Publisher Health

Bipolar disorder affects millions of Americans, causing dramatic swings in mood and, in some people, additional effects such as memory problems.
While bipolar disorder is linked to many genes, each one making small contributions to the disease, scientists don’t know just how those genes ultimately give rise to the disorder’s effects.
However, in new research, scientists at the University of Wisconsin-Madison have found for the first time that disruptions to a particular protein called Akt can lead to the brain changes characteristic of bipolar disorder. The results offer a foundation for research into treating the often-overlooked cognitive impairments of bipolar disorder, such as memory loss, and add to a growing understanding of how the biochemistry of the brain affects health and disease.
The Cahill lab and their colleagues at Michigan State University published their findings March 24 in Neuron.
Akt is a kinase, a type of protein that adds tags of the molecule phosphate to other proteins. These phosphate tags can act as on or off switches, changing how other proteins work, ultimately influencing vital functions. In neurons, those functions can include how cells signal to one another, which can affect thinking and mood. When the Akt pathway is revved up, a lot of other proteins get phosphate tags. When it’s quieter, those phosphate tags are absent.
The researchers discovered that men with bipolar disorder have reduced activity of this pathway, known at Akt-mTOR, in a brain region crucial for attention and memory. And when the researchers disrupted the pathway in mice, the rodents developed memory problems and crucial brain connections withered away, simulating changes in humans with bipolar disorder.

A possible explanation for why many cancer drugs that kill tumor cells in mouse models won’t work in human trials has been found by researchers with The University of Texas Health Science Center at Houston (UTHealth) School of Biomedical Informatics and McGovern Medical School.
The research was published today in Nature Communications.
In the study, investigators reported the extensive presence of mouse viruses in patient-derived xenografts (PDX). PDX models are developed by implanting human tumor tissues in immune-deficient mice, and are commonly used to help test and develop cancer drugs.
“What we found is that when you put a human tumor in a mouse, that tumor is not the same as the tumor that was in the cancer patient,” said W. Jim Zheng, PhD, professor at the School of Biomedical Informatics and senior author on the study. “The majority of tumors we tested were compromised by mouse viruses.”
Using a data-driven approach, researchers analyzed 184 data sets generated from sequencing PDX samples. Of the 184 samples, 170 showed the presence of mouse viruses.
The infection is associated with significant changes in tumors, and Zheng says that could affect PDX as a drug testing model for humans.
“When scientists are looking for a way to kill a tumor using the PDX model, they assume the tumor in the mouse is the same as cancer patients, but they are not. It makes the results of a cancer drug look promising when you think the medication kills the tumor — but in reality, it will not work in human trial, as the medication kills the virus-compromised tumor in mouse,” Zheng said.
He hopes his findings will change researchers’ approach to find a way to kill tumor cells.
“We all share the common goal of hoping to find a cure for cancer. There are 210 ongoing NIH-funded projects relevant to PDX models, with a combined annual fiscal year budget of over $116 million. We need to tighten up quality control and use models that are not compromised so that the treatments we give to future patients are effective,” Zheng said.
This work is a collaboration between the Texas Therapeutics Institute, Institute of Molecular Medicine (IMM) at McGovern Medical School, and the Data Science and Informatics Core for Cancer Research at the School of Biomedical Informatics.
“As a team, we synergized the strengths of McGovern Medical School’s virology research and School of Biomedical Informatics’ data analysis expertise, and it has led to the success of this project,” said Zhiqiang An, PhD, co-senior author of the study, professor and Robert A. Welch Distinguished University Chair in Chemistry at McGovern Medical School.
The study is partly supported by the Cancer Prevention and Research Institute of Texas through grant RP170668, RP150551, and RP190561; the National Institutes of Health through grants 1UL1TR003167 and R01AG066749; and the Welch Foundation AU-0042-20030616.
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Materials provided by University of Texas Health Science Center at Houston. Original written by Jeannette Sanchez. Note: Content may be edited for style and length.

Type I Diabetes Mellitus (T1D) is an autoimmune disorder leading to permanent loss of insulin-producing beta-cells in the pancreas. In a new study, researchers from The University of Tokyo developed a novel device for the long-term transplantation of iPSC-derived human pancreatic beta-cells.
T1D develops when autoimmune antibodies destroy pancreatic beta-cells that are responsible for the production of insulin. Insulin regulates blood glucose levels, and in the absence of it high levels of blood glucose slowly damage the kidneys, eyes and peripheral nerves. Because the body loses the ability to produce insulin over time, the current mainstay of treatment for T1D is to inject insulin. An exciting research endeavor over the past decade has been to find ways to replace lost beta-cells by means of cell therapy.
“Cell therapy is an exciting, but challenging, approach to treat type I diabetes mellitus,” says lead author of the study Professor Shoji Takeuchi. “The challenge arises from the difficulty to make large amounts of human beta-cells in a dish, and more importantly, to achieve safe and effective transplantation. In this study, we wanted to develop a novel construct that enables successful transplantation of beta-cells in the long-term.”
To achieve their goal, the researchers developed a lotus-root-shaped cell-encapsulated construct (LENCON) and packaged it with human iPSC-derived pancreatic beta-cells, which are a limitless cell source and allow for the production of any number of beta-cells. The necessity for such an encapsulation technique arises from the fact that immune cells of the recipient could destroy the newly transplanted cells. To prevent this from happening, the researchers constructed the LENCON graft with millimeter thickness. The millimeter-thick graft diameters have previously been shown to mitigate the body’s immune response to a foreign body. At millimeter thickness, oxygen and nutrients could not be supplied to the center of the cells, but by using a lotus root shape, the cells were placed only near the edge of the graft where oxygen and nutrients can diffuse sufficiently, creating an environment in which the cells could survive, even in the millimeter-thick graft.
Having designed the LENCON, the question was if it would effectively control blood glucose levels in the long-term without provoking an immune response. To address this question, the researchers transplanted the construct in immunodeficient and immunocompetent diabetic mice. The former helped investigate the efficacy of the graft on controlling blood glucose levels in the absence of an immune response, while the latter approach tackled both goals. The researchers found that LENCON was able to maintain normal blood glucose levels for more than 180 days in the former mice, and was able to be removed without adhesion after more than one year of transplantation in the latter mice.
“These are striking results that show how LENCON can successfully and safely be used in the setting of type I diabetes mellitus. Our results suggest that LENCON could offer a novel option for cell therapy for type I diabetes mellitus,” says the first author of the study Dr. Fumisato Ozawa.
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Materials provided by Institute of Industrial Science, The University of Tokyo. Note: Content may be edited for style and length.

UConn researcher Paulo Verardi, associate professor of pathobiology and veterinary science in the College of Agriculture, Health and Natural Resources, has demonstrated the success of a vaccine against Zika virus and recently published his findings in Scientific Reports, a Nature Research publication. He has also filed provisional patent for the novel vaccine platform technology used to generate the vaccine, as well as genetic modifications made to the vaccine that significantly enhance expression of the vaccine antigen.
Verardi, a Brazilian native, was in Brazil visiting family in the summer of 2015 when the Zika outbreak first began to make waves and soon reached epidemic status.
Back in the United States, Verardi kept tabs on the Zika epidemic and its emerging connection to microcephaly, a serious birth defect that causes babies to be born with small heads and underdeveloped brains.
In October of that year, Verardi called then-Ph.D.-student Brittany Jasperse (CAHNR ’19) into his office and told her he wanted to apply their newly developed vaccine platform and start developing a vaccine for Zika virus.
Verardi and Jasperse were among the first researchers in the US to receive NIH funding to generate a vaccine against Zika virus, thanks to Verardi recognizing the significance of Zika virus early.
Modern advancements in genomic technology have expediated the vaccine development process. In the past, researchers needed to have access to the actual virus. Now just obtaining the genetic sequence of the virus can be sufficient to develop a vaccine, as was the case for the Zika vaccine Verardi and Jasperse developed, and the COVID-19 vaccines currently approved for emergency use in the United States and abroad.

The human body is an incredibly designed machine, and mechanical processes such as those in the lymphatic system play major roles in maintaining healthy tissue and organs.
Donny Hanjaya-Putra is an assistant professor whose work lies at the intersection of engineering and medicine. He studies the lymphatic system — the part of the immune system that rids the body of toxins and other unwanted materials. He looks at how to restore dysfunctional lymphatic networks, which are associated with a wide range of diseases, including cancer, cardiovascular disease, diabetes, neurological conditions and metabolic syndromes.
Now Hanjaya-Putra and his team — bioengineering doctoral student Laura Alderfer, along with Elizabeth Russo, a 2019 graduate; Adriana Archilla, a student from Syracuse University; and Brian Coe, class of ’19 — have demonstrated how extracellular matrix stiffness affects lymphatic vessel function.
The team is combining this knowledge with polymer science and mechanical engineering to build new lymphatic cord-like structures, which help restore normal behavior to dysfunctional lymphatic systems and allow the body to fight the disease.
“Cells can sense mechanical stimuli, such as matrix stiffness, and this activates certain genes to promote lymphatic formation,” said Hanjaya-Putra. “We used hydrogels made from hyaluronic acid (a natural sugar molecule) to enhance the cell-binding motif with appropriate mechanical stimuli (matrix stiffness) in a 2D model of lymphatic vessels and successfully stimulated new lymphatic vessel formations.”
The team has published its findings in The FASEB Journal of the Federation of American Societies for Experimental Biology.
This type of research is only possible, Hanjaya-Putra said, because of advances in imaging and stem cell biology.
“Traditionally, medical students spent hours studying the cardiovascular system, but not as much emphasis was placed on the lymphatic system,” said Hanjaya-Putra. “The reason, in large part, was due to the difficulty in visualizing lymphatic vessels, which are transparent.
“Recent advances have allowed us to use specific cell markers to distinguish between blood endothelial cells and lymphatic endothelial cells, so we can now see and study these very important networks in vitro and in vivo.”
Hanjaya-Putra and his team are now developing hydrogels that can be implanted under the skin to promote wound healing as well as gels that can be injected into the body at the site of injury.
Alderfer, the lead author on the FASEB article, was awarded a Fulbright U.S. Student Program Grant to study at the University of Helsinki. She will be studying lymphatic vessel formation in vivo in wound and cardiac injury models with Kari Alitalo, a global leader in the research of lymphatic vessels and translational cancer biology.
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Materials provided by University of Notre Dame. Original written by Nina Welding. Note: Content may be edited for style and length.

Physicists on the hunt for a rarely seen magnetic spin texture have discovered another object that bears its hallmarks, hidden in the structure of ultra-thin magnetic films, that they have called an incommensurate spin crystal.
A team from the University of Warwick reports the findings in the journal Nature Communications, which could offer new possibilities for technologies such as computer memory and storage.
The researchers initially set out to find a Skyrmion, a whirling magnetic spin texture theorised to exist in particular magnetic materials and that are of great interest to physicists due to their unique properties and potential for a new generation of energy efficient data storage. To find them, scientists look for abnormal behaviour of the Hall effect; this causes electrons moving through a conducting material to behave differently, measured as resistivity.
To induce this effect, the team created samples by combining an extremely thin film of a ferroelectric material, lead titanate, with another thin film of a ferromagnet, strontium ruthanate. These layers are atomically flat, a mere five to six unit cells (3 nanometres) thick.
The ferroelectric layer induces an electric field that warps the atomic structure of the ferromagnet, breaking its symmetry. Using atomical precision electron microscopy, they measured this symmetry breaking, and were also able to separately measure the electrical resistivity of the material and confirmed the presence of features akin to the Topological Hall effect, as would be expected for a Skyrmion.
Then the researchers used Magnetic Force Microscopy to examine the topology of the material’s atomic structure, which formed a lattice based on rectangles — not hexagons, as they would expect. Within this lattice are magnetic domains where Skyrmions would be found as individual, isolated particles. Instead, these domains formed more like beads on a string or necklace, with beads that never quite form a perfect circle.
Lead author Sam Seddon, a PhD student in the University of Warwick Department of Physics, said: “Once you make careful examination of the images, you realise, actually, this doesn’t present like a Skyrmion at all.
“A Skyrmion causes its own complicated Hall effect and when similar-looking effects are observed it is often treated as a signature of the Skyrmion. We’ve found a very ordered domain structure, just as a Skyrmion lattice would form, however they are simply chiral and not topologically protected. What this shows with real-space imaging evidence is that you don’t need a topological domain to cause a Hall effect of this kind.”
Ferroelectric and ferromagnetic materials are important for technologies such as computer memory and storage. For example, materials very similar to lead titanate are often used for the computer memory in the electronic systems in cars, due to their robustness and ability to operate at extreme temperatures.
Co-author Professor Marin Alexe from the University of Warwick said: “There is interest in these types of interfaces between ferroelectric and ferromagnet materials, such as for new types of computer memory. Because ferroelectric polarisation can be switched permanently, this modifies a quantum effect in a ferromagnet and that might give us direction for materials for the next quantum computers. These will need stable materials which work at extreme temperatures, are low-power consumption, and can store information for a long time, so all the ingredients are here.
“Topology is the translation of certain mathematical concepts into real life and is now at the core of new discoveries in physics. At the University of Warwick we have an extraordinary and advanced infrastructure which allows us to tackle a problem from theoretical point of view, to looking at atomic structure, right up to looking into functional properties at extreme temperatures and fields, especially magnetic fields. We are able to offer foundations for engineers to develop new technologies from.”
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Materials provided by University of Warwick. Note: Content may be edited for style and length.

An aggressive type of brain cancer, glioblastoma has no cure. Patients survive an average of 15 months after diagnosis, with fewer than 10% of patients surviving longer than five years. While researchers are investigating potential new therapies via ongoing clinical trials, a new study from Washington University in St. Louis suggests that a minor adjustment to the current standard treatment — giving chemotherapy in the morning rather than the evening — could add a few months to patients’ survival.
The study appears online in the journal Neuro-Oncology Advances.
Average overall survival for all patients in the study was about 15 months after diagnosis. Those receiving the chemotherapy drug temozolomide in the morning had an average overall survival of about 17 months post diagnosis, compared with an average overall survival of about 13½ months for those taking the drug in the evening, a statistically significant difference of about 3½ months.
“We are working hard to develop better treatments for this deadly cancer, but even so, the best we can do right now is prolong survival and try to preserve quality of life for our patients,” said co-senior author and neuro-oncologist Jian L. Campian, MD, PhD, an associate professor of medicine at the School of Medicine. “These results are exciting because they suggest we can extend survival simply by giving our standard chemotherapy in the morning.”
Co-senior authors Joshua B. Rubin, MD, PhD, a professor of pediatrics and of neuroscience at the School of Medicine, and Erik D. Herzog, PhD, the Viktor Hamburger Distinguished Professor and a professor of biology in Arts & Sciences, developed a collaboration to study circadian rhythms and their effect on glioblastoma. Rubin and Herzog published studies in which they analyzed mouse models of glioblastoma and found improved effectiveness for temozolomide when given in the morning.
“In my lab, we were studying daily rhythms in astrocytes, a cell type found in the healthy brain,” Herzog said. “We discovered some cellular events in healthy cells varied with time of day. Working with Dr. Rubin, we asked if glioblastoma cells also have daily rhythms. And if so, does this make them more sensitive to treatment at certain times? Very few clinical trials consider time of day even though they target a biological process that varies with time of day and with a drug that is rapidly cleared from the body. We will need clinical trials to verify this effect, but evidence so far suggests that the standard-of-care treatment for glioblastoma over the past 20 years could be improved simply by asking patients to take the approved drug in the morning.”
In the current study, the researchers — led by co-first authors Anna R. Damato, a graduate student in neuroscience in the Division of Biology & Biomedical Sciences, and Jingqin (Rosy) Luo, PhD, an associate professor of surgery in the Division of Public Health Sciences and co-director of Siteman Cancer Center Biostatistics Shared Resource — also observed that among a subset of patients with what are called MGMT methylated tumors, the improved survival with morning chemotherapy was more pronounced. Patients with this tumor type tend to respond better to temozolomide in general. For the 56 patients with MGMT methylated tumors, average overall survival was about 25½ months for those taking the drug in the morning and about 19½ months for those taking it in the evening, a difference of about six months, which was statistically significant.

A Penn Medicine patient with a genetic form of childhood blindness gained vision, which lasted more than a year, after receiving a single injection of an experimental RNA therapy into the eye. The clinical trial was conducted by researchers at the Scheie Eye Institute in the Perelman School of Medicine at the University of Pennsylvania. Results of the case, detailed in a paper published today in Nature Medicine, show that the treatment led to marked changes at the fovea, the most important locus of human central vision.
The treatment was designed for patients diagnosed with Leber congenital amaurosis (LCA) — an eye disorder that primarily affects the retina — who have a CEP290 mutation, which is one of the more commonly implicated genes in patients with the disease. Patients with this form of LCA suffer from severe visual impairment, typically beginning in infancy.
“Our results set a new standard of what biological improvements are possible with antisense oligonucleotide therapy in LCA caused by CEP290 mutations,” said co-lead author Artur V. Cideciyan, PhD, a research professor of Ophthalmology. “Importantly, we established a comparator for currently-ongoing gene editing therapies for the same disease, which will allow comparison of the relative merits of two different interventions.”
In an international clinical trial led at Penn Medicine by Cideciyan and Samuel G. Jacobson, MD, PhD, a professor of Ophthalmology, participants received an intraocular injection of an antisense oligonucleotide called sepofarsen. This short RNA molecule works by increasing normal CEP290 protein levels in the eye’s photoreceptors and improving retinal function under day vision conditions.
In a 2019 study published in Nature Medicine, Cideciyan, Jacobson, and collaborators found that injections of sepofarsen repeated every three months resulted in continued vision gains in 10 patients. The eleventh patient, whose treatment was detailed in the latest Nature Medicine paper, received only one injection and was examined over a 15-month period. Prior to treatment, the patient had reduced visual acuity, small visual fields, and no night vision. After the initial dose, the patient decided to forgo the quarterly maintenance doses, because the regular dosing could lead to cataracts.
After a single injection of sepofarsen, more than a dozen measurements of visual function and retinal structure showed large improvements supporting a biological effect from the treatment. A key finding from the case was that this biological effect was relatively slow in uptake. The researchers saw vision improvement after one month, but the patient’s vision reached a peak effect after month two. Most striking, the improvements remained when tested over 15 months after the first and only injection.

Infants born by cesarean section have a relatively meager array of bacteria in the gut. But by the age of three to five years they are broadly in line with their peers. This is shown by a study that also shows that it takes a remarkably long time for the mature intestinal microbiota to get established.
Fredrik Bäckhed, Professor of Molecular Medicine at Sahlgrenska Academy, University of Gothenburg, has been heading this research. The study, conducted in collaboration with Halland County Hospital in Halmstad, is now published in the journal Cell Host & Microbe.
Professor Bäckhed and his group have previously demonstrated that the composition of children’s intestinal microbiota is affected by their mode of delivery and diet. In the current study, the researchers examined in detail how the composition of intestinal bacteria in 471 children born at the hospital in Halmstad had developed.
The first fecal sample was collected when each child was a newborn infant. Thereafter, sampling took place at 4 months, 12 months, 3 years and 5 years. The scientists were thus able to follow the successive incorporation of various bacteria into the children’s gut microbiota.
At birth, the infant’s intestine has already been colonized by bacteria and other microorganisms. During the first few years of life, the richness of species steadily increases. What is now emerging is a considerably more detailed picture of this developmental trajectory.
One key conclusion is that the intestinal microbiota forms an ecosystem that takes a long time to mature. Even at 5 years of age, the system is incomplete. The maturation process can look very different from one child to another, and take varying lengths of time.

The governor is expected to sign the law, which would make New Mexico the 16th state to permit recreational use.New Mexico was set to become the 16th state to legalize recreational marijuana after the Legislature passed a bill on Wednesday, joining a national movement to rethink antidrug laws that are increasingly seen as impediments to racial justice and the economy.Gov. Michelle Lujan Grisham, a Democrat, said she would sign the bill, which would also expunge the criminal records of people who possessed marijuana for personal use. She said in a statement that workers, entrepreneurs and the government would benefit from the new industry, creating jobs and tax revenue.“And those who have been harmed by this country’s failed war on drugs, disproportionately communities of color, will benefit from our state’s smart, fair and equitable new approach to past low-level convictions,” she said.The bill passed on the same day that New York State legalized recreational marijuana. Lawmakers in both states said they were motivated to produce a legal, tax-revenue-generating industry that formerly operated underground, and to end arrests for low-level offenses.Under the New Mexico law, people over 21 would be permitted to have up to two ounces of marijuana, and individuals could have six plants at home, or up to 12 per household. Sales would begin no later than April 2022 and be taxed at 12 percent, eventually rising to 18 percent, plus gross receipts taxes.The industry will be regulated by the state and produce an estimated $20 million in revenue for the state in 2023, plus $10 million for local governments, according to a fiscal analysis cited by The Albuquerque Journal.New Mexico’s measure is part of a growing consensus in the United States in favor of marijuana decriminalization, with 91 percent of Americans in 2019 supporting legal medical or recreational use, according to the Pew Research Center. Voters in Arizona, Montana, New Jersey and South Dakota opted to legalize recreational marijuana in November, while Mississippi and South Dakota became the 34th and 35th states to allow medical marijuana.The New Mexico bill passed over Republican objections, but not all were opposed to legalization; some just clashed over the details, including how the industry would be taxed, licensed and regulated.Supporters, including Emily Kaltenbach, senior director for resident states and New Mexico for the Drug Policy Alliance, hailed the passage of the law.“Today’s passage of the cannabis legalization and expungement package will ensure equitable opportunities for farmers and other small businesses, and long overdue justice — including automatic expungement — for those with past cannabis arrests or convictions,” she said in a statement.About 100 prisoners will have their sentences reconsidered under the new law, according to The Associated Press.