weight, subcutaneous/epigonadal fat mass, and bone fat volume were increased. Thy-1 deficiency was accompanied by reduced expression of specific Wnt ligands with simultaneous increase of the Wnt inhibitors sclerostin and dickkopf-1 and an altered responsiveness to Wnt. They demonstrated that disturbed bone remodeling in osteoporosis and dysregulated adipose tissue accumulation in patients with obesity were mirrored by reduced serum Thy-1 concentrations. Their findings provide new insights into the mutual regulation of bone formation and obesity and open new perspectives to monitor and to interfere with the dysregulated balance of adipogenesis and osteogenesis in obesity and osteoporosis.

Read more, please click http://stm.sciencemag.org/content/10/453/eaao6806

4. Profiling the origin, dynamics, and function of traction force in B cell activation B lymphocytes use B cell receptors (BCRs) to recognize membrane-bound antigens to further initiate cell spreading and contraction responses during B cell activation. Junyi Wang at Tsinghua University in Beijing, China and his colleagues combined traction force microscopy and live-cell imaging to profile the origin, dynamics, and function of traction force generation in these responses. They showed that B cell activation required the generation of 10 to 20 nN of traction force when encountering antigens presented by substrates with stiffness values from 0.5 to 1 kPa, which mimic the rigidity of antigen-presenting cells in vivo. Perturbation experiments revealed that F-actin remodeling and myosin- and dynein-mediated contractility contributed to traction force generation and B cell activation. Moreover, membrane-proximal BCR signaling molecules (including Lyn, Syk, Btk, PLC-γ2, BLNK, and Vav3) and adaptor molecules (Grb2, Cbl, and Dok-3) linking BCR microclusters and motor proteins were also required for the sustained generation of these traction forces. They found a positive correlation between the strength of the traction force and the mean fluorescence intensity of the BCR microclusters. Furthermore, they demonstrated that isotype-switched memory B cells expressing immunoglobulin G (IgG)–BCRs generated greater traction forces than did mature naïve B cells expressing IgM-BCRs during B cell activation. Last, they observed that primary B cells from patients with rheumatoid arthritis generated greater traction forces than did B cells from healthy donors in response to antigen stimulation. Together, these data delineate the origin, dynamics, and function of traction force during B cell activation.

Read more, please click http://stke.sciencemag.org/content/11/542/eaai9192

5. G protein signaling–biased agonism at the κ-opioid receptor is maintained in striatal neurons Biased agonists of G protein–coupled receptors may present a means to refine receptor signaling in a way that separates side effects from therapeutic properties. Several studies have shown that agonists that activate the κ-opioid receptor (KOR) in a manner that favors G protein coupling over β-arrestin2 recruitment in cell culture may represent a means to treat pain and itch while avoiding sedation and dysphoria. Although it is attractive to speculate that the bias between G protein signaling and β-arrestin2 recruitment is the reason for these divergent behaviors, little evidence has emerged to show that these signaling pathways diverge in the neuronal environment. Jo-Hao Ho at The Scripps Research Institute in Jupiter, USA and his colleagues further explored the influence of cellular context on biased agonism at KOR ligand–directed signaling toward G protein pathways over β-arrestin–dependent pathways and found that this bias persists in striatal neurons. These findings advance our understanding of how a G protein–biased agonist signal differs between cell lines and primary neurons, demonstrate that measuring [35S]GTPγS binding and the regulation of adenylyl cyclase activity are not necessarily orthogonal assays in cell lines, and emphasize the contributions of the environment to assessing biased agonism.

Read more, please click http://stke.sciencemag.org/content/11/542/eaar4309

[abbkine]

BioAdvisers said on Biotech Advisers

Optimizing drug combinations against multiple myeloma using a quadratic phenotypic optimization platform (QPOP)

Content introduction:

Optimizing drug combinations against multiple myeloma using a quadratic phenotypic optimization platform (QPOP)

Laminin 511 is a target antigen in autoimmune pancreatitis

Thy-1 (CD90) promotes bone formation and protects against obesity

Profiling the origin, dynamics, and function of traction force in B cell activation

G protein signaling–biased agonism at the κ-opioid receptor is maintained in striatal neurons

1. Optimizing drug combinations against multiple myeloma using a quadratic phenotypic optimization platform (QPOP) Multiple myeloma is an incurable hematological malignancy that relies on drug combinations for first and secondary lines of treatment. The inclusion of proteasome inhibitors, such as bortezomib, into these combination regimens has improved median survival. Resistance to bortezomib, however, is a common occurrence that ultimately contributes to treatment failure, and there remains a need to identify improved drug combinations. Masturah Bte Mohd Abdul Rashid at National University of Singapore in Singapore and his colleagues developed the quadratic phenotypic optimization platform (QPOP) to optimize treatment combinations selected from a candidate pool of 114 approved drugs. QPOP uses quadratic surfaces to model the biological effects of drug combinations to identify effective drug combinations without reference to molecular mechanisms or predetermined drug synergy data. Applying QPOP to bortezomib-resistant multiple myeloma cell lines determined the drug combinations that collectively optimized treatment efficacy. They found that these combinations acted by reversing the DNA methylation and tumor suppressor silencing that often occur after acquired bortezomib resistance in multiple myeloma. Successive application of QPOP on a xenograft mouse model further optimized the dosages of each drug within a given combination while minimizing overall toxicity in vivo, and application of QPOP to ex vivo multiple myeloma patient samples optimized drug combinations in patient-specific contexts.

Read more, please click http://stm.sciencemag.org/content/10/453/eaan0941

2. Laminin 511 is a target antigen in autoimmune pancreatitis Autoimmune pancreatitis (AIP), a major manifestation of immunoglobulin G4–related disease (IgG4-RD), is an immune-mediated disorder, but the target autoantigens are still unknown. Masahiro Shiokawa at Kyoto University Graduate School of Medicine in Kyoto, Japan and his colleagues previously reported that IgG in patients with AIP induces pancreatic injuries in mice by binding the extracellular matrix (ECM). In the current study, they identified an autoantibody against laminin 511-E8, a truncated laminin 511, one of the ECM proteins, in patients with AIP. Anti–laminin 511-E8 IgG was present in 26 of 51 AIP patients (51.0%), but only in 2 of 122 controls (1.6%), by enzyme-linked immunosorbent assay. Because truncated forms of other laminin family members in other organs have been reported, they confirmed that truncated forms of laminin 511 also exist in human and mouse pancreas. Histologic studies with patient pancreatic tissues showed colocalization of patient IgG and laminin 511. Immunization of mice with human laminin 511-E8 induced antibodies and pancreatic injury, fulfilling the pathologic criteria for human AIP. Four of 25 AIP patients without laminin 511-E8 antibodies had antibodies against integrin α6β1, a laminin 511 ligand. AIP patients with laminin 511-E8 antibodies exhibited distinctive clinical features, as the frequencies of malignancies or allergic diseases were significantly lower in patients with laminin 511-E8 antibodies than in those without. The discovery of these autoantibodies should aid in the understanding of AIP pathophysiology and possibly improve the diagnosis of AIP.

Read more, please click http://stm.sciencemag.org/content/10/453/eaaq0997

3. Thy-1 (CD90) promotes bone formation and protects against obesity Osteoporosis and obesity result from disturbed osteogenic and adipogenic differentiation and present emerging challenges for our aging society. Because of the regulatory role of Thy-1 in mesenchyme-derived fibroblasts, Ann-Kristin Picke at Technische Universität Dresden in Dresden, Germany and his colleagues investigated the impact of Thy-1 expression on mesenchymal stem cell (MSC) fate between osteogenic and adipogenic differentiation and consequences for bone formation and adipose tissue development in vivo. MSCs from Thy-1–deficient mice have decreased osteoblast differentiation and increased adipogenic differentiation compared to MSCs from wild-type mice. Consistently, Thy-1–deficient mice exhibited decreased bone volume and bone formation rate with elevated cortical porosity, resulting in lower bone strength. In parallel, body weight, subcutaneous/epigonadal fat mass, and bone fat volume were increased. Thy-1 deficiency was accompanied by reduced expression of specific Wnt ligands with simultaneous increase of the Wnt inhibitors sclerostin and dickkopf-1 and an altered responsiveness to Wnt. They demonstrated that disturbed bone remodeling in osteoporosis and dysregulated adipose tissue accumulation in patients with obesity were mirrored by reduced serum Thy-1 concentrations. Their findings provide new insights into the mutual regulation of bone formation and obesity and open new perspectives to monitor and to interfere with the dysregulated balance of adipogenesis and osteogenesis in obesity and osteoporosis.

Read more, please click http://stm.sciencemag.org/content/10/453/eaao6806

4. Profiling the origin, dynamics, and function of traction force in B cell activation B lymphocytes use B cell receptors (BCRs) to recognize membrane-bound antigens to further initiate cell spreading and contraction responses during B cell activation. Junyi Wang at Tsinghua University in Beijing, China and his colleagues combined traction force microscopy and live-cell imaging to profile the origin, dynamics, and function of traction force generation in these responses. They showed that B cell activation required the generation of 10 to 20 nN of traction force when encountering antigens presented by substrates with stiffness values from 0.5 to 1 kPa, which mimic the rigidity of antigen-presenting cells in vivo. Perturbation experiments revealed that F-actin remodeling and myosin- and dynein-mediated contractility contributed to traction force generation and B cell activation. Moreover, membrane-proximal BCR signaling molecules (including Lyn, Syk, Btk, PLC-γ2, BLNK, and Vav3) and adaptor molecules (Grb2, Cbl, and Dok-3) linking BCR microclusters and motor proteins were also required for the sustained generation of these traction forces. They found a positive correlation between the strength of the traction force and the mean fluorescence intensity of the BCR microclusters. Furthermore, they demonstrated that isotype-switched memory B cells expressing immunoglobulin G (IgG)–BCRs generated greater traction forces than did mature naïve B cells expressing IgM-BCRs during B cell activation. Last, they observed that primary B cells from patients with rheumatoid arthritis generated greater traction forces than did B cells from healthy donors in response to antigen stimulation. Together, these data delineate the origin, dynamics, and function of traction force during B cell activation.

Read more, please click http://stke.sciencemag.org/content/11/542/eaai9192

5. G protein signaling–biased agonism at the κ-opioid receptor is maintained in striatal neurons Biased agonists of G protein–coupled receptors may present a means to refine receptor signaling in a way that separates side effects from therapeutic properties. Several studies have shown that agonists that activate the κ-opioid receptor (KOR) in a manner that favors G protein coupling over β-arrestin2 recruitment in cell culture may represent a means to treat pain and itch while avoiding sedation and dysphoria. Although it is attractive to speculate that the bias between G protein signaling and β-arrestin2 recruitment is the reason for these divergent behaviors, little evidence has emerged to show that these signaling pathways diverge in the neuronal environment. Jo-Hao Ho at The Scripps Research Institute in Jupiter, USA and his colleagues further explored the influence of cellular context on biased agonism at KOR ligand–directed signaling toward G protein pathways over β-arrestin–dependent pathways and found that this bias persists in striatal neurons. These findings advance our understanding of how a G protein–biased agonist signal differs between cell lines and primary neurons, demonstrate that measuring [35S]GTPγS binding and the regulation of adenylyl cyclase activity are not necessarily orthogonal assays in cell lines, and emphasize the contributions of the environment to assessing biased agonism.

Read more, please click http://stke.sciencemag.org/content/11/542/eaar4309

[mjfass]

BTE without context - part 2

[bioadvisers]

Bioadvisers shared on Biotech Advisers

Optimizing drug combinations against multiple myeloma using a quadratic phenotypic optimization platform (QPOP)

Content introduction:

Optimizing drug combinations against multiple myeloma using a quadratic phenotypic optimization platform (QPOP)

Laminin 511 is a target antigen in autoimmune pancreatitis

Thy-1 (CD90) promotes bone formation and protects against obesity

Profiling the origin, dynamics, and function of traction force in B cell activation

G protein signaling���biased agonism at the κ-opioid receptor is maintained in striatal neurons

1. Optimizing drug combinations against multiple myeloma using a quadratic phenotypic optimization platform (QPOP) Multiple myeloma is an incurable hematological malignancy that relies on drug combinations for first and secondary lines of treatment. The inclusion of proteasome inhibitors, such as bortezomib, into these combination regimens has improved median survival. Resistance to bortezomib, however, is a common occurrence that ultimately contributes to treatment failure, and there remains a need to identify improved drug combinations. Masturah Bte Mohd Abdul Rashid at National University of Singapore in Singapore and his colleagues developed the quadratic phenotypic optimization platform (QPOP) to optimize treatment combinations selected from a candidate pool of 114 approved drugs. QPOP uses quadratic surfaces to model the biological effects of drug combinations to identify effective drug combinations without reference to molecular mechanisms or predetermined drug synergy data. Applying QPOP to bortezomib-resistant multiple myeloma cell lines determined the drug combinations that collectively optimized treatment efficacy. They found that these combinations acted by reversing the DNA methylation and tumor suppressor silencing that often occur after acquired bortezomib resistance in multiple myeloma. Successive application of QPOP on a xenograft mouse model further optimized the dosages of each drug within a given combination while minimizing overall toxicity in vivo, and application of QPOP to ex vivo multiple myeloma patient samples optimized drug combinations in patient-specific contexts.

Read more, please click http://stm.sciencemag.org/content/10/453/eaan0941

2. Laminin 511 is a target antigen in autoimmune pancreatitis Autoimmune pancreatitis (AIP), a major manifestation of immunoglobulin G4–related disease (IgG4-RD), is an immune-mediated disorder, but the target autoantigens are still unknown. Masahiro Shiokawa at Kyoto University Graduate School of Medicine in Kyoto, Japan and his colleagues previously reported that IgG in patients with AIP induces pancreatic injuries in mice by binding the extracellular matrix (ECM). In the current study, they identified an autoantibody against laminin 511-E8, a truncated laminin 511, one of the ECM proteins, in patients with AIP. Anti–laminin 511-E8 IgG was present in 26 of 51 AIP patients (51.0%), but only in 2 of 122 controls (1.6%), by enzyme-linked immunosorbent assay. Because truncated forms of other laminin family members in other organs have been reported, they confirmed that truncated forms of laminin 511 also exist in human and mouse pancreas. Histologic studies with patient pancreatic tissues showed colocalization of patient IgG and laminin 511. Immunization of mice with human laminin 511-E8 induced antibodies and pancreatic injury, fulfilling the pathologic criteria for human AIP. Four of 25 AIP patients without laminin 511-E8 antibodies had antibodies against integrin α6β1, a laminin 511 ligand. AIP patients with laminin 511-E8 antibodies exhibited distinctive clinical features, as the frequencies of malignancies or allergic diseases were significantly lower in patients with laminin 511-E8 antibodies than in those without. The discovery of these autoantibodies should aid in the understanding of AIP pathophysiology and possibly improve the diagnosis of AIP.

Read more, please click http://stm.sciencemag.org/content/10/453/eaaq0997

3. Thy-1 (CD90) promotes bone formation and protects against obesity Osteoporosis and obesity result from disturbed osteogenic and adipogenic differentiation and present emerging challenges for our aging society. Because of the regulatory role of Thy-1 in mesenchyme-derived fibroblasts, Ann-Kristin Picke at Technische Universität Dresden in Dresden, Germany and his colleagues investigated the impact of Thy-1 expression on mesenchymal stem cell (MSC) fate between osteogenic and adipogenic differentiation and consequences for bone formation and adipose tissue development in vivo. MSCs from Thy-1–deficient mice have decreased osteoblast differentiation and increased adipogenic differentiation compared to MSCs from wild-type mice. Consistently, Thy-1–deficient mice exhibited decreased bone volume and bone formation rate with elevated cortical porosity, resulting in lower bone strength. In parallel, body weight, subcutaneous/epigonadal fat mass, and bone fat volume were increased. Thy-1 deficiency was accompanied by reduced expression of specific Wnt ligands with simultaneous increase of the Wnt inhibitors sclerostin and dickkopf-1 and an altered responsiveness to Wnt. They demonstrated that disturbed bone remodeling in osteoporosis and dysregulated adipose tissue accumulation in patients with obesity were mirrored by reduced serum Thy-1 concentrations. Their findings provide new insights into the mutual regulation of bone formation and obesity and open new perspectives to monitor and to interfere with the dysregulated balance of adipogenesis and osteogenesis in obesity and osteoporosis.

Read more, please click http://stm.sciencemag.org/content/10/453/eaao6806

4. Profiling the origin, dynamics, and function of traction force in B cell activation B lymphocytes use B cell receptors (BCRs) to recognize membrane-bound antigens to further initiate cell spreading and contraction responses during B cell activation. Junyi Wang at Tsinghua University in Beijing, China and his colleagues combined traction force microscopy and live-cell imaging to profile the origin, dynamics, and function of traction force generation in these responses. They showed that B cell activation required the generation of 10 to 20 nN of traction force when encountering antigens presented by substrates with stiffness values from 0.5 to 1 kPa, which mimic the rigidity of antigen-presenting cells in vivo. Perturbation experiments revealed that F-actin remodeling and myosin- and dynein-mediated contractility contributed to traction force generation and B cell activation. Moreover, membrane-proximal BCR signaling molecules (including Lyn, Syk, Btk, PLC-γ2, BLNK, and Vav3) and adaptor molecules (Grb2, Cbl, and Dok-3) linking BCR microclusters and motor proteins were also required for the sustained generation of these traction forces. They found a positive correlation between the strength of the traction force and the mean fluorescence intensity of the BCR microclusters. Furthermore, they demonstrated that isotype-switched memory B cells expressing immunoglobulin G (IgG)–BCRs generated greater traction forces than did mature naïve B cells expressing IgM-BCRs during B cell activation. Last, they observed that primary B cells from patients with rheumatoid arthritis generated greater traction forces than did B cells from healthy donors in response to antigen stimulation. Together, these data delineate the origin, dynamics, and function of traction force during B cell activation.

Read more, please click http://stke.sciencemag.org/content/11/542/eaai9192

5. G protein signaling–biased agonism at the κ-opioid receptor is maintained in striatal neurons Biased agonists of G protein–coupled receptors may present a means to refine receptor signaling in a way that separates side effects from therapeutic properties. Several studies have shown that agonists that activate the κ-opioid receptor (KOR) in a manner that favors G protein coupling over β-arrestin2 recruitment in cell culture may represent a means to treat pain and itch while avoiding sedation and dysphoria. Although it is attractive to speculate that the bias between G protein signaling and β-arrestin2 recruitment is the reason for these divergent behaviors, little evidence has emerged to show that these signaling pathways diverge in the neuronal environment. Jo-Hao Ho at The Scripps Research Institute in Jupiter, USA and his colleagues further explored the influence of cellular context on biased agonism at KOR ligand–directed signaling toward G protein pathways over β-arrestin–dependent pathways and found that this bias persists in striatal neurons. These findings advance our understanding of how a G protein–biased agonist signal differs between cell lines and primary neurons, demonstrate that measuring [35S]GTPγS binding and the regulation of adenylyl cyclase activity are not necessarily orthogonal assays in cell lines, and emphasize the contributions of the environment to assessing biased agonism.

Read more, please click http://stke.sciencemag.org/content/11/542/eaar4309

[alluctor]

dominion

the easiest thing to do in wrestling is to just live through the story as told, take it in as it is given to you, accepting all its problems and warts without complaint, and living through the emotions as they are meant to be lived through. but it’s also the hardest thing, because stories requite so much, and we require so much out of our stories. sometimes, you can just bliss out and enjoy something on a level that is so perfect because it demands nothing out of you - you feel the feelings through your body, the excitement, the anguish, the happiness, the sadness. but other times, your brain gets in the way, because nothing makes sense, or parts make sense, but the whole doesn’t. you want to invest, but you can’t. something just doesn’t allow you to ignore these things. 

there’s also disappointment of two kinds in wrestling - the disappointment you feel when you live through a story, and its sudden turn leaves you wanting, though it makes sense and even your feeling makes sense in it, but more visceral is the disappointment you feel when something happens, and none of it makes sense - to you, within the story, none of it. 

in the past i’ve been the mark who’s been overwhelmed by stories and have found it easy to give myself to that feeling of excitement or sadness or whatever. sometimes i’m completely able to just enjoy something so fully that nothing else matters. your favorite wrestler does his or her things and you love it and you want them to win. simple, perfect.

i think i’m still there, sometimes, when it comes to new japan. i’m definitely there with guys like ishii, or kushida, or hiromu or even less massive faves like juice. i trust the stories i’m being told. i mark out like hell. i’m just a big fan of whatever is thrown at me.

but then there’s other things, stories where i have to think it through and ponder a bit, consider all the implications because i just can’t give into the feeling  - the feeling is not there. that’s been the tale with this okada reign. it started out so sublime and then turned into something else when naito lost - partly because of the story they told with that loss, partly because of the fact they even had him in the match, if he was going to lose. it disappointed me in a visceral way, in a quite unexpected way, but i figured, okay, whatever, let’s see where it goes. 

naito is fine now, but okada less so. something about the reign’s latter half just failed to move him forward in terms of character development. he won, and he won, and then he won again, but like, why? how? you could make the argument facing him moved along the opponents, but i’d argue even that isn’t the case. SANADA was not radically altered by getting close to beating the champion. neither was sabre jr. tanahashi again, bested by the new ace, a cool little story but i just couldn’t sink my teeth deep enough into it. 

then there’s kenny. i’ve written before how torn i have been about his 2018. a story that should be manna from the heavens to me, a golden lovers mark, simply hasn’t hit the mark, because kenny has lost so little and gained so much and for what? where’s the growth. where’s the suffering, the realization of the error of his ways. “i was a jerk, but my ex forgave me, and i said some things but my best friends also forgave me” .. i don’t know. i’ve read plenty of justifications, explanations and elaborations on the topic. none of it lands for me, emotionally. some of the BTE stuff is fine, but in the context of this bigger, larger thing, his path to this whole new (old?) version of himself, it’s not hitting me where it needs to hit me. 

but it is hitting plenty of people. i’m happy for them! but i can’t lie. and while i won’t harsh anybody’s buzz, i guess i also can’t keep quiet. and i’m torn, because kenny as iwgp champion is somebody else other than okada and right now that feels very right to me, but the details in the journey that it took does not.

in positive news, however, i did love the tag match - both of them, in fact. the bucks winning is fine, because i genuinely love the bucks in njpw - these days they have the sort of tag matches i can always invest myself in. and evil and sanada are gonna be just fine. i liked, maybe even loved, naito vs jericho, in all its oddities, osaka still booing naito and chanting for jericho, even as he heeled it up in every conceivable way. naito lost a belt he did not need or want, and he’s coming out with the sympathy on his side regardless. hiromu’s the right winner, much as i like ospreay. rey being lost in a weird six man with bullet club bullshit is whatever. 

suzuki / sabre vs yano / ishii was fantastic. this ishii vs suzuki feud has no rhyme or reason to it, but it makes sense on that level where i just go “YES!” on the inside whenever i think about it. i think suzuki might win the revpro title. and that’s cool as fuck.

i’ve said it before, as much as i joke, “no more white guys in puro 2018″ it’s not about white or japanese, it’s about whose stories make sense to prioritize and whose don’t, in terms of crowd connection and appeal and longevity. kenny yes, i may argue details until dawn, however, and think they told an emotionally incomplete story there, as much as they tried not to. juice, yes, he’s a cheesy bro but he’s *our* cheesy bro. jay white, sure, even if he’s not as over as maybe he ought to be. hiromu, sho & yoh, evil, despy, every damn dojo guy you better do right by (even oka when the time comes, even if he’s the worst), because those guys suffered and ate shit just to get there, and the crowd will always give them the time of day because of it. ospreay? debatable, but the kid’s shown he may stick around. elgin? nah, lose it, mr harold meij can use a google. no excuses. hangman? white mediocrity. cody? must we? flip? don’t fuck with me.

it’s a balancing act. i’ll continue to look at them critically to see how they continue to do on it. but at least now, i’m optimistic. i’m not pessimistic and feeling withered by the emotions i’ve been put through.

[mjfass]

BTE without context - part 1

[mjfass]

That are so many things that happened on BTE that are soooooooo questionable without context. I LOVE IT.

[abbkine]

BioAdvisers said on Biotech Advisers

Optimizing drug combinations against multiple myeloma using a quadratic phenotypic optimization platform (QPOP)

Content introduction:

Optimizing drug combinations against multiple myeloma using a quadratic phenotypic optimization platform (QPOP)

Laminin 511 is a target antigen in autoimmune pancreatitis

Thy-1 (CD90) promotes bone formation and protects against obesity

Profiling the origin, dynamics, and function of traction force in B cell activation

G protein signaling–biased agonism at the κ-opioid receptor is maintained in striatal neurons

1. Optimizing drug combinations against multiple myeloma using a quadratic phenotypic optimization platform (QPOP) Multiple myeloma is an incurable hematological malignancy that relies on drug combinations for first and secondary lines of treatment. The inclusion of proteasome inhibitors, such as bortezomib, into these combination regimens has improved median survival. Resistance to bortezomib, however, is a common occurrence that ultimately contributes to treatment failure, and there remains a need to identify improved drug combinations. Masturah Bte Mohd Abdul Rashid at National University of Singapore in Singapore and his colleagues developed the quadratic phenotypic optimization platform (QPOP) to optimize treatment combinations selected from a candidate pool of 114 approved drugs. QPOP uses quadratic surfaces to model the biological effects of drug combinations to identify effective drug combinations without reference to molecular mechanisms or predetermined drug synergy data. Applying QPOP to bortezomib-resistant multiple myeloma cell lines determined the drug combinations that collectively optimized treatment efficacy. They found that these combinations acted by reversing the DNA methylation and tumor suppressor silencing that often occur after acquired bortezomib resistance in multiple myeloma. Successive application of QPOP on a xenograft mouse model further optimized the dosages of each drug within a given combination while minimizing overall toxicity in vivo, and application of QPOP to ex vivo multiple myeloma patient samples optimized drug combinations in patient-specific contexts.

Read more, please click http://stm.sciencemag.org/content/10/453/eaan0941

2. Laminin 511 is a target antigen in autoimmune pancreatitis Autoimmune pancreatitis (AIP), a major manifestation of immunoglobulin G4–related disease (IgG4-RD), is an immune-mediated disorder, but the target autoantigens are still unknown. Masahiro Shiokawa at Kyoto University Graduate School of Medicine in Kyoto, Japan and his colleagues previously reported that IgG in patients with AIP induces pancreatic injuries in mice by binding the extracellular matrix (ECM). In the current study, they identified an autoantibody against laminin 511-E8, a truncated laminin 511, one of the ECM proteins, in patients with AIP. Anti–laminin 511-E8 IgG was present in 26 of 51 AIP patients (51.0%), but only in 2 of 122 controls (1.6%), by enzyme-linked immunosorbent assay. Because truncated forms of other laminin family members in other organs have been reported, they confirmed that truncated forms of laminin 511 also exist in human and mouse pancreas. Histologic studies with patient pancreatic tissues showed colocalization of patient IgG and laminin 511. Immunization of mice with human laminin 511-E8 induced antibodies and pancreatic injury, fulfilling the pathologic criteria for human AIP. Four of 25 AIP patients without laminin 511-E8 antibodies had antibodies against integrin α6β1, a laminin 511 ligand. AIP patients with laminin 511-E8 antibodies exhibited distinctive clinical features, as the frequencies of malignancies or allergic diseases were significantly lower in patients with laminin 511-E8 antibodies than in those without. The discovery of these autoantibodies should aid in the understanding of AIP pathophysiology and possibly improve the diagnosis of AIP.

Read more, please click http://stm.sciencemag.org/content/10/453/eaaq0997

3. Thy-1 (CD90) promotes bone formation and protects against obesity Osteoporosis and obesity result from disturbed osteogenic and adipogenic differentiation and present emerging challenges for our aging society. Because of the regulatory role of Thy-1 in mesenchyme-derived fibroblasts, Ann-Kristin Picke at Technische Universität Dresden in Dresden, Germany and his colleagues investigated the impact of Thy-1 expression on mesenchymal stem cell (MSC) fate between osteogenic and adipogenic differentiation and consequences for bone formation and adipose tissue development in vivo. MSCs from Thy-1–deficient mice have decreased osteoblast differentiation and increased adipogenic differentiation compared to MSCs from wild-type mice. Consistently, Thy-1–deficient mice exhibited decreased bone volume and bone formation rate with elevated cortical porosity, resulting in lower bone strength. In parallel, body weight, subcutaneous/epigonadal fat mass, and bone fat volume were increased. Thy-1 deficiency was accompanied by reduced expression of specific Wnt ligands with simultaneous increase of the Wnt inhibitors sclerostin and dickkopf-1 and an altered responsiveness to Wnt. They demonstrated that disturbed bone remodeling in osteoporosis and dysregulated adipose tissue accumulation in patients with obesity were mirrored by reduced serum Thy-1 concentrations. Their findings provide new insights into the mutual regulation of bone formation and obesity and open new perspectives to monitor and to interfere with the dysregulated balance of adipogenesis and osteogenesis in obesity and osteoporosis.

Read more, please click http://stm.sciencemag.org/content/10/453/eaao6806

4. Profiling the origin, dynamics, and function of traction force in B cell activation B lymphocytes use B cell receptors (BCRs) to recognize membrane-bound antigens to further initiate cell spreading and contraction responses during B cell activation. Junyi Wang at Tsinghua University in Beijing, China and his colleagues combined traction force microscopy and live-cell imaging to profile the origin, dynamics, and function of traction force generation in these responses. They showed that B cell activation required the generation of 10 to 20 nN of traction force when encountering antigens presented by substrates with stiffness values from 0.5 to 1 kPa, which mimic the rigidity of antigen-presenting cells in vivo. Perturbation experiments revealed that F-actin remodeling and myosin- and dynein-mediated contractility contributed to traction force generation and B cell activation. Moreover, membrane-proximal BCR signaling molecules (including Lyn, Syk, Btk, PLC-γ2, BLNK, and Vav3) and adaptor molecules (Grb2, Cbl, and Dok-3) linking BCR microclusters and motor proteins were also required for the sustained generation of these traction forces. They found a positive correlation between the strength of the traction force and the mean fluorescence intensity of the BCR microclusters. Furthermore, they demonstrated that isotype-switched memory B cells expressing immunoglobulin G (IgG)–BCRs generated greater traction forces than did mature naïve B cells expressing IgM-BCRs during B cell activation. Last, they observed that primary B cells from patients with rheumatoid arthritis generated greater traction forces than did B cells from healthy donors in response to antigen stimulation. Together, these data delineate the origin, dynamics, and function of traction force during B cell activation.

Read more, please click http://stke.sciencemag.org/content/11/542/eaai9192

5. G protein signaling–biased agonism at the κ-opioid receptor is maintained in striatal neurons Biased agonists of G protein–coupled receptors may present a means to refine receptor signaling in a way that separates side effects from therapeutic properties. Several studies have shown that agonists that activate the κ-opioid receptor (KOR) in a manner that favors G protein coupling over β-arrestin2 recruitment in cell culture may represent a means to treat pain and itch while avoiding sedation and dysphoria. Although it is attractive to speculate that the bias between G protein signaling and β-arrestin2 recruitment is the reason for these divergent behaviors, little evidence has emerged to show that these signaling pathways diverge in the neuronal environment. Jo-Hao Ho at The Scripps Research Institute in Jupiter, USA and his colleagues further explored the influence of cellular context on biased agonism at KOR ligand–directed signaling toward G protein pathways over β-arrestin–dependent pathways and found that this bias persists in striatal neurons. These findings advance our understanding of how a G protein–biased agonist signal differs between cell lines and primary neurons, demonstrate that measuring [35S]GTPγS binding and the regulation of adenylyl cyclase activity are not necessarily orthogonal assays in cell lines, and emphasize the contributions of the environment to assessing biased agonism.

Read more, please click http://stke.sciencemag.org/content/11/542/eaar4309

[theglowafterdark]

And this is what bte was all about. Damn, I miss it.

BTE without context - part 2