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.
This past May (2019) the symposium “Psychedelic Therapy in Society: Exploring the Mechanisms of Action and Delivery of Care” was hosted by the International Forum on Consciousness at the BioPharmaceutical Technology Center on the Promega Madison Campus.
Having the good fortune to work across the street at Promega, I was able to attend this two-day conference and learn from leading researchers in psychedelics and about their use in therapy.
My interest in psychedelics is relatively new. I didn’t experiment with these substances during high school or college years. But in recent years, I’ve seen a close relative struggle with profound anxiety related to terminal disease, and another with substance abuse and depression. The lessons learned from each experience is that the battery of medicines used to treat such illness can result in additional problems for which there are currently not good medication options. And in some cases, traditional medications can cause further health problems. Continue reading “Psychedelics as Therapeutic Agents: Current Research, Potential Benefits”
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.
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.
We are in the midst of a very intense time of the year, with holidays and seasonal celebrations like Thanksgiving (recently past), Hanukkah this week and Christmas a mere two-plus weeks away.
Wrap that up with a New Year’s celebration and “Wham”—more friends, family and food/alcohol than one normally enjoys in a three-month period.
Yet it can also be the season of SAD—seasonal affective disorder when the amount of daylight decreases daily, and for those of us in the northern latitudes, cold weather intensifies. We’re eating more, getting less sunshine and quite probably less exercise. Hibernation is great for bears, not so good for humans.
It’s the wintertime blues. For myself and many, once the solstice passes and day length starts to increase, mood improves. But noticeable day-length increases don’t really occur here until mid-February. That’s a long time to feel the blues.
Since about 2000 we’ve learned a lot about the bacteria in our guts. We’ve learned that the right bacterial communities in our gastrointestinal system can make us feel better, think better and even help avoid obesity (1). My colleague Isobel has previously blogged about how certain gut bacteria can improve immunotherapy outcomes.
Conversely, the wrong bacteria in our guts can have negative consequences on health and cognition.
Along the way we’ve learned that gut bacterial flora can be influenced by what we eat, certain medications like antibiotics, and even stressful events. We now know that fermented foods like yogurt, sauerkraut, kombucha and that horrible-smelling stuff (kimchi) that another colleague eats are happy food for the good gut bacteria.
XWe use cookies and similar technologies to make our website work, run analytics, improve our website, and show you personalized content and advertising. Some of these cookies are essential for our website to work. For others, we won’t set them unless you accept them. To learn more about our approach to Privacy we invite you to Read More
By clicking “Accept All”, you consent to the use of ALL the cookies. However you may visit Cookie Settings to provide a controlled consent.
We use cookies and similar technologies to make our website work, run analytics, improve our website, and show you personalized content and advertising. Some of these cookies are essential for our website to work. For others, we won’t set them unless you accept them. To find out more about cookies and how to manage cookies, read our Cookie Policy.
If you are located in the EEA, the United Kingdom, or Switzerland, you can change your settings at any time by clicking Manage Cookie Consent in the footer of our website.
Necessary cookies are absolutely essential for the website to function properly. These cookies ensure basic functionalities and security features of the website, anonymously.
Cookie
Duration
Description
cookielawinfo-checbox-analytics
11 months
This cookie is set by GDPR Cookie Consent plugin. The cookie is used to store the user consent for the cookies in the category "Analytics".
cookielawinfo-checbox-functional
11 months
The cookie is set by GDPR cookie consent to record the user consent for the cookies in the category "Functional".
cookielawinfo-checbox-others
11 months
This cookie is set by GDPR Cookie Consent plugin. The cookie is used to store the user consent for the cookies in the category "Other.
cookielawinfo-checkbox-advertisement
1 year
The cookie is set by GDPR cookie consent to record the user consent for the cookies in the category "Advertisement".
cookielawinfo-checkbox-necessary
11 months
This cookie is set by GDPR Cookie Consent plugin. The cookies is used to store the user consent for the cookies in the category "Necessary".
cookielawinfo-checkbox-performance
11 months
This cookie is set by GDPR Cookie Consent plugin. The cookie is used to store the user consent for the cookies in the category "Performance".
gdpr_status
6 months 2 days
This cookie is set by the provider Media.net. This cookie is used to check the status whether the user has accepted the cookie consent box. It also helps in not showing the cookie consent box upon re-entry to the website.
lang
This cookie is used to store the language preferences of a user to serve up content in that stored language the next time user visit the website.
viewed_cookie_policy
11 months
The cookie is set by the GDPR Cookie Consent plugin and is used to store whether or not user has consented to the use of cookies. It does not store any personal data.
Analytical cookies are used to understand how visitors interact with the website. These cookies help provide information on metrics the number of visitors, bounce rate, traffic source, etc.
Cookie
Duration
Description
SC_ANALYTICS_GLOBAL_COOKIE
10 years
This cookie is associated with Sitecore content and personalization. This cookie is used to identify the repeat visit from a single user. Sitecore will send a persistent session cookie to the web client.
vuid
2 years
This domain of this cookie is owned by Vimeo. This cookie is used by vimeo to collect tracking information. It sets a unique ID to embed videos to the website.
WMF-Last-Access
1 month 18 hours 24 minutes
This cookie is used to calculate unique devices accessing the website.
_ga
2 years
This cookie is installed by Google Analytics. The cookie is used to calculate visitor, session, campaign data and keep track of site usage for the site's analytics report. The cookies store information anonymously and assign a randomly generated number to identify unique visitors.
_gid
1 day
This cookie is installed by Google Analytics. The cookie is used to store information of how visitors use a website and helps in creating an analytics report of how the website is doing. The data collected including the number visitors, the source where they have come from, and the pages visted in an anonymous form.
Advertisement cookies are used to provide visitors with relevant ads and marketing campaigns. These cookies track visitors across websites and collect information to provide customized ads.
Cookie
Duration
Description
IDE
1 year 24 days
Used by Google DoubleClick and stores information about how the user uses the website and any other advertisement before visiting the website. This is used to present users with ads that are relevant to them according to the user profile.
test_cookie
15 minutes
This cookie is set by doubleclick.net. The purpose of the cookie is to determine if the user's browser supports cookies.
VISITOR_INFO1_LIVE
5 months 27 days
This cookie is set by Youtube. Used to track the information of the embedded YouTube videos on a website.
Performance cookies are used to understand and analyze the key performance indexes of the website which helps in delivering a better user experience for the visitors.
Cookie
Duration
Description
YSC
session
This cookies is set by Youtube and is used to track the views of embedded videos.
_gat_UA-62336821-1
1 minute
This is a pattern type cookie set by Google Analytics, where the pattern element on the name contains the unique identity number of the account or website it relates to. It appears to be a variation of the _gat cookie which is used to limit the amount of data recorded by Google on high traffic volume websites.