The inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), which form tetrameric channels, play pivotal roles in regulating the spatiotemporal patterns of intracellular calcium signals. Mutations in IP3Rs have been increasingly associated with many debilitating human diseases such as ataxia, Gillespie syndrome, and generalized anhidrosis. However, how these mutations affect IP3R function, and how the perturbation of as-sociated calcium signals contribute to the pathogenesis and severity of these diseases remains largely uncharacterized. Moreover, many of these diseases occur as the result of autosomal dominant inheritance, suggesting that WT and mutant subunits associate in heterotetrameric channels. How the in-corporation of different numbers of mutant subunits within the tetrameric channels affects its activities and results in different disease phenotypes is also unclear. In this report, we investigated representative disease-associated missense mutations to determine their effects on IP3R channel activity. Additionally, we designed concatenated IP3R constructs to create tetrameric channels with a predefined subunit composition to explore the functionality of heteromeric channels. Using calcium imaging techniques to assess IP3R channel function, we observed that all the mutations studied resulted in severely attenuated Ca2+ release when expressed as homotetramers. However, some heterotetramers retained varied degrees of function dependent on the composition of the tetramer. Our findings suggest that the effect of mutations depends on the location of the mutation in the IP3R structure, as well as on the stoichiometry of mutant subunits assembled within the tetrameric channel. These studies provide insight into the pathogenesis and penetrance of these devastating human diseases.

Visual Abstract

α-Synuclein (α-Syn) is a protein implicated in the pathogenesis of Parkinson's disease (PD). It is an intrinsically disordered protein that binds acidic phospholipids. Growing evidence supports a role for α-Syn in membrane trafficking, including, mechanisms of endocytosis and exocytosis, although the exact role of α-Syn in these mechanisms is currently unclear. Here we investigate the associations of α-Syn with the acidic phosphoinositides (PIPs), phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2). Our results show that α-Syn colocalizes with PIP2 and the phosphorylated active form of the clathrin adaptor protein 2 (AP2) at clathrin-coated pits. Using endocytosis of transferrin as an indicator for clathrin-mediated endocytosis (CME), we find that α-Syn involvement in endocytosis is specifically mediated through PI(4,5)P2 levels on the plasma membrane. In accord with their effects on PI(4,5)P2 levels, the PD associated A30P, E46K, and A53T mutations in α-Syn further enhance CME in neuronal and nonneuronal cells. However, lysine to glutamic acid substitutions at the KTKEGV repeat domain of α-Syn, which interfere with phospholipid binding, are ineffective in enhancing CME. We further show that the rate of synaptic vesicle (SV) endocytosis is differentially affected by the α-Syn mutations and associates with their effects on PI(4,5)P2 levels, however, with the exception of the A30P mutation. This study provides evidence for a critical involvement of PIPs in α-Syn–mediated membrane trafficking.

About 1,100 workers will be laid off indefinitely in January from the Jeep Gladiator plant in Toledo, Ohio, Stellantis officials announced Wednesday.

Wendi McLendon-Covey, David Alan Grier and Allison Tolman discuss the comedy in their harried medical characters on "St. Denis Medical," premiering Tuesday on NBC.

In the spring of 1945, with the Third Reich crumbling, the Nazis hid their stolen art in a sealed salt mine. But when U.S. troops arrived, they found that the opening to the mine had been destroyed.

The CIA burglar who went rogue: http://j.mp/UpJtCJ Using the Enigma and the Sigaba, world powers encrypted their messages in hopes of catching their opponents by surprise.

Do you ever wonder what secrets lie beneath the sands of Egypt? Prepare to be astonished as we unveil the untouched tomb of King Tutankhamun. --- For more videos from Smithsonian Magazine: https://www.smithsonianmag.com/videos/ Digital Editorial Director: Brian Wolly Supervising Producer & Scriptwriter: Michelle Mehrtens Video Editor: Sierra Theobald

The Dutch seized the majority of the items in the aftermath of a brutal 1906 conflict that killed an estimated 1,000 Balinese

The Gestapo seized the Impressionist painting from storage after its owners fled from their home in Vienna. Now, the piece has been returned to their granddaughters

The metropolis is an important center for paleontological research, but until now, fossils of plants and fish were the only remains of dinosaur-era life found there

The robbers only made away with two of the screen prints, which they swiped from a gallery in the Netherlands. They abandoned the other artworks on the street

Erin Kitt-Lewis, associate director of education for the Ross and Carol Nese College of Nursing’s Tressa Nese and Helen Diskevich Center of Geriatric Nursing Excellence, has been named a 2024 Distinguished Educator in Gerontological Nursing by the National Hartford Center of Gerontological Nursing Excellence. 

The Competition Tribunal issued an interim order that should allow online betting platform Lottoland access to Google Ads.

The BJP on Tuesday rejected the assertion that actor-turned-politician Mithun Chakraborty's purse was stolen during a rally in Jharkhand's Dhanbad, claiming that it was misplaced and later found.

The Centre on Monday informed the Supreme Court of framing the "Menstrual Hygiene Policy for School Going Girls" approved by the Union Health Ministry.

The BJP on Tuesday rejected the assertion that actor-turned-politician Mithun Chakraborty's purse was stolen during a rally in Jharkhand's Dhanbad, claiming that it was misplaced and later found.

"I decided to quit before Laal Singh Chadha," Aamir Khan said

While the PCB wants to organise all ICC Champions Trophy matches at home, the BCCI has refused to send the Indian team across the border.

Anushka Sharma and Virat Kohli seemed to have a good South Indian meal at the restaurant. Anushka also reposted the restaurants post ionher Instagram Stories

Gun dealer under investigation for lax prevention of shoplifted ammo Attorney General Kathy Jennings, through her Office of Impact Litigation, has asked the Superior Court to enforce a subpoena against Cabela’s, Inc. (“Cabela’s”) seeking answers about a half-million rounds of ammunition that were shoplifted from its Christiana location.  After more than three months, Cabela’s has […]

This afternoon President Trump ordered flags at all U.S. government buildings and facilities to be flown at half-staff until sunset on January 13, 2021 as a sign of respect for the service and sacrifice of United States Capitol Police Officers Brian D. Sicknick and Howard Liebengood, and all Capitol Police Officers and law enforcement across […]

As sign of respect for the service and sacrifice of the victims of the attack at the United States Capitol on Friday, April 2, 2021, President Biden ordered flags at all U.S. government buildings and facilities to be flown at half-staff until sunset on April 6, 2021. In concurrence with the President’s order, Governor Carney […]

Starting Dec. 15, all requests for a homebound vaccination or booster will be filtered through a toll-free number – 1-888-491-4988 – to be assessed and scheduled. Live operators will staff the toll-free line from 8 a.m. to 8 p.m. Monday through Friday, and 8:30 a.m. to 6 p.m. Saturdays.

Due to a reduction in the Air Quality Index (AQI) CASH BOOTHS at the toll plazas OPENED at 4:45 pm today, June 8, 2023. The Delaware Division of Motor Vehicles (DMV) will continue to monitor the AQI forecast and determine the effects it may have, if any, on DMV operations for Friday, June 9, 2023. Residents […]

The Delaware Judiciary welcomed its first “facility” or comfort dog to the Leonard L. Williams Justice Center in partnership with the Delaware Capitol Police.

Nathaniel McQueen Jr., Secretary of the Department of Safety and Homeland Security, announced Major Elmer C. Harris as the Chief of the Delaware Capitol Police. The Department of Safety and Homeland Security (DSHS) and the Delaware Capitol Police (DCP) held a ceremony to mark the start of Chief Elmer C. Harris’s role as Chief of […]

1. Pakistan Government's Firm Stance On Champions Trophy, Report Says PCB Told To...  NDTV Sports
2. ICC in a catch-22 situation amid PCB's steadfast stance on hosting Champions Trophy  Cricbuzz
3. Champions Trophy: PCB wants an explanation in writing from India for refusal to travel  ESPNcricinfo
4. 'Duniya bewakoof hai': Basit Ali gives unique solution to India-Pakistan Champions Trophy stand-off  The Times of India
5. Champions Trophy : Rizwan's welcome message for KL Rahul and Suryakumar  India Today

[GroundUp] Former Lavender Hill gangster died on 29 October

JAPANESE rescuers battled the clock and powerful aftershocks yesterday to find survivors of a New Year’s Day earthquake that killed at least 48 people and caused widespread destruction. The 7.5-magnitude

Senior Chinese and US officials held multiple rounds of meetings in Malta on Saturday and Sunday, agreeing to maintain high-level exchanges and hold consultations on Asia-Pacific affairs, maritime affairs

Check here each week to keep up with the latest from John MacArthur's pulpit at Grace Community Church.

MINNEAPOLIS, MINNESOTA — Huldah Momanyi Hiltsley made history November 5 by becoming the first Kenyan-born immigrant elected to the Minnesota House of Representatives. She describes her victory as a testament to resilience, determination and the realization of the American dream. Standing in the State Capitol for the first time on the morning of her orientation, Hiltsley told VOA she was overwhelmed with emotions and eager to start her journey as an elected official. “I am super excited,” Hiltsley said. “Today is orientation day for new legislators, and to be standing in this Capitol as an African immigrant woman is a tremendous honor. I’m just overexcited right now.” She said this milestone did not come easily. Her path to the Minnesota State Capitol was marked by struggles, including a fight against an immigration system that nearly led to her family’s deportation. She credits much of her success to the community support and the intervention of the late U.S. Senator Paul Wellstone, whose advocacy she said ultimately secured her family’s green cards and, later, citizenship. “Getting to this moment honestly is just a testament to the struggles that my family has gone through to be in this country,” she said. There has been a media frenzy surrounding Hiltsley’s victory and it has captured the attention of Kenyan media, with celebrations taking place in her hometown, Nyamemiso village, which is eight hours from Nairobi, Kenya's capital. Despite the attention, Hiltsley said she remains humble.  “I’m that little girl from that little village somewhere in the middle of Kenya, and now I’m in the spotlight of this media frenzy. And so, I’m still trying to really appreciate the magnitude of the moment,” she said. Hiltsley said she has a desire to inspire others, particularly young girls in Kenya and the United States. "It is still surreal,” she said, adding that “if I can make it to this point, I can be a role model to somebody to remind them that it is possible that our wildest dreams are possible. And that would be something that I would look back and say, wow, I’ve made a difference in somebody’s life.” Her legislative priorities Looking ahead, Hiltsley said she is committed to championing issues that matter to her constituents in Minnesota’s Legislative District 38A. Her priorities include community-centered public safety policies, affordable housing options, workers’ rights and support for small businesses — many of which are run by African immigrants. “The resources are out here,” she said, promising to empower her community. “It is my job to go back to my community and tell them, hey, there are resources here. This is how this system works. Let’s work together to mobilize and make sure that we are also taking a piece of the pie,” she said. As the first Kenyan American woman in Minnesota's Legislature, Hiltsley said she recognizes the weight and responsibility of her position. She described it as “an honor that I don’t take lightly.” “I don’t want to be the last,” she, adding that she hopes "this moment right here is a testimony that you can come to this country, work hard, take care of business, know your craft, stick to it, be consistent and get to where you want to.” Her message to those who have yet to succeed in their political campaigns is clear: Perseverance is key. “Be consistent. Keep going. There’s enough space in this Legislature for more people of color, especially immigrants, because that’s the voice that is missing,” Hiltsley said. Changing political scene Hiltsley shared her thoughts on the changing political landscape in Washington, particularly with the coming administration under President-elect Donald Trump. While acknowledging the challenges, she said she will stay focused on serving her constituents in Minnesota, regardless of politics. “We are here to serve the people, and it doesn’t matter if you are Democrat or Republican,” she said. “We are here as legislators to serve the people of Minnesota.” Hiltsley also shared her heartfelt message to fellow Kenyans who have been celebrating her historic achievement. “This is a historical moment, and I’m honored to be a Kenyan American,” she said. “Let’s continue celebrating this victory, but after that, we have work to do.” She said her eyes are set on not just her role in Minnesota, but also finding ways to collaborate with Kenya’s leaders to address issues facing the country, including corruption and a lack of strong leadership. “Kenya has unlimited potential,” she said. “It’s up to our leaders to do right by the people.” Hiltsley will officially take her seat in the Minnesota State House of Representatives and be sworn in on January 7. Representatives are elected to serve two-year terms. This story originated in VOA’s Swahili Service. Salem Solomon contributed to the report from Washington.

La enseñanza bíblica en profundidad de John MacArthur lleva la verdad transformadora de la Palabra de Dios a millones de personas cada día.

La enseñanza bíblica en profundidad de John MacArthur lleva la verdad transformadora de la Palabra de Dios a millones de personas cada día.

On January 6, 2021, white insurrectionists stormed the U.S. Capitol, proudly displayed the confederate flag, and set up gallows on the Capitol grounds.

The eastern region of Baalbek, Lebanon was believed to be a “safe zone” for residents, and refugees who had been displaced by the increased hostilities across the country. That changed on October 29, when an Israeli airstrike on the region resulted in over sixty casualties, including two children. On October 30, the Israeli Defense Forces […]

Police on Wednesday are investigating the theft of a large number of gold items after a search at a Nicosia gold shop. The owner of the property, aged 78, has been arrested and taken into custody for questioning. According to the police, the search happened as part of an ongoing investigation into a spate of […]

Title: bitolterol mesylate
Category: Medications
Created: 12/31/1997 12:00:00 AM
Last Editorial Review: 5/20/2022 12:00:00 AM

Title: Stress May Take Greatest Toll on Younger Women's Hearts: Study
Category: Health News
Created: 8/24/2016 12:00:00 AM
Last Editorial Review: 8/25/2016 12:00:00 AM

Title: Prehistoric People Drank Animal Milk, Despite Lactose Intolerance
Category: Health News
Created: 7/27/2022 12:00:00 AM
Last Editorial Review: 7/28/2022 12:00:00 AM

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy treatment, routinely manifesting as increased pain sensitivity (allodynia) in distal extremities. Despite its prevalence, effective treatment options are limited. Cannabinoids are increasingly being evaluated for their ability to treat chronic pain conditions, including CIPN. While previous studies have revealed sex differences in cannabinoid-mediated antinociception in acute and chronic pain models, there is a paucity of studies addressing potential sex differences in the response of CIPN to cannabinoid treatment. Therefore, we evaluated the long-term antiallodynic efficacy of cannabinoid receptor type 1 (CB₁)-selective, cannabinoid receptor type 2 (CB₂)-selective, and CB₁/CB₂ mixed agonists in the cisplatin CIPN model, using both male and female mice. CB₁ selective agonism was observed to have sex differences in the development of tolerance to antiallodynic effects, with females developing tolerance more rapidly than males, while the antiallodynic effects of selective CB₂ agonism lacked tolerance development. Compound-specific changes to the female estrous cycle and female plasma estradiol levels were noted, with CB₁ selective agonism decreasing plasma estradiol while CB₂ selective agonism increased plasma estradiol. Chronic administration of a mixed CB₁/CB₂ agonist resulted in increased mRNA expression of proinflammatory cytokines and endocannabinoid regulatory enzymes in female spinal cord tissue. Ovarian tissue was noted to have proinflammatory cytokine mRNA expression following administration of a CB₂ acting compound while selective CB₁ agonism resulted in decreased proinflammatory cytokines and endocannabinoid regulatory enzymes in testes. These results support the need for further investigation into the role of sex and sex hormones signaling in pain and cannabinoid-mediated antinociceptive effects.

Unidentified Anomalous Phenomena -- that's UAPs for short -- are the centerpiece of a hearing Wednesday co-conducted by the two subcommittees of the House Oversight and Accountability Committee. The joint hearing is titled "Unidentified Anomalous Phenomena: Exposing the Truth."