While you and I are getting some shut eye each night, things are happening in our brains. Good things. Therapeutic things.
Think of it as brainwashing of a sort. There is a multiplicity of brain activities going on during sleep, and a November 1 paper in Science shows for the first time when and where in the brain these activities occur, and how they are connected.
Here’s a bit of backstory.
To assess both the progression and pathogenesis of Alzheimer’s disease (AD), as well as the efficacy of AD drugs in clinical trials, there has been interest in the concentrations of amyloid-beta (Aβ) and tau protein in cerebral spinal fluid (CSF).
There is nothing like a bit of recognition to energize your efforts, right? Promega was recently awarded the 2019 Distinguished Performer: Sustainability award, as one of the Deloitte Wisconsin 75 awardees.
This award is not so much a feather in our cap, as fuel for our sustainability fire both in Madison, and globally. Here are a few details on the award and why Promega was chosen.
Standing, walking, running. When was the last time you gave your skeleton a second thought? How about when that car barely missed you in the parking lot? Or a deer ran in front of you? Maybe you just missed a car door opening on your bike ride today?
Your bones were involved in your response to that sudden shock/surprise, but not the way you think.
You may have jumped, swerved or hit the brake pedal (congratulations on the excellent reflexes) and yes, bones were involved in all of those actions. But a new article in Cell Metabolism reveals that bone is the essential component in initiation of that response.
The review “Kinase Inhibitors: the road ahead” was recently published in Nature Reviews Drug Discovery. In it, authors Fleur Ferguson and Nathanael Gray provide an up-to-date look at the “biological processes and disease areas that kinase-targeting small molecules are being developed against”. They note the related challenges and the strategies and technologies being used to efficiently generate highly-optimized kinase inhibitors.
This review describes the state of the art for kinase inhibitor therapeutics. To understand why kinase inhibitors are so important in the development of cancer (and other) therapeutics research, let’s start with the role of kinases in cellular physiology.
The cause of type 1 diabetes (T1D) is not well understood. What is known is that in T1D, immune cells attack pancreatic islet cells that produce insulin. In addition, insulin is an autoantigen that activates T cells in diabetic persons.
A new discovery by Ahmed et al. could further T1D understanding. These findings are also setting B and T cell paradigms on their ear.
About B Cells and T Cells
B cells (B lymphocytes) are part of the cellular immune response. They act by means of surface receptor molecules that are immunoglobulins. These B cell receptors are created by highly variable gene rearrangements that result in a huge variety of these surface immunoglobulin molecules. The beauty of B cell receptors (BCR) lies in the fact that, through random gene rearrangements comes a such large variety of B cell surface receptors, that any foreign antigen that makes its way into the body is recognized and snagged by a B cell receptor.
In my science blog research/writing, news reports are usually pulled from US sources. But interesting scientific research is obviously being conducted in many places around the globe. When this story from Namibia came along, there was so much I didn’t know. It was time to catch up.
Namibia is Exactly Where in Africa?
Namibia is one of the world’s youngest countries, having gained independence from South Africa in 1990. Situated northwest of the country of South Africa on the Atlantic Ocean, Namibia is arid, composed largely of desert.
This blog is about research conducted at the Sam Nujoma Research Center, University of Namibia, on Henties Bay. Henties Bay (not shown on this map) is in the region of Erongo, located in the center of Namibia along the coast. Henties Bay has become a tourist destination in part due to the abundance of fish and marine life found there.
Life in the 21st century is full of electronic devices and apps purported to make life easier. Many of us can binge watch movies, videos and news on our phones. There are wireless headphones, electric bicycles, self-operating vacuum cleaners, wine in boxes with taps—and so much more.
This life is, however, not without challenges.
In the event that you or yours ends up in the hospital, the stay could be complicated by an unplanned, unwanted and potentially lethal infection.
As announced at SLAS in Washington, D.C. recently, we are excited to have NanoBRET Target Engagement (TE) Intracellular Kinase Assays awarded the SelectScience Reviewers’ Choice for Drug Discovery and Development Product of the Year 2018!
PROTACs or Proteolysis-Targeting Chimeras are an emerging tool in protein degradation studies, potentially suited to any need involving the removal of a specific protein. These small-molecule chimeras are exciting due to: 1) their target specificity; and 2) their ability to enable target destruction versus target inhibition. Here we discuss a paper that presents a roadmap for PROTAC development.
Destruction/Inhibition: Is There a Difference? An analogy that microbiologists (and wrestlers or anyone that has ever spent time in a locker room shower) would understand, is fungicidal versus fungistatic compounds. A fungicidal compound kills fungus. A fungistatic compound just slows the fungus down a bit.
A small-molecule inhibitor attaches to its target protein, but for how long? What inhibitor testing must be done to determine how long the inhibition lasts?
On the other hand, a small-molecule agent that causes protein degradation first targets the protein of interest, then attaches ubiquitin to that target. Once a protein is marked with ubiquitin, it’s a dead man. E3 ligase must be involved, but if the ubiquitin is added by E3, the end is near. Next stop, Hades.
This ubiquitinated protein is headed to the proteasome and proteins that go there don’t come back. Ubiquitination was called the ‘molecular kiss of death’ when this discovery was awarded the Nobel prize in Chemistry in 2004.
About PROTACs
PROTACs are degrader molecules composed of three parts: 1) a ligand that is specific for the target protein; 2) a ligand for E3 ligase; and 3) a linker molecule that connects the two ligands. The E3 ligase is one of three enzymes that can add ubiquitin to a cellular component, but only ubiquitins added by the E3 ligase cause targeting to the proteasome (Zoppi et al.).
Have you ever had a day where you feel exceptionally good? As intake on the world kind of good? You feel so much better than the previous couple of days that you stop to wonder why.
Then it dawns on you.
The sun is out. It’s been cloudy for the past week but now—SUNSHINE.
You go out to lunch or for a walk just to take in those rays. Sure, it feels warmer than your darkened office space, but it’s the light rather than warmth that’s making a difference.
You purposely don’t wear sunglasses and it feels like the light is coming in through your eyes and massaging that part of your brain that is your happy zone. Are you imagining it or is the sun really affecting how you feel?
In a study reported in the September 2018 issue of Cell we learn that this is not a figment of your or my imagination (1). There is, in fact, a type of retinal cell that transports sunlight directly to the part of our brains that affects mood.
Eyes and the Body’s Master Clock
Circadian rhythms are innate time-keeping functions found in all multicellular organisms. This subject of the 2017 Nobel prize in Physiology or Medicine, circadian rhythms are fueled by daily light-dark cycles and are critical to the function of neurologic, immune, musculoskeletal and cardiac tissues (2). Nearly every mammalian cell is affected by circadian rhythms.
The human body has a circadian master clock, the suprachiasmatic nucleus or SCN. The SCN is a highly innervated tissue located in the hypothalamus (see image). It is connected directly to the retina by the optic nerve, and thus is influenced by external light and dark.
The retina of the eye is the light-gathering instrument for this organ. Historically, it’s been understood that the retina is composed of two cell types, rods and cones, that function in transmitting light and images to the optic nerve, which sends those signals to the brain.
Studies by Hattar et al. in the early 2000s identified another cell found in the retina, the melanopsin-containing intrinsically photoactive retinal ganglion cells (ipRGCs) as the transmitter of circadian light signals (3). Through this direct connection to the SCN, the circadian master clock, the ipRGCs can influence a wide range of light-dependent functions independent of image processing (4).
Now Fernandez et al. have identified multiple types of ipRGCs. They showed that ipRGCs that mediate the effects of light on learning work via the SCN, while the pathway for light influencing emotions is different.
They discovered a new target of ipRGC cells, the perihabenular nucleus (PHb). The PHb is a newly recognized thalamic region of the brain. The authors showed that the connection between light and mood is regulated by ipRGCs through the PHb versus the SCN. They show that the PHb is integrated into other mood-regulating centers of the thalamic region.
In Conclusion
Daylight, and lack thereof, does affect both our mood and our ability to learn. In this 2018 report, we have learned that the pathways for these effects are distinct, and gain an understanding of a new thalamic region by which the light and mood actions occur. This information could influence the development of better drugs and/or therapies for major depressive disorders.
For those of us with seasonal affective disorder, the evidence is undeniable—lack of light can cause issues, from sleep-wake problems, to mood and learning issues.
And while we can’t create sunshine, a special lamp or lightbox may help to gain some full-spectrum light. To learn more about how to choose such a lamp and when to use it, see this Mayo clinic article for details.
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