Stem Cell Drugs Surprise Researchers: Could Lead to Better Drugs in the Future (Medicine)

Chemotherapy destroys stem cells, which then cannot develop into immune cells and become part of the body’s defences. There are drugs that can remedy this, but previously we did not know exactly how these drugs worked. Now, a study conducted in mice by researchers at the University of Copenhagen details their function providing new knowledge that may improve stem cell transplantation and lead to better drug design in the future.

Your immune system is always busy fighting incoming threats. It consists of a system of cells, and when there is a shortage of cells, it affects the performance of the immune system.

This is seen in e.g. cancer patients following chemotherapy. This is because chemotherapy targets all the cells in your body, including the stem cells in your bone marrow, which were meant to develop into new immune cells. This means that the immune system then lacks cells to fight new infections.

There are drugs that can harvest stem cells from the bone marrow, so that they can be returned to the patients after treatment. They then develop into new immune cells, enabling the body to once again fight incoming threats. But previously, we lacked detailed knowledge of how these drugs worked.

Now, a study conducted in mice by researchers at the University of Copenhagen demonstrates how the medicine works at the cell level – and, surprisingly, how one of the two applied and tested drugs is more effective than the other, despite the fact that the other drug, on paper, appears to be the most effective of the two. This discovery may not just help improve stem cell transplantation; it may also lead to improved drugs in the future.

“We have tested two drugs for stem cell transplantation which appear to have the same effect. What they do is block a receptor, causing the bone marrow to release stem cells into the blood. What the new study shows, though, is that they do not just block the receptor; one of the two drugs also affects other signalling pathways in the cell. And in short, that makes it more effective than the other of the two drugs,” says PhD Student Astrid Sissel Jørgensen from the Department of Biomedical Sciences at the University of Copenhagen.

“We used to believe that all we had to do was block the receptor, and that the two drugs had the same effect. It now appears that there is more to it,” she says. 

Directly relevant to the current use of medicine

The drugs tested by the researchers mobilize stem cells by acting as CXCR4 receptor antagonists. This means that they inhibit or reduce activity of the receptor. Several drugs target this receptor, including drugs inhibiting HIV replication. 

“The drugs not only block the receptor’s normal signalling. One of the two drugs we have tested also affect some of the other cell pathways and even make the receptor withdraw into the cell and disappear from the surface,” explains Professor Mette Rosenkilde, who is the corresponding author of the study. The study results reveal that one of the two drugs makes the bone marrow release more stem cells into the blood.

This knowledge about how drugs affect cell pathways differently is also known as biased signalling. And it is things like these that make one of the drugs more effective in practice than on paper.

According to the researchers, the new knowledge on biased signalling challenges our current view of these drugs.

“The results of our study directly influence our view of drugs used for stem cell transplantation. In the long term, though, it may also affect our view of future drugs, and how new drugs should be designed to have the best possible effect, both in connection with stem cell mobilisation, but also for treating HIV infections, where this particular receptor also plays a main role,” says Mette Rosenkilde.

Read the entire study, ’Biased action of the CXCR4-targeting drug plerixafor is essential for its superior hematopoietic stem cell mobilization’, here.


Featured image: The study reveals that one of the two drugs suprisingly makes the bone marrow release more stem cells into the blood than the other drug tested (Colourbox).


Provided by University of Copenhagen

‘Good’ Bacteria Show Promise for Clinical Treatment of Crohn’s Disease, Ulcerative Colitis (Medicine)

Balfour Sartor, MD, Midget Distinguished Professor of Medicine, Microbiology and Immunology, is the senior author of a study that shows how a novel consortium of bacteria that live in the digestive tracts of healthy individuals can be used to prevent and treat aggressive colitis in humanized mouse models.

A new study published in Nature Communications demonstrates that a consortium of bacteria designed to complement missing or underrepresented functions in the imbalanced microbiome of inflammatory bowel disease (IBD) patients, prevented and treated chronic immune-mediated colitis in humanized mouse models. The study’s senior author, Balfour Sartor, MD, Midget Distinguished Professor of Medicine, Microbiology and Immunology, Co-Director of the UNC Multidisciplinary IBD Center, said the results are encouraging for future use treating Crohn’s disease and ulcerative colitis patients.

“The idea with this treatment is to restore the normal function of the protective bacteria in the gut, targeting the source of IBD, instead of treating its symptoms with traditional immunosuppressants that can cause side effects like infections or tumors,” Sartor said.

The live bacteria consortia, called GUT-103 and GUT-108, were developed by biotech firm Gusto Global. GUT-103 is comprised of 17 strains of bacteria that work together to protect and feed each other. GUT-108 is a refined version of GUT-103, using 11 human isolates related to the 17 strains. These combinations permit the bacteria to stay in the colon for an extended amount of time, as opposed to other probiotics that are not capable of living in the gut and pass through the system quickly.

GUT-103 and GUT-108 were given orally three times a week to “germ-free” mice (no bacteria present) that had been specially developed and treated with specific human bacteria, creating a humanized mouse model. The therapeutic bacteria consortia worked by addressing upstream targets, rather than targeting a single cytokine to block downstream inflammation responses, and reversed established inflammation.

“It also decreased pathobionts – bacteria that can cause harm – while expanding resident protective bacteria, and produced metabolites promoting mucosal healing and immunoregulatory responses,” Sartor said. “Simply put – the treatment increased the good guys and decreased the bad guys.”

Because of the robust results seen in this study, and the need for more alternative therapies for Crohn’s disease, Sartor would like to see GUT-103 and GUT-108 studied in Phase 1 and 2 clinical trials in the future. He plans to continue his work with Gusto Global to further explore uses of the bacterial consortia.

This work was funded by Gusto Global, LLC. Daniel Van der Lelie, PhD, Chief Executive Officer of Gusto Global, is the first author of this study. Germ-free mice were provided by grants from the National Institutes of Health (NIH) and the Crohn’s and Colitis Foundation.

Featured image: Balfour Sartor, MD © UNC Health


Reference: van der Lelie, D., Oka, A., Taghavi, S. et al. Rationally designed bacterial consortia to treat chronic immune-mediated colitis and restore intestinal homeostasis. Nat Commun 12, 3105 (2021). https://doi.org/10.1038/s41467-021-23460-x


Provided by UNC Health

Scientists Develop Transparent Electrode That Boosts Solar Cell Efficiency (Material Science)

Developing new ultrathin metal electrodes has allowed researchers to create semitransparent perovskite solar cells that are highly efficient and can be coupled with traditional silicon cells to greatly boost the performance of both devices, said an international team of scientists. The research represents a step toward developing completely transparent solar cells.

“Transparent solar cells could someday find a place on windows in homes and office buildings, generating electricity from sunlight that would otherwise be wasted,” said Kai Wang, assistant research professor of materials science and engineering at Penn State and co-author on the study. “This is a big step — we finally succeeded in making efficient, semitransparent solar cells.”

Traditional solar cells are made from silicon, but scientists believe they are approaching the limits of the technology in the march to create ever more efficient solar cells. Perovskite cells offer a promising alternative and stacking them on top of the traditional cells can create more efficient tandem devices, the scientists said.

“We’ve shown we can make electrodes from a very thin, almost few atomic layers of gold,” said Shashank Priya, associate vice president for research and professor of materials science and engineering at Penn State. “The thin gold layer has high electrical conductivity and at the same time it doesn’t interfere with the cell’s ability to absorb sunlight.”

The perovskite solar cell that the team developed achieved 19.8% efficiency, a record for a semitransparent cell. And when combined with a traditional silicon solar cell, the tandem device achieved 28.3% efficiency, up from 23.3% from the silicon cell alone. The scientists reported their findings in the journal Nano Energy.

“A 5% improvement in efficiency is giant,” Priya said. “This basically means you are converting about 50 watts more sunlight for every square meter of solar cell material. Solar farms can consist of thousands of modules, so that adds up to a lot of electricity, and that’s a big breakthrough.”

In previous research, ultrathin gold film showed promise as a transparent electrode in perovskite solar cells, but issues in creating a uniform layer resulted in poor conductivity, the scientists said.

The team found that chromium used as a seed layer allowed the gold to form on top in a continuous ultrathin layer with good conductive properties.

“Normally, if you grow a thin layer of something like gold, the nanoparticles will couple together and gather like small islands,” said Dong Yang, assistant research professor of materials science and engineering at Penn State. “Chromium has a large surface energy that provides a good place for the gold to grow on top of, and it actually allows the gold to form a continuous thin film.”

Perovskite solar cells are composed of five layers and other materials tested as transparent electrodes damaged or degraded layers of the cells. The scientists said solar cells made with the gold electrodes are stable and maintain high efficiencies over time in laboratory tests.

“This breakthrough in the design of tandem cell architecture based on a transparent electrode offers an efficient route toward the transition to perovskite and tandem solar cells,” said Yang.

Also contributing to this research from Penn State were Tao Ye and Jungjin Yoon, postdoctoral scholars; and Yuchen Hou, a doctoral student.

Xiaorong Zhang, Shaanxi Normal University, China; Shengzhong Liu, Chinese Academy of Sciences; Congcong Wu, Hubei University, China; and Mohan Sanghadasa, U.S. Army Combat Capabilities Development Command, also contributed to the research.

The Office of Naval Research, the Army Rapid Innovation Fund, and the Air Force Office of Scientific Research provided funding for this research.

Featured image: Scientists found using a chromium seed layer allowed them to grow ultrathin gold film that serves as a transparent electrode with good conductivity for perovskite solar cells. Image: Penn State


Reference: Dong Yang, Shashank Priya et al., “28.3%-efficiency perovskite/silicon tandem solar cell by optimal transparent electrode for high efficient semitransparent top cell”, Nano energy. Vol. 84, June 2021. https://doi.org/10.1016/j.nanoen.2021.105934


Provided by Penn State University

Cheap Alloy Rivals Expensive Platinum To Boost Fuel Cells (Chemistry)

As the cleanest renewable energy, hydrogen energy has attracted special attention in the research. Yet the commercialization of traditional proton exchange membrane fuel cells (PEMFCs), which consume hydrogen and produce electricity, is seriously restricted due to the chemical reaction of PEMFCs cathode largely relies on expensive platinum-based catalysts.

A solution is to change the acidic electrolyte of PEMFCs to alkaline. Such fuel cells are called anion exchange membrane fuel cells (AEMFCs), and they allow for the use of cheaper metal elements like Co, Ni or Mn to design electrocatalysts.

The research team led by Prof. GAO Minrui from University of Science and Technology of China (USTC) followed this solution and developed a practical and scalable way to manufacture a novel Ni-W-Cu alloy, Ni5.2WCu2.2, as the cathode for AEMFCs. The result was published on Nature Communications.

Synthesis diagram of Ni5.2WCu2.2 and a Ni5.2WCu2.2 electrode of size 3×10cm² obtained in this way. © QIN Shuai et al.

The team first grew Cu(OH)2 nanowires from a three-dimensional foam copper skeleton by anodic oxidation. The obtained nanowires were then immersed in a solution containing Ni and W elements. After hydrothermal synthesis and annealing, the Ni-W-Cu alloy is produced.

The ternary Ni5.2WCu2.2 alloy can catalyze the oxidation of hydrogen in alkaline medium 4.31 times more efficient than the benchmark platinum/carbon anode.

It has an oxidation potential as high as 0.3V in comparison with the reversible hydrogen electrode and can maintain high activity for up to 20h under such overpotential, proceeding anodes based on non-platinum-group metals.

The alloy catalyst also showed excellent resistance to CO poisoning, and maintained high activity in 20000 ppm CO/H2 mixed atmosphere.

Analysis showed that the projected density of states of Ni5.2WCu2.2 alloy lies in the lowest at Fermi level, which indicates that the alloy has the optimal hydrogen binding energy. The multiple-element alloying effect renders the Ni-based alloy a high activity catalyst and offers oxidation resistance.

This work sheds light on further exploration of multiple-element alloys composed of cheap metals, thereby aiding the development of more efficient hydrogen oxidation catalysts for AEMFC anodes.

Featured image: The left figure shows platinum price trends over the past two decades and the right figure explains the alternative: anion exchange membrane fuel cells (AEMFCs). © QIN Shuai et al.


Reference: Qin, S., Duan, Y., Zhang, XL. et al. Ternary nickel–tungsten–copper alloy rivals platinum for catalyzing alkaline hydrogen oxidation. Nat Commun 12, 2686 (2021). https://doi.org/10.1038/s41467-021-22996-2


Provided by University of Science and Technology of China

BESSY II: New Insights into Switchable MOF Structures at the MX Beamlines (Material Science)

Metal-organic framework compounds (MOFs) are widely used in gas storage, material separation, sensor technology or catalysis. A team led by Prof. Dr. Stefan Kaskel, TU Dresden, has now investigated a special class of these MOFs at the MX beamlines of BESSY II. These are “switchable” MOFs that can react to external stimuli. Their analysis shows how the behaviour of the material is related to transitions between ordered and disordered phases. The results have now been published in Nature Chemistry.

Metal-organic framework compounds (MOFs) consist of inorganic and organic groups and are characterised by a large number of pores into which other molecules can be incorporated. MOFs are therefore interesting for many applications, for example for the storage of gases, but also for substance separation, sensor technology or catalysis. Some of these MOF structures react to different guest molecules by changing their structures. They are thus considered switchable.

One of these is “DUT-8”, a material that has now been studied at the MX beamlines of BESSY II.  “MOF crystals can be analysed very well at the MX beamlines,” says HZB expert Dr. Manfred Weiss, who heads the MX team.  “MOF crystals have many things in common with protein crystals. For example, both are interspersed with large pores, which are filled with liquid in the protein crystals, while those in MOFs provide space for guest molecules,” Weiss explains.

“The diffraction patterns that DUT-8 showed on the HZB-MX beamlines were extremely complex. We were now able to attribute this to various transitions between ordered and less ordered phases,” explains Stefan Kaskel. The enclosed guest molecule directs the network into one of over a thousand possible disorder configurations.  The results contribute to a better understanding of switching processes and gas exchange reactions in such MOF structures, so that future functional MOF materials can be developed in a targeted manner.

The investigations were supported by the DFG programme (FOR2433).

Featured image: View into a MOF crystal exemplified by DUT-8. The massive pores are clearly discernible. © TU Dresden


Reference: S. Ehrling, E. M. Reynolds, V. Bon, I. Senkovska, T. E. Gorelik, J. D. Evans, M. Rauche, M. Mendt, Manfred S. Weiss, A. Pöppl, E. Brunner, U. Kaiser, A. L. Goodwin and S. Kaskel, “Adaptive response of a metal–organic framework through reversible disorder–disorder transitions”, Nature Chemistry (2021). DOI: 10.1038/s41557-021-00684-4


Provided by HZB

Plant Flowering in Low-nitrogen Soils: A Mechanism Revealed (Botany)

Scientists from Japan, Europe and the USA have described  a pathway leading to the accelerated flowering of plants in low-nitrogen soils. These findings could eventually lead to increases in agricultural production.

Nitrogen is one of the three macronutrients required by plants for growth and development, along with phosphorus and potassium. Nitrogen-rich condition induces plant growth, particularly the growth of stems and leaves, while delaying flowering. On the other hand, in some plants, low-nitrogen conditions lead to a change from growth mode to reproductive mode, therefore accelerating flowering. However, the molecular mechanisms that regulate flowering under these conditions are not known.

A team of scientists led by Associate Professor Takeo Sato of Hokkaido University’s Graduate School of Life Science has revealed the molecular mechanism responsible for the acceleration of flowering in Arabidopsis under low nitrogen conditions. Their findings were published in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS).

Arabidopsis, a cruciferous plant, is well known as a model plant in biology and has an extensive database of its protein expression. In the current study,  the team first identified a set of proteins involved in flowering that became active as a result of changes in nitrogen level. One of these was the gene regulation factor FLOWERING BHLH 4 (FBH4). Through experiments using FBH4 deficient plants, this protein was found to be responsible for accelerated flowering under low-nitrogen conditions.

FBH4 is necessary for accelerated flowering in Arabidopsis. Accelerated flowering is only seen in the wild type(left), but not in FBH4 deficient plants (right) plants, under low-nitrogen conditions (Miho Sanagi, et al. Proceedings of the National Academy of Sciences of the United States of America. May 11, 2021).

Further investigation suggested that FBH4 is extensively phosphorylated by another protein called SnRK1. Low-nitrogen conditions suppress SnRK1 activity, which in turn results in the dephosphorylation of FBH4. The dephosphorylated FBH4 moves to the nucleus to activate genes responsible for flowering. Dephosphorylated FBH4 is also responsible for controlling the expression of other genes vital for plant survival under low nitrogen conditions, particularly those related to nitrogen recycling and remobilization.

The scientists concluded that, in response to inadequate nitrogen, Arabidopsis plants appear to precisely control gene expression related to developmental and metabolic processes required for flowering through FBH4. “The FBH family of genes is present in major crop plants,” says Takeo Sato. “Crop plants exhibit early flowering under low-nitrogen conditions; if we can control FBH activities in these crop plants, it might be an effective way to sustainably increase agricultural production.”

Takeo Sato, with Arabidopsis plants in the culture room (Photo: Takeo Sato).

Original Article:

Miho Sanagi, et al. Low nitrogen conditions accelerate flowering by modulating the phosphorylation state of FLOWERING BHLH 4 in ArabidopsisProceedings of the National Academy of Sciences of the United States of America. May 11, 2021. DOI: 10.1073/pnas.2022942118

Funding:

This work was supported by Grants-in-Aid for Scientific Research (17K08190, 20K05949, 26292188, 18H02162) and Research Fellowships for Young Scientists from the Japan Society for the Promotion of Science (JSPS), the Northern Advancement Center for Science & Technology (NOASTEC) foundation, the Hokkaido University Young Scientist Support Program, the National Institutes of Health (R01GM079712), the National Science Foundation (IOS-1656076), Next-Generation BioGreen 21 Program (PJ013386) from the Rural Development Administration, Republic of Korea, and the Max Planck Society.

Featured image: Arabidopsis plants used in one of the experiments during the study (Photo: Takeo Sato).


Provided by Hokkaido University

New Drug Combination Found to be Effective Against High-risk Leukaemia (Medicine)

Australian scientists have found what could prove to be a new and effective way to treat a particularly aggressive blood cancer in children.

Acute lymphoblastic leukaemia, or ALL, is the most common cancer diagnosed in children. Despite dramatic improvements in the survival of children with ALL over past several decades, children who develop ‘high risk’ ALL – subtypes that grow aggressively and are often resistant to standard treatments – often relapse, and many of these children die from their disease.

One common type of high-risk ALL for which new therapies are urgently needed is ‘Philadelphia chromosome-like ALL’ (Ph–like ALL), named for its similarity to another type, Ph–positive ALL. Shared genetic characteristics of these two types of high-risk ALL have led scientists to hypothesise that they may respond to similar treatments; specifically, a newer class of drugs known as kinase inhibitors.

However, experiments have shown that cases of Ph–like ALL that contain a genetic mutation known as CRLF2r – about half of all cases of this subtype – respond poorly to kinase inhibitors when used as a single agent. Scientists have since been investigating whether kinase inhibitors are more effective when used in combination with other agents.

In new research published this week in the international journal Leukemia, scientists at Children’s Cancer Institute tested more than 5000 drugs in combination with the kinase inhibitor, ruxolitinib, finding that ruxolitinib worked synergistically with several types of commonly used anticancer drugs, the most effective being glucocorticoids, topoisomerase I and II inhibitors, microtubule targeting agents, and antimetabolites.

“New therapies are urgently needed for high-risk ALL,” said lead researcher Professor Richard Lock, Head of the Blood Cancers Theme at Children’s Cancer Institute. “We are very encouraged by our results, which suggest we could be on the way to developing a more effective way to treat this cancer in some children.”

Based on their in vitro findings, the researchers then carried out in vivo testing in living models of disease known as ‘patient-derived xenograft models’ (PDXs) or ‘avatars’: mice specially bred to grow leukaemia cells taken from individual patients with CRLF2r Ph-like ALL. Results showed that the addition of ruxolitinib to a common treatment regimen called VXL (consisting of vincristine, dexamethasone, and L-asparaginase) enhanced treatment efficacy in two out of three avatars, achieving long-term suppression of leukaemia growth in one of these.

“The enhanced effect of treatment when ruxolitinib was added, and the variety of drug classes found to synergize with ruxolitinib in our laboratory, suggest promising potential for kinase inhibitors in the treatment of Ph-like ALL,” said Professor Lock. “We hope this leads to improved treatment options for children with this leukaemia in the near future.”


Reference: Alessandra Di Grande, Sofie Peirs, Paul D. Donovan, Maaike Van Trimpont, Julie Morscio, Beatrice Lintermans, Lindy Reunes, Niels Vandamme, Steven Goossens, Hien Anh Nguyen, Arnon Lavie, Richard B. Lock, Jochen H. M. Prehn, Pieter Van Vlierberghe, Triona Ní Chonghaile; The spleen as a sanctuary site for residual leukemic cells following ABT-199 monotherapy in ETP-ALL. Blood Adv 2021; 5 (7): 1963–1976. doi: https://doi.org/10.1182/bloodadvances.2021004177


Provided by Children’s Cancer Institute


About Children’s Cancer Institute

Originally founded by two fathers of children with cancer in 1976, Children’s Cancer Institute is the only independent medical research institute in Australia wholly dedicated to research into the causes, prevention and cure of childhood cancer. More than 40 years on, our vision remains unchanged – to save the lives of all children with cancer and to eliminate their suffering. The Institute has grown to now employ nearly 300 researchers, operational staff and students, and has established a national and international reputation for scientific excellence. Our focus is on translational research, and we have an integrated team of laboratory researchers and clinician scientists who work together in partnership to discover new treatments which can be progressed from the lab bench to the beds of children on wards in our hospitals as quickly as possible. These new treatments are specifically targeting childhood cancers, so we can develop safer and more effective drugs and drug combinations that will minimize side-effects and ultimately give children with cancer the best chance of a cure with the highest possible quality of life. More at http://www.ccia.org.au.

Want To Reduce Your Depression Risk? Wake Up An Hour Earlier (Psychiatry)

Waking up just one hour earlier could reduce a person’s risk of major depression by 23%, suggests a sweeping new genetic study published May 26 in the journal JAMA Psychiatry.

The study of 840,000 people, by researchers at University of Colorado Boulder and the Broad Institute of MIT and Harvard, represents some of the strongest evidence yet that chronotype—a person’s propensity to sleep at a certain time —influences depression risk.

It’s also among the first studies to quantify just how much, or little, change is required to influence mental health.

As people emerge, post-pandemic, from working and attending school remotely— a trend that has led many to shift to a later sleep schedule—the findings have important implications.

“We have known for some time that there is a relationship between sleep timing and mood, but a question we often hear from clinicians is: How much earlier do we need to shift people to see a benefit?” said senior author Celine Vetter, assistant professor of integrative physiology at CU Boulder. “We found that even one-hour earlier sleep timing is associated with significantly lower risk of depression.”

Previous observational studies have shown that night owls are as much as twice as likely to suffer from depression as early risers, regardless of how long they sleep. But because mood disorders themselves can disrupt sleep patterns, researchers have had a hard time deciphering what causes what.

Other studies have had small sample sizes, relied on questionnaires from a single time point, or didn’t account for environmental factors which can influence both sleep timing and mood, potentially confounding results.

In 2018, Vetter published a large, long term study of 32,000 nurses showing that “early risers” were up to 27% less likely to develop depression over the course of four years, but that begged the question: What does it mean to be an early riser?

How your genes influence when you wake up

To get a clearer sense of whether shifting sleep time earlier is truly protective, and how much shift is required, lead author Iyas Daghlas turned to data from the DNA testing company 23 and Me and the biomedical database UK Biobank. Daghlas then used a method called “Mendelian randomization” that leverages genetic associations to help decipher cause and effect.

“Our genetics are set at birth so some of the biases that affect other kinds of epidemiological research tend not to affect genetic studies,” said Daghlas, who graduated in May from Harvard Medical School.

More than 340 common genetic variants, including variants in the so-called “clock gene” PER2, are known to influence a person’s chronotype, and genetics collectively explains 12-42% of our sleep timing preference.

The researchers assessed deidentified genetic data on these variants from up to 850,000 individuals, including data from 85,000 who had worn wearable sleep trackers for 7 days and 250,000 who had filled out sleep-preference questionnaires. This gave them a more granular picture, down to the hour, of how variants in genes influence when we sleep and wake up.

In the largest of these samples, about a third of surveyed subjects self-identified as morning larks, 9% were night owls and the rest were in the middle. Overall, the average sleep mid-point was 3 a.m., meaning they went to bed at 11 p.m. and got up at 6 a.m.

With this information in hand, the researchers turned to a different sample which included genetic information along with anonymized medical and prescription records and surveys about diagnoses of major depressive disorder.

Using novel statistical techniques, they asked: Do those with genetic variants which predispose them to be early risers also have lower risk of depression?

The answer is a firm yes.

Each one-hour earlier sleep midpoint (halfway between bedtime and wake time) corresponded with a 23% lower risk of major depressive disorder.

Put another way, if someone who normally goes to bed at 1 a.m. goes to bed at midnight instead and sleeps the same duration, they could cut their risk by 23%; if they go to bed at 11 p.m., they could cut it by about 40%.

It’s unclear from the study whether those who are already early risers could benefit from getting up even earlier. But for those in the intermediate range or evening range, shifting to an earlier bedtime would likely be helpful.

Light days, dark nights key

What could explain this effect?

Some research suggests that getting greater light exposure during the day, which early-risers tend to get, results in a cascade of hormonal impacts that can influence mood.

Others note that having a biological clock, or circadian rhythm, that trends differently than most peoples’ can in itself be depressing.

“We live in a society that is designed for morning people, and evening people often feel as if they are in a constant state of misalignment with that societal clock,” said Daghlas.

He stresses that a large randomized clinical trial is necessary to determine definitively whether going to bed early can reduce depression. “But this study definitely shifts the weight of evidence toward supporting a causal effect of sleep timing on depression.”

For those wanting to shift themselves to an earlier sleep schedule, Vetter offers this advice:

“Keep your days bright and your nights dark,” she says. “Have your morning coffee on the porch. Walk or ride your bike to work if you can, and dim those electronics in the evening.”


Reference: Daghlas I, Lane JM, Saxena R, Vetter C. Genetically Proxied Diurnal Preference, Sleep Timing, and Risk of Major Depressive Disorder. JAMA Psychiatry. 2021 May 26. doi: 10.1001/jamapsychiatry.2021.0959. Epub ahead of print. PMID: 34037671.


Provided by University of Colorado Boulder

Tiniest of Moments Proves Key for Baby’s Healthy Brain (Neuroscience)

School of Medicine researchers have shed new light on how our brains develop, revealing that the very last step in cell division is crucial for the brain to reach its proper size and function. 

The new findings identify a potential contributor to microcephaly, a birth defect in which the head is underdeveloped and abnormally small. That’s because the head grows as the brain grows. The federal Centers for Disease Control estimates that microcephaly affects from 1 in 800 children to 1 in 5,000 children in the United States each year. The condition is associated with learning disabilities, developmental delays, vision and hearing loss, movement impairment and other problems.

“By understanding the genetic causes of microcephaly, even though they are rare, we can also help to understand how some viral infections can cause of microcephaly, such as Zika virus or cytomegalovirus,” said researcher Noelle D. Dwyer, PhD, of UVA’s Department of Cell Biology.

UNDERSTANDING BRAIN DEVELOPMENT

Dwyer and her team aim to understand how small changes in individual cells can lead to dramatic changes in the brain. In this case, they have identified an important role for abscission, the final step in cell division. During abscission, a new, or “daughter,” cell severs its connection to its “mother” cell. Think of it like cutting the cord when a new baby arrives in the world.

Scientists have suspected that a particular cellular protein, Cep55, is essential for proper abscission. Dwyer wanted to investigate that, to determine what would happen if the protein were absent. She and her colleagues were surprised to find that abscission could still occur in their lab mice. However, the process took longer than usual, and the failure rate went up substantially.

Notably, the neural stem cells that failed abscission signaled that they needed to be removed from the brain, the researchers report. That led to massive numbers of cells dying and being removed. That’s in contrast to cells elsewhere in the body, which don’t call for their own removal when abscission fails.

“Neural stem cells in the prenatal brain seem to have tighter ‘quality control’ than cells in other parts of the body. If their DNA or organelles are damaged, they have this hair-trigger response to sacrifice themselves, so that they don’t make abnormal brain cells that might cause brain malfunction, or brain tumors,” Dwyer said. “Brain can still function. Other tissues seem to have a higher tolerance for damaged cells and don’t activate this cell-death response.”

Blocking the neural stem cells’ signal for removal helped the brains of lab mice grow larger, Dwyer found, but this restored only part of the brain’s normal size. Further, normal brain organization and function remained disrupted. This shows the importance of proper abscission in healthy brain development, the researchers say.

Dwyer noted that blocking the cell death signal with drugs or gene therapy could help restore brain growth in certain types of microcephaly, but it also might make brain function worse. “That’s why it’s important to test these ideas in animal models and cell-culture models,” she said.

UVA’s new findings align with what scientists have known about the gene that makes the Cep55 protein. People who have mutations in the Cep55 gene suffer severe defects in their brain and central nervous system, while the rest of their bodies are relatively spared. Dwyer’s new research helps explain why that is.

The new findings also benefit the battle against cancer. “Cep55 mutations are also found associated with many human cancers, so understanding the normal function of Cep55 in dividing cells in the brain helps inform cancer researchers how its altered function could lead to abnormal cell division that can initiate or fuel tumor growth,” Dwyer said.

Dwyer noted the important contributions of Jessica Little and Katrina McNeely, who recently completed their PhDs in Dwyer’s lab. Little is an MD-PhD student in UVA’s Cell & Developmental Biology program who graduated this spring; McNeely was a Neuroscience graduate student who defended her dissertation last year.

FINDINGS PUBLISHED

The researchers have published their findings in the Journal of Neuroscience. The research team consisted of Little, McNeely, Nadine Michel, Christopher J. Bott, Kaela S. Lettieri, Madison R. Hecht, Sara A. Martin and Dwyer. Little and McNeely are listed as co-first authors on the paper.

The research was supported by the National Institutes of Health, grants RO1NS076640, R21NS106162, R01HD102492 and F30HD093290; and a UVA Cell and Molecular Biology Training Grant, T32GM008136.

Featured image: Noelle D. Dwyer, PhD, and her team have made new discoveries about brain development. © UVA Health


Provided by UVA Health