Date: May 7, 2020

As COVID-19 continues to impact communities around the world, people and families everywhere are spending more time at home. In light of this, we’re launching a throwback Doodle series looking back at some of our popular interactive Google Doodle games!

Stay and play at home with today’s featured throwback: 

Our 2017 Doodle game celebrating the birth of Hip Hop!
 

 

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Levodopa-induced dyskinesia (LID) poses a significant health care challenge for Parkinson’s disease (PD) patients. Amantadine is currently the only drug proven to alleviate LID. Although its efficacy in treating LID is widely assumed to be mediated by blockade of N-methyl-D-aspartate (NMDA) glutamate receptors, our experiments demonstrate that at therapeutically relevant concentrations, amantadine preferentially blocks inward-rectifying K+ channel type 2 (Kir2) channels in striatal spiny projection neurons (SPNs) — not NMDA receptors. In so doing, amantadine enhances dendritic integration of excitatory synaptic potentials in SPNs and enhances — not antagonizes — the induction of long-term potentiation (LTP) at excitatory, axospinous synapses. Taken together, our studies suggest that the alleviation of LID in PD patients is mediated by diminishing the disparity in the excitability of direct- and indirect-pathway SPNs in the on state, rather than by disrupting LTP induction. This insight points to a pharmacological approach that could be used to effectively ameliorate LID and improve the quality of life for PD patients.

The renaissance of complement diagnostics and therapeutics has introduced precision medicine into a widened field of complement-mediated diseases. In particular, complement-mediated diseases (or complementopathies) with ongoing or published clinical trials of complement inhibitors include paroxysmal nocturnal hemoglobinuria, cold agglutinin disease, hemolytic uremic syndrome, nephropathies, HELLP syndrome, transplant-associated thrombotic microangiopathy, antiphospholipid antibody syndrome, myasthenia gravis, and neuromyelitis optica. Recognizing that this field is rapidly expanding, we aim to provide a state-of-the-art review of (a) current understanding of complement biology for the clinician, (b) novel insights into complement with potential applicability to clinical practice, (c) complement in disease across various disciplines (hematology, nephrology, obstetrics, transplantation, rheumatology, and neurology), and (d) the potential future of precision medicine. Better understanding of complement diagnostics and therapeutics will not only facilitate physicians treating patients in clinical practice but also provide the basis for future research toward precision medicine in this field.

Chronic pancreatitis (CP) is considered an irreversible fibroinflammatory pancreatic disease. Despite numerous animal model studies, questions remain about local immune characteristics in human CP. We profiled pancreatic immune cell characteristics in control organ donors and CP patients including those with hereditary and idiopathic CP undergoing total pancreatectomy with islet autotransplantation. Flow cytometric analysis revealed a significant increase in the frequency of CD68+ macrophages in idiopathic CP. In contrast, hereditary CP samples showed a significant increase in CD3+ T cell frequency, which prompted us to investigate the T cell receptor β (TCRβ) repertoire in the CP and control groups. TCRβ sequencing revealed a significant increase in TCRβ repertoire diversity and reduced clonality in both CP groups versus controls. Interestingly, we observed differences in Vβ-Jβ gene family usage between hereditary and idiopathic CP and a positive correlation of TCRβ rearrangements with disease severity scores. Immunophenotyping analyses in hereditary and idiopathic CP pancreases indicate differences in innate and adaptive immune responses, which highlights differences in immunopathogenic mechanisms of disease among subtypes of CP. TCR repertoire analysis further suggests a role for specific T cell responses in hereditary versus idiopathic CP pathogenesis, providing insights into immune responses associated with human CP.

Nerve growth factor (NGF) regulates many aspects of neuronal biology by retrogradely propagating signals along axons to the targets of those axons. How this occurs when axons contain a plethora of proteins that can silence those signals has long perplexed the neurotrophin field. In this issue of the JCI, Li et al. suggest an answer to this vexing problem, while exploring why the Elp1 gene that is mutated in familial dysautonomia (FD) causes peripheral neuropathy. They describe a distinctive function of Elp1 as a protein that is required to sustain NGF signaling by blocking the activity of its phosphatase that shuts off those signals. This finding helps explain the innervation deficits prominent in FD and reveals a unique role for Elp1 in the regulation of NGF-dependent TrkA activity.

Curing HIV infection will require the elimination of a reservoir of infected CD4+ T cells that persists despite HIV-specific cytotoxic T cell (CTL) responses. Although viral latency is a critical factor in this persistence, recent evidence also suggests a role for intrinsic resistance of reservoir-harboring cells to CTL killing. This resistance may have contributed to negative outcomes of clinical trials, where pharmacologic latency reversal has thus far failed to drive reductions in HIV reservoirs. Through transcriptional profiling, we herein identified overexpression of the prosurvival factor B cell lymphoma 2 (BCL-2) as a distinguishing feature of CD4+ T cells that survived CTL killing. We show that the inducible HIV reservoir was disproportionately present in BCL-2hi subsets in ex vivo CD4+ T cells. Treatment with the BCL-2 antagonist ABT-199 was not sufficient to drive reductions in ex vivo viral reservoirs when tested either alone or with a latency-reversing agent (LRA). However, the triple combination of strong LRAs, HIV-specific T cells, and a BCL-2 antagonist uniquely enabled the depletion of ex vivo viral reservoirs. Our results provide rationale for novel therapeutic approaches targeting HIV cure and, more generally, suggest consideration of BCL-2 antagonism as a means of enhancing CTL immunotherapy in other settings, such as cancer.

Treating neuropathic pain is challenging and novel non–opioid-based medicines are needed. Using unbiased receptomics, transcriptomic analyses, immunofluorescence, and in situ hybridization, we found that the expression of the orphan GPCR Gpr160 and GPR160 increased in the rodent dorsal horn of the spinal cord following traumatic nerve injury. Genetic and immunopharmacological approaches demonstrated that GPR160 inhibition in the spinal cord prevented and reversed neuropathic pain in male and female rodents without altering normal pain response. GPR160 inhibition in the spinal cord attenuated sensory processing in the thalamus, a key relay in the sensory discriminative pathways of pain. We also identified cocaine- and amphetamine-regulated transcript peptide (CARTp) as a GPR160 ligand. Inhibiting endogenous CARTp signaling in spinal cord attenuated neuropathic pain, whereas exogenous intrathecal CARTp evoked painful hypersensitivity through GPR160-dependent ERK and cAMP response element–binding protein (CREB). Our findings de-orphanize GPR160, identify it as a determinant of neuropathic pain and potential therapeutic target, and provide insights into its signaling pathways. CARTp is involved in many diseases including depression and reward and addiction; de-orphanization of GPR160 is a major step forward understanding the role of CARTp signaling in health and disease.

The physical integrity of endothelial cells (ECs) lining the blood vessels regulates the inflammatory response. Both innate immunity and inflammatory disorders hinge on the EC-neutrophil interaction. Neutrophil binding, rolling, and migrating along and between ECs is associated with vascular permeability. In this issue of the JCI, Owen-Woods et al. tracked neutrophils in vivo in venules of mouse striated muscle and revealed how endothelial permeability can affect neutrophil trafficking. Strikingly, many neutrophils that migrated between EC junctions were able to rejoin the blood circulation. Further, the chemokine and neutrophil chemoattractant, CXCL1, drove this reverse transendothelial migration (rTEM). This paradigm-shifting study provides a mechanism for distal organ damage as well as an explanation for sepsis-associated acute respiratory distress syndrome.

Hypoxia-inducible factor (HIF) is strikingly upregulated in many types of cancer, and there is great interest in applying inhibitors of HIF as anticancer therapeutics. The most advanced of these are small molecules that target the HIF-2 isoform through binding the PAS-B domain of HIF-2α. These molecules are undergoing clinical trials with promising results in renal and other cancers where HIF-2 is considered to be driving growth. Nevertheless, a central question remains as to whether such inhibitors affect physiological responses to hypoxia at relevant doses. Here, we show that pharmacological HIF-2α inhibition with PT2385, at doses similar to those reported to inhibit tumor growth, rapidly impaired ventilatory responses to hypoxia, abrogating both ventilatory acclimatization and carotid body cell proliferative responses to sustained hypoxia. Mice carrying a HIF-2α PAS-B S305M mutation that disrupts PT2385 binding, but not dimerization with HIF-1β, did not respond to PT2385, indicating that these effects are on-target. Furthermore, the finding of a hypomorphic ventilatory phenotype in untreated HIF-2α S305M mutant mice suggests a function for the HIF-2α PAS-B domain beyond heterodimerization with HIF-1β. Although PT2385 was well tolerated, the findings indicate the need for caution in patients who are dependent on hypoxic ventilatory drive.

Increased microvascular permeability to plasma proteins and neutrophil emigration are hallmarks of innate immunity and key features of numerous inflammatory disorders. Although neutrophils can promote microvascular leakage, the impact of vascular permeability on neutrophil trafficking is unknown. Here, through the application of confocal intravital microscopy, we report that vascular permeability–enhancing stimuli caused a significant frequency of neutrophil reverse transendothelial cell migration (rTEM). Furthermore, mice with a selective defect in microvascular permeability enhancement (VEC-Y685F-ki) showed reduced incidence of neutrophil rTEM. Mechanistically, elevated vascular leakage promoted movement of interstitial chemokines into the bloodstream, a response that supported abluminal-to-luminal neutrophil TEM. Through development of an in vivo cell labeling method we provide direct evidence for the systemic dissemination of rTEM neutrophils, and showed them to exhibit an activated phenotype and be capable of trafficking to the lungs where their presence was aligned with regions of vascular injury. Collectively, we demonstrate that increased microvascular leakage reverses the localization of directional cues across venular walls, thus causing neutrophils engaged in diapedesis to reenter the systemic circulation. This cascade of events offers a mechanism to explain how local tissue inflammation and vascular permeability can induce downstream pathological effects in remote organs, most notably in the lungs.

Hello! Hope you and yours are all well and safe during these stressful times. If you need an action-packed adventure to escape with, Ends of the Earth is on sale this week only for $0.99! On a Montana camping trip, single dad Jason is surprised by his attraction to Ben, an older park ranger. But when Jason’s daughter is kidnapped, […]

We're still waiting to hear news about Apple Card's performance relative to the major card issuers, but that hasn't stopped Samsung from announcing plans to launch an "innovative" debit card as part of a new mobile-first money management platform the company has been developing over the last year.


Announced on Thursday in a blog post by Samsung Pay vice-president Sang Ahn, the forthcoming debit card is in partnership with finance company SoFi and will be backed by a cash management account.

"In 2020, Samsung Pay will be expanding our service from being a rewarding way to shop and pay, to also being a rewarding way to manage money," writes Ahn. "Over the past year we have been busy developing a mobile-first money management platform. Our vision is to help consumers better manage their money so that they can achieve their dreams and goals. Now more than ever, mobile financial services and money management tools will play an even bigger role in our daily lives while also opening up new possibilities."

The debit card is scheduled to launch this summer. Other than that, Samsung hasn't offered any details on how it will work, but expect it to integrate with Samsung's existing mobile payment system.

Launched in August 2019, ‌Apple Card‌ is a credit card linked to Apple Pay and built into the Wallet app on iPhone. Apple partnered with Goldman Sachs to launch the card, and in October the investment bank hailed it as "the most successful credit-card launch ever." Nine months later, neither Apple nor Goldman Sachs has offered any concrete details on its performance.

During the global health crisis, Apple has introduced an ‌Apple Card‌ Assistance Program that allows ‌‌Apple Card‌‌ holders to skip their March and April payments without incurring interest charges for that billing cycle. For more details on how the card works, check out our comprehensive Apple Card guide.
This article, "Samsung Announces 'Innovative' Debit Card Launching this Summer" first appeared on MacRumors.com

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Apple's plan to release an updated version of AirPods later this year has been delayed due to the global health crisis, according to the Nikkei Asian Review.


This lines up with a recent report from analyst Ming-Chi Kuo, who said that mass production of third-generation AirPods will begin in the first half of 2021, followed by mass production of second-generation AirPods Pro between the fourth quarter of 2021 and the first quarter of 2022. Kuo also expects Apple's rumored high-end over-ear headphones to enter mass production at some point in mid-2020.

Kuo did acknowledge rumors of new AirPods coming in the second half of 2020, but he said they are "more likely to be the new Beats model." Last month, leaker Jon Prosser claimed that Apple was planning to release so-called "AirPods X" around September or October with a BeatsX-like design for sports and running.

Apple's second-generation AirPods launched in March 2019, while the AirPods Pro were released at the end of October.

This article, "Apple's Plan to Introduce New AirPods Later This Year Reportedly Delayed" first appeared on MacRumors.com

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Apple has been selling audio accessories since December 2016 when the original AirPods launched. We now have the ‌AirPods‌ 2 and the AirPods Pro, and Apple is planning to add to its lineup with new over-ear Apple-branded headphones.

Apple already sells over-ear headphones under its Beats brand, but as with the ‌AirPods‌, Apple is also working on headphones that will be Apple branded rather than Beats branded. These headphones are said to be aimed at the high-end market.

Design

The headphones will feature an all-new design, and while we don't know a lot about it, we do know some details shared by Bloomberg.

Apple is said to be working on two versions of the high-end over-ear headphones, including a premium version with leather-like fabrics and a fitness-focused model that uses lighter, breathable materials with small perforations for better airflow.

Prototypes of the headphones have been described as having a retro-like look with over-ear cups that swivel along with a headband connected with thin metal arms.

Apple is planning to attach the ear pads and the head padding to the headphone's frame magnetically, allowing users to swap different colors and variants in and out for customization purposes.

An icon representing the headphones was found in the code in a leaked version of iOS 14, but little detail can be gleaned from the imagery.

Rumored Features

According to Apple analyst Ming-Chi Kuo, Apple's over-ear headphones will feature Active Noise Cancellation, a high-end feature baked into the Beats Studio 3 headphones, Solo Pro headphones, and the ‌AirPods Pro‌.

Active Noise Cancellation is designed to cut down on ambient noise so you can focus on what you're listening to. If it mimics ANC on the ‌AirPods Pro‌, there will be a transparency mode that will enable noise cancelling features, but with an option to continue to hear what's going on around you.

Sound quality is expected to be better than the sound quality of the ‌AirPods‌.

Pricing

Apple could price the new headphones at around $350.

Launch Date

Current rumors indicate the headphones will launch at some point in 2020, though a specific date has not yet been nailed down. Mass production on the headphones is scheduled to begin in mid-2020, which perhaps suggests a fall 2020 launch.

There were rumors indicating that Apple initially planned to launch the headphones at some point in 2019, but that did not happen.

Over-Ear Headphones Rumor History

• Mass Production on Apple's High-End Headphones Rumored to Start in Mid-2020


• Apple to Unveil High-End Over-Ear Wireless Headphones With Magnetically Swappable Parts Later This Year


• Apple Reportedly Targeting WWDC for Over-Ear Headphones Launch, New 'AirPods X' Later in the Year


• Icon for Apple's Rumored Over-Ear Noise Canceling Headphones Discovered in Leaked iOS 14 Code


• Apple-Branded Over-Ear Headphones Said to Launch as Early as Second Half of 2019


• Apple's Upcoming Over-Ear Wireless Headphones to Target High-End Noise-Canceling Market


• KGI: Apple Developing High-End Over-Ear Headphones, Launching Late 2018 at the Earliest

Guide Feedback

Have a question about Apple's over-ear headphones, know of something we left out, or want to offer feedback? Send us an email here.
This article, "Apple's Work on High-End Over-Ear Headphones: Everything We Know" first appeared on MacRumors.com

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Contributors this month include 2cross2affliction, dronon, GreenReaper, Rakuen Growlithe, and Sonious.

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Contributors this month include 2cross2affliction, dronon, earthfurst, GreenReaper, Rakuen Growlithe, and Sonious.

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Bonesy the Dog

Camo the Chameleon

Dodger the Fox

Empress the Cat

Gunner the Dog

Hamirez the Hamster

Kitsune the Fox

Kyo the Robot Cat

Remus the Wolf

Scales the Dragon

Woodsy the Puppet Dog

Contributors this month include 2cross2affliction, dronon, earthfurst, GreenReaper, and mwalimu.

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— seeya soon, boring details about today’s comic: made with:

Erowid Exp104849

Erowid Exp98591

After being elected in 2008 on "hope and change", "change you can believe in", and "change the way Washington works", President Obama now says that he cannot change Washington from the inside? Then why should we re-elect him in 2012? Continue reading →

Cornel West and Tavis Smiley criticize President Barack Obama for being to the right of even President Richard Nixon. Continue reading →

Thinking of using TurboTax to file your tax returns? Think again. The Minnesota Department of Revenue advises against using Intuit software to file tax returns! It found unacceptable errors in Intuit tax software, including TurboTax, ProSeries, Lacerte, and Intuit online. Continue reading →

Is your standard charge for a speech $300,000?  According to an article appearing on the website of the Las Vegas Review-Journal, and a May 31, 2013 email, Clinton’s standard contract usually includes: Round-trip transportation on a chartered private jet “e.g., a Gulfstream … Continue reading →

A year ago this month the U.S. Department of Justice announced that the banking giant JPMorgan Chase would avoid criminal charges by agreeing to pay $13 billion to settle claims that it had routinely overstated the quality of mortgages it … Continue reading →

Vermont Sen. Bernie Sanders talks about the need for a "serious debate about serious issues," and whether he plans to challenge Hillary Clinton for the Democratic nomination. Sanders also adds that America needs to hear Hillary Clinton's opinions on the TPP, middle class struggles, and the Keystone XL pipeline. Continue reading →

Hillary Faces Questions About Cash Donations to Clinton Foundation. Continue reading →

Clinton Cash - do you trust Bill and Hillary Clinton in positions of power Continue reading →

"I think I'm the only candidate who's prepared to take on the billionaire class," Sanders, I-Vt., told ABC's George Stephanopoulos on "This Week." "We need a political revolution in this country involving millions of people who are prepared to stand up and say, enough is enough, and I want to help lead that effort." Continue reading →

The response of Senator Richard Blumenthal to my letter in opposition to the Trans-Pacific Partnership (TPP). Ask yourselves how American labor can compete against Vietnamese workers earning on average $0.56 per hour. Continue reading →

Democratic presidential candidate Sen. Bernie Sanders explains why he thinks he thinks his record of “strong and bold leadership” could help him best candidate Hillary Clinton in the Democratic primary. Continue reading →

Bernie Sanders offers a real deal to the middle class and not the raw deal of Hillary Clinton Continue reading →

The Senate considered H.R. 1314, the legislative vehicle for trade promotion authority reauthorization.?It would give the president broad fast-track authority when negotiating trade agreements and require Congress to consider treaties without an amendment process. Senator Bernie Sanders speaks out against this bill before the Senate on May 12, 2015. Continue reading →

Senator Bernie Sanders does not think that Hillary Clinton can stand up and fight for the middle class. Continue reading →

Even though Corporate America has anointed Hillary Clinton as its next President, Senator Bernie Sanders' populist message is already in a week's time raising individual contributions totaling millions of dollars from hundreds of thousands of people! Continue reading →

Video and transcript of Farron Cousins' discussion of Hillary Clinton's fake populism on Ring of Fire TV, May 18, 2015. Continue reading →