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Saturday, July 2, 2022

Expect CDC to seek bigger spend for quarantine stations 'to prevent next pandemic'

 In today’s interconnected world, people, packages, and animals can circumnavigate the globe in less than a day. This speed of connection makes it easier to visit far-flung family members, conduct overseas business, and seek a better or safer life — but it also allows for the rapid spread of diseases that threaten the health of every community.

Diseases with pandemic potential are becoming increasingly common as humans encroach upon the natural world, putting people in closer contact with animals and environments that can spread illness. The capacity of frontline health organizations to swiftly and efficiently contain illness has not always kept pace with how quickly diseases now spread.

One agency essential to preventing the spread of disease is the Centers for Disease Control and Prevention’s Division of Global Migration and Quarantine. This division serves as a first line of defense against global health threats by managing a network of quarantine stations that play a vital part in identifying infectious diseases and preventing their spread before they enter communities.

More than 1 million travelers enter the United States on a typical day through 300 ports of entry. The Division of Global Migration and Quarantine manages quarantine stations at the 20 international airports and land-border crossings where most international travelers arrive. It is responsible for screening sick travelers, notifying other passengers about possible exposures, and restricting the importation of animals or products that may carry disease.

The CDC asked the National Academies of Sciences, Engineering, and Medicine (NASEM) to convene a group of experts to assess the division and make recommendations based on its performance during Covid-19. This working group, which we participated in, commended the division and its workers for responding admirably to the Herculean task they faced. They were asked to use new tools and intervene at an unprecedented scale.

Yet the division’s responses were impeded because it lacked modern data systems, a well-trained workforce capable of surge capacity, adequate funding, and strong legal powers.

The NASEM report, “Improving the CDC Quarantine Station Network’s Response to Emerging Threats,” offers a roadmap for supporting and strengthening the Division of Global Migration and Quarantine to anticipate and respond effectively to prevent the next pandemic before it takes hold. Here are some of the report’s key recommendations. We and our colleagues hope the CDC and federal government will adopt them to prepare for — and help stop — the next pandemic.

Consistent and increased funding. Core funding for the Division of Global Migration and Quarantine has stagnated over the past decade, even as the agency has faced more frequent and complex threats, like Middle East Respiratory Syndrome, Zika, Ebola, the H1N1 flu, and now Covid-19. The division relies heavily on boom-or-bust surge funding, but needs more reliable funding streams to adequately support its immense responsibilities.

To avoid costly delays, the review committee recommends that the Department of Health and Human Services create a surge fund the division can quickly access during an emergency outbreak.

While the division oversees more than 300 ports of entry, it has funding to operate only 20 quarantine stations, limiting its ability to quickly contain widespread disease threats. The CDC should explore a user-fee program that would, for example, charge maritime and aviation industries for the quarantine and regulatory services it provides them. This could provide consistent funding to run these stations.

Expand CDC’s regulatory authority during public health emergencies. During the Covid-19 pandemic, virtually all CDC orders made under the Public Health Service Act were legally challenged, and many were significantly delayed or blocked by federal courts. The CDC needs to be given ample powers to act decisively in public health emergencies. Congress should modernize this act to ensure that the CDC has the authority to effectively prevent or mitigate current and future public health threats — while still ensuring protections for individual rights and freedoms.

Build a robust and resilient workforce. During Covid-19, the agency has struggled with many unfilled positions and inadequate staffing that led to lapses in coverage at quarantine stations, burnout, and high turnover. The NASEM committee recommended a recruitment, training, and retention plan committed to diversity, equity, and inclusion, along with innovative strategies to meet its unique workforce needs. The committee suggested a “Ready Reserve Corps” of well-trained and experienced professionals who would be pre-approved and available to meet a surge in workforce needs during emergencies.

Develop playbooks for future emergencies. The Division of Global Migration and Quarantine needs detailed plans and playbooks based on the most worrisome and likely infectious disease threats. It should develop these in collaboration with key international organizations, as well as state, local, and tribal health agencies. Plans should be informed by the lessons learned during the response to Covid-19 and include considerations for equity and the ethical care of vulnerable populations.

Embrace new technologies. The division should expand innovative technologies to help detect outbreaks and slow the spread of diseases. Such technologies can help gather health data from large numbers of incoming travelers, trace disease transmission, and alert travelers to exposures. In tandem, it should develop a system to ensure that technologies are used ethically and respect privacy rights.

Add a maritime unit. As Covid-19 took hold, cruise ships became a significant source of transmission. To improve the ability to collaborate with the cruise industry to prevent disease, the CDC’s maritime unit should be permanently housed within its Division of Global Migration and Quarantine.


Michele Barry is a professor and senior associate dean of Global Health at Stanford University, director of the Stanford Center for Innovation in Global Health, a member of the Board of Global Health for the National Academy of Medicine, and chair emeritus of the Consortium of Universities for Global Health. Lawrence O. Gostin is a professor and faculty director of the O’Neill Institute for National and Global Health Law at Georgetown Law, director of the World Health Organization Collaborating Center on Public Health Law and Human Rights, and author of “Global Health Security: A Blueprint for the Future” (Harvard University Press, 2021).

https://www.statnews.com/2022/07/01/improve-cdcs-quarantine-stations-to-prevent-the-next-pandemic/

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Helping babies to sleep more

 Over the last decade, researchers and staff working on Penn State's INSIGHT study have trained new mothers in skills that -- among other things -- help newborns sleep more during the night. New research from Penn State's Center for Childhood Obesity Research (CCOR) shows that second children in these families also slept longer.

New parents often want infants to sleep because the parents are tired, but sleep is critical to health and development. The researchers in CCOR study sleep because it affects whether children develop obesity. Sleep also affects a child's capacity for emotional regulation and cognitive development. What is more, research shows that sleep deprived parents are more likely to develop depression and be involved in traffic accidents. Infant sleep can be important for the whole family's health and well-being.

Responsive parenting

The INSIGHT study -- an acronym for intervention nurses start infants growing on healthy trajectories -- began in 2012 with CCOR researchers training 279 mothers of first-born infants in responsive parenting practices. Responsive parenting involves responding to children in a timely, sensitive, and age-appropriate manner, based on the child's presenting needs.

In INSIGHT, the mothers were taught how to respond to infant behavior states like fussiness, alertness (feeding and interactive play), drowsiness, and sleeping. The training included several specific recommendations about bedtime routines and responding to nighttime waking.

Children in the INSIGHT intervention group slept longer each night and were more likely to soothe themselves to sleep than children in the control group. Significantly, these children also had lower body mass indices (BMIs) for the first three years of their lives.

Understanding 'spillover' effects

As the INSIGHT study progressed, it led the investigators to explore whether the training also affected children who were later born into INSIGHT families.

"Many parents say things like, 'Oh, I did everything right with my first child, and then I had no time for the others,'" explained Emily Hohman, assistant research professor in CCOR. "So, in order to understand whether the effects of INSIGHT spill over to other siblings, we launched a new study where we do not provide any training or intervention for parents or children. We just track information about second-born children in families where mothers received the INSIGHT training for their first-born."

Hohman led a team of researchers who examined data from 117 mothers from the original INSIGHT study who were having a second child, about half of whom had received the responsive parenting training with their firstborn child. The team used a brief questionnaire to assess second-born children's sleep behavior and duration when the children were three, 16, and 52 weeks old.

In a recent publication in the journal Pediatrics, the researchers demonstrated that second-born children in INSIGHT families slept an average of 40 minutes longer per night than second-born children in the control group. The second-born INSIGHT children also slept more than 50 minutes longer per 24-hour period, had earlier bedtimes in early life, and were more likely to fall asleep in under 15 minutes.

This is not the first study that has shown that the effects of INSIGHT spilled over to second-born children. Other studies have demonstrated that second-born children in INSIGHT families have lower body-mass indices (BMIs) as infants than children in the control group. Additionally, parental feeding practices and infants' dietary intake were healthier than those of children from control group families.

How parents can promote better sleep for their infants (and themselves)

The INSIGHT study trained mothers, but responsive parenting skills are useful for anyone who provides care to children. At bedtime, responsive parenting involves establishing healthy routines, responding to children according to their development and needs, and teaching children to soothe themselves as much as possible.

For parents who do not know anything about responsive parenting, Hohman recommends starting by establishing a bedtime. "People sometimes think that if they keep their babies awake with them later at night, then the baby will sleep later. But the research shows that early establishment of a bedtime between seven and eight o'clock will help babies sleep longer," said Hohman.

Once a regular bedtime is established, research indicates that consistent bedtime routines also promote longer sleep. The routine should be soothing and include things like baths and reading, while avoiding overly stimulating activities like rowdy play. The routine will help the child prepare for sleep. Additionally, infants who are not yet rolling over can be swaddled to increase their sense of calm.

To help children learn to soothe themselves to sleep, parents are encouraged to put their children to bed while they are drowsy but still awake. Self-soothing is a valuable skill, and the sooner children learn it, the better they and their parents will sleep.

Nighttime waking is inevitable; newborns and infants wake throughout the night for many reasons, including hunger. This does not mean that feeding should always be a parent's first response when their baby wakes. Hohman and her colleagues encourage parents to use "lighter touch" soothing methods like offering the baby a pacifier, words of reassurance, and gentle touches. More engaged soothing, like holding, rocking and feeding, should only be used if the baby remains distressed or shows signs of hunger.

"No one likes to hear their baby cry, and everyone wants to get back to sleep as soon as possible," said Hohman. "But a baby can only learn to soothe themselves when they are not being soothed by someone else. During the daytime, parents should feel free to use more active soothing strategies like holding or rocking, but these should be used more judiciously at nighttime in order to promote better sleep."

Helping families everywhere

The study results indicate that intervening with first-time parents could be an efficient way to help multiple children in a family.

"Our outcomes suggest that pediatricians may have a new tool to help promote better infant sleeping and prevent unhealthy infant weight gain," Hohman said. "Pediatricians typically have a lot of visits with new families. If those clinicians help new parents build responsive parenting skills, the benefits could extend to the parents, their newborns, and any potential future children in those families."

Jennifer Savage Williams, associate professor of nutritional sciences at Penn State and director of CCOR; Michele E. Marini, retired CCOR staff member; Stephanie Anzman-Frasca, associate professor of pediatrics at University of Buffalo; Orfeu M. Buxton, Elizabeth Fenton Susman Professor of Biobehavioral Health at Penn State; Eric Loken, associate professor of educational psychology at University of Connecticut; and Ian M. Paul, professor of pediatrics and public health sciences at Penn State College of Medicine all contributed to this research.

This research was funded by the National Institute of Diabetes and Digestive and Kidney Diseases.

Story Source:

Materials provided by Penn State. Original written by Aaron Wagner. Note: Content may be edited for style and length.

Journal Reference:

  1. Emily E. Hohman, Jennifer S. Savage, Michele E. Marini, Stephanie Anzman-Frasca, Orfeu M. Buxton, Eric Loken, Ian M. Paul. Effect of the INSIGHT Firstborn Parenting Intervention on Secondborn Sleep. Pediatrics, 2022; DOI: 10.1542/peds.2021-055244

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How bacteria adhere to cells: Basis for developing new class of antibiotics

 The adhesion of bacteria to host cells is always the first and one of the decisivesteps in the development of infectious diseases. The purpose of this adhesion by infectious pathogens is first to colonize the host organism (i.e., the human body), and then to trigger an infection, which in the worst case can end fatally. Precise understanding of the bacteria's adhesion to host cells is a key to finding therapeutic alternatives that block this critical interaction in the earliest possible stage of an infection.

Critical interaction with the human protein fibronectin

In collaboration with other researchers, scientists from University Hospital Frankfurt and Goethe University Frankfurt have now explained the exact bacterial adhesion mechanism using the human-pathogenic bacterium Bartonella henselae. This pathogen causes "cat-scratch disease," a disease transmitted from animals to humans. In an international collaborative project led by the Frankfurt research group headed by Professor Volkhard Kempf, the bacterial adhesion mechanism was deciphered with the help of a combination of in-vitro adhesion tests and high-throughput proteomics. Proteomics is the study of all the proteins present in a cell or a complex organism.

The scientists have shed light on a key mechanism: the bacterial adhesion to the host cells can be traced back to the interaction of a certain class of adhesins -- called "trimeric autotransporter adhesins" -- with fibronectin, a protein often found in human tissue. Adhesins are components on the surface of bacteria which enable the pathogen to adhere to the host's biological structures. Homologues of the adhesin identified here as critical are also present in many other human-pathogenic bacteria, such as the multi-resistant Acinetobacter baumannii, which the World Health Organization (WHO) has classified as the top priority for research into new antibiotics.

State-of-the-art protein analytics were used to visualize the exact points of interaction between the proteins. In addition, it was possible to show that experimental blocking of these processes almost entirely prevents bacterial adhesion. Therapeutic approaches that aim to prevent bacterial adhesion in this way could represent a promising treatment alternative as a new class of antibiotics (known as "anti-ligands") in the constantly growing domain of multi-resistant bacteria.

Story Source:

Materials provided by Goethe University Frankfurt. Note: Content may be edited for style and length.

Journal Reference:

  1. Diana J. Vaca, Arno Thibau, Matthias S. Leisegang, Johan Malmström, Dirk Linke, Johannes A. Eble, Wibke Ballhorn, Martin Schaller, Lotta Happonen, Volkhard A. J. Kempf. Interaction of Bartonella henselae with Fibronectin Represents the Molecular Basis for Adhesion to Host Cells. Microbiology Spectrum, 2022; 10 (3) DOI: 10.1128/spectrum.00598-22

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Leukemia-killing compounds discovered

 Researchers from Rice University and the University of Texas MD Anderson Cancer Center have discovered potential new drugs that work in concert with other drugs to deliver a deadly one-two punch to leukemia.

The potential drugs are still years away from being tested in cancer patients, but a recently published study in the journal Leukemia highlights their promise and the innovative methods that led to their discovery.

In previous studies, the research groups of Rice biochemist Natasha Kirienko and MD Anderson physician-scientist Marina Konopleva screened some 45,000 small-molecule compounds to find a few that targeted mitochondria. In the new study, they chose eight of the most promising compounds, identified between five and 30 closely related analogs for each and conducted tens of thousands of tests to systematically determine how toxic each analog was to leukemia cells, both when administered individually or in combination with existing chemotherapy drugs like doxorubicin.

"One of the big challenges was to establish optimal conditions and doses for testing on both cancer cells and healthy cells," said study lead author Svetlana Panina, a researcher at the University of Texas at Austin who conducted the research during her postdoctoral studies at Rice. "The results from our previously published cytotoxicity assay were helpful, but very little is known about these small-molecule compounds. None of them had been thoroughly described in other studies, and we had to essentially start from scratch to determine how much to use, what they do in cells, everything. All the doses and treatment conditions had to be adjusted by multiple preliminary experiments."

In prior work, Kirienko's lab had shown the eight compounds targeted energy-producing machinery inside cells called mitochondria. Dozens to thousands of mitochondria are at work every minute in every living cell, and like all machines, they wear out with use. The eight compounds induce mitophagy, the housekeeping routine cells use to decommission and recycle mitochondria that are past their prime.

During times of extreme stress, cells can temporarily forgo mitophagy to get an emergency energy boost. Cancer is notorious for hijacking these sorts of programs to fuel pathological growth. For example, previous research has shown leukemia cells have far more damaged mitochondria than healthy cells and are also more sensitive to mitochondrial damage than healthy cells.

Kirienko and Konopleva reasoned that mitophagy-inducing drugs might weaken leukemia cells and make them more susceptible to chemotherapy.

"We hypothesized that if they activate mitophagy, they may be particularly toxic to leukemia cells," said Kirienko, the corresponding author of the new study. "And indeed, we found that six of the eight small-molecule compounds were deadly to leukemia cells. We then wanted to study them more in depth. So we looked at closely related molecules, and we looked at combinations."

When two or more drugs are given in combination, researchers can also administer them individually and compare the effectiveness of each regimen.

"There is a number called synergy coefficient that quantifies interactions between drugs," Kirienko said. "If the coefficient is negative, the drugs are antagonistic and work against one another. Zero means no effect, and positive numbers indicate positive interactions. Anything above 10 is considered synergistic."

For example, one currently prescribed drug combination for leukemia -- doxorubicin and cytarabine -- has a synergy coefficient of 13, Kirienko said. The team's experiments showed several mitophagy-inducing compounds were significantly more synergistic with doxorubicin. The most synergistic, a compound called PS127B, had a coefficient of 29.

"The point of synergy is that there are concentrations, or dosages, where a single drug doesn't kill," Kirienko said. "There is no death of healthy cells or cancer cells. But administering those same concentrations in combination can kill a considerable amount of cancer cells and still not affect healthy cells."

The team started by testing the toxicity of its mitophagy-inducing compounds and combinations against acute myeloid leukemia (AML) cells, the most commonly diagnosed form of the disease. They then tested the six most effective AML-killing compounds against other forms of leukemia and found five were also effective at killing acute lymphoblastic leukemia (ALL) cells and chronic myelogenous leukemia (CML) cells. Control studies found all the mitophagy-inducing drugs caused far less harm to healthy cells.

In their final experiments, the researchers tested one of the most effective mitochondria-targeting compounds, PS127E, using a cutting-edge technique called a patient-derived xenograft (PDX) model. In PDX, also referred to as a "mouse clinical trial," mice are implanted with cancer cells from a leukemia patient. Once the cells grow, the mouse is exposed to a drug or combination of drugs as a closer-than-cells test of the treatment's effect. PDX tests on one compound, PS127E, showed it was effective at killing AML cells in mice.

"Although this is very promising, we're still some distance from having a new treatment we can use in the clinic," Kirienko said. "We still have a lot to discover. For example, we need to better understand how the drugs work in cells. We need to refine the dose we think would be best, and perhaps most importantly, we need to test on a wide variety of AML cancers. AML has a lot of variations, and we need to know which patients are most likely to benefit from this treatment and which are not. Only after we've done that work, which may take a few years, would we be able to start testing in humans."

Additional study co-authors include Jingqi Pei and Elissa Tjahjono of Rice, Natalia Baran, Shraddha Patel, Gheath Alatrash and Sergej Konoplev of MD Anderson, and Leonid Stolbov and Vladimir Poroikov of the Institute of Biomedical Chemistry in Moscow.

The research was supported by the Cancer Prevention and Research Institute of Texas (RR150044), the National Institutes of Health (R35GM129294, R01CA231364, P50CA100632) and the Russian Federation Fundamental Research Program (1220301001705).

Story Source:

Materials provided by Rice University. Original written by Jade Boyd. Note: Content may be edited for style and length.

Journal Reference:

  1. Svetlana B. Panina, Jingqi Pei, Natalia Baran, Elissa Tjahjono, Shraddha Patel, Gheath Alatrash, Sergej Konoplev, Leonid A. Stolbov, Vladimir V. Poroikov, Marina Konopleva, Natalia V. Kirienko. Novel mitochondria-targeting compounds selectively kill human leukemia cells. Leukemia, 2022; DOI: 10.1038/s41375-022-01614-0

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Identifying cognitive impairments with multiple drawing tasks

 Changes in drawing traits have been reported in people with early-stage cognitive impairments, but most studies have used a single drawing task only. In a study published recently in the Journal of Alzheimer's Disease, researchers from the University of Tsukuba and IBM Research have found that they could classify people with normal cognition, mild cognitive impairment (MCI), and Alzheimer's disease (AD) with much greater accuracy by combining traits extracted from five different drawing tasks than by using just one or two tasks.

Around 75% of people with dementia have not been diagnosed, and this is partly because there is a lack of accurate screening tests that can be done outside of a doctor's office or hospital. Recently, the quest for better screening techniques has become more important as new therapies are developed that can slow the progression of cognitive impairment. Researchers at the University of Tsukuba wanted to address this lack of accurate screening tests using the automatic analysis of drawing.

"Although it's clear that motion- and pause-related drawing traits can be used to screen for cognitive impairments, most screening tests remain relatively inaccurate" says senior author of the study Professor Tetsuaki Arai. "We wondered what might happen if we were to analyze these traits while people performed a range of different drawing tasks."

To do this, the researchers used five different drawing tests that capture different aspects of cognition and are commonly used when diagnosing AD and MCI. While these tests were being performed, 22 different drawing features -- relating to pen pressure, pen posture, speed, and pauses -- were automatically analyzed per test. The researchers then compared these features with scores from seven different tests of cognitive function, and used a computer-based program to see how well the drawing traits could be used to identify people with normal cognition, MCI, or AD.

"We were surprised by how well the combination of drawing traits extracted from multiple tasks worked by capturing different, complementary aspects of cognitive impairments," explains Professor Arai. "The three-group classification accuracy of all five tests was 75.2%, which was almost 10% better than that of any of the tests by themselves."

In addition, the majority of the drawing features that were different between the three groups had greater changes between the normal and AD subjects compared with the normal and MCI subjects -- this is important because MCI is often considered an early (and less severe) form of AD.

"Although this was a relatively small study, the results are encouraging," says Professor Arai. "Our results pave the way for better screening tests for cognitive impairments."

With the ever-increasing numbers of therapies targeting the early stages of cognitive impairment, screening tests are becoming more important. Better screening will lead to earlier diagnoses, which will in turn improve patients' quality of life.

This work was supported by the Japan Society for the Promotion of Science, KAKENHI (grants 19H01084 and 18K18164). The funders did not play any active role in either the scientific investigation or the reporting of the study.


Story Source:

Materials provided by University of Tsukuba. Note: Content may be edited for style and length.

Journal Reference:

  1. Masatomo Kobayashi, Yasunori Yamada, Kaoru Shinkawa, Miyuki Nemoto, Kiyotaka Nemoto, Tetsuaki Arai. Automated Early Detection of Alzheimer’s Disease by Capturing Impairments in Multiple Cognitive Domains with Multiple Drawing Tasks. Journal of Alzheimer's Disease, 2022; 1 DOI: 10.3233/JAD-215714

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Floating in space might be fun, but it's hard on earthly bodies

 Ever wondered if you have anything in common with an astronaut? Turns out there are 206 things -- your bones. It's these parts of our body that are the focus of a research study on bone loss in astronauts, and the important question of whether bone can be re-gained after returning to Earth.

The TBone study was started in 2015 by Dr. Steven Boyd, PhD, director of the McCaig Institute for Bone and Joint Health and professor in the Cumming School of Medicine. The study has followed 17 astronauts before and after spaceflight over the last seven years to understand whether bone recovers after 'long-duration' spaceflight. Findings are published in Scientific Reports, and while it might not seem like it matters to you here on Earth, the research is important to better understand bone health generally.

"Bone loss happens in humans -- as we age, get injured, or any scenario where we can't move the body, we lose bone," says Dr. Leigh Gabel, PhD, assistant professor in Kinesiology, and lead author of the study.

"Understanding what happens to astronauts and how they recover is incredibly rare. It lets us look at the processes happening in the body in such a short time frame. We would have to follow someone for decades on Earth to see the same amount of bone loss," Gabel says.

The researchers travelled to Johnson Space Center in Houston, Texas to scan the wrists and ankles of the astronauts before they left for space, on their return to Earth, and then at six- and 12-months.

"We found that weight-bearing bones only partially recovered in most astronauts one year after spaceflight," she says. "This suggests the permanent bone loss due to spaceflight is about the same as a decade worth of age-related bone loss on Earth."

This loss happens because bones that would normally be weight-bearing on Earth, like your legs, don't have to carry weight in microgravity -- you just float.

"We've seen astronauts who had trouble walking due to weakness and lack of balance after returning from spaceflight, to others who cheerfully road their bike on Johnson Space Center campus to meet us for a study visit. There is quite a variety of response among astronauts when they return to Earth, says Boyd.

Former UCalgary Chancellor and astronaut, Dr. Robert Thirsk, BSc (Eng)'76, Hon. LLD'09, MD, knows firsthand how bizarre the return to Earth can be. "Just as the body must adapt to spaceflight at the start of a mission, it must also readapt back to Earth's gravity field at the end," says Thirsk. "Fatigue, light-headedness, and imbalance were immediate challenges for me on my return. Bones and muscles take the longest to recover following spaceflight. But within a day of landing, I felt comfortable again as an Earthling."

Some astronauts who flew on shorter missions, under six months, recovered bone strength and density in the lower body, compared to those who flew for longer durations.

Access to astronauts is rare -- the study team includes two members from the European Space Agency (ESA), Dr. Anna-Maria Liphardt, PhD, and Martina Heer, PhD, as well as two from NASA, Dr. Scott Smith, PhD, and Dr. Jean Sibonga, PhD. The study was funded by the Canadian Space Agency and conducted in partnership with ESA, NASA and astronauts from North America, Europe, and Asia.

As future space missions are exploring travel to more distant locations, the study's next iteration will explore the effects of even longer trips, to support astronauts who may one day travel beyond the International Space Station.

As Thirsk says, "Astronauts will venture to deep space this decade and, in the coming centuries, humanity will populate other star systems. Let's push back the frontiers of space exploration now to make this vision possible."

Dr. Leigh Gabel, PhD, is an assistant professor in the Faculty of Kinesiology, a member at the McCaig Institute for Bone and Joint Health in Cumming School of Medicine and a member of the Alberta Children's Hospital Researcher Institute. 

Dr. Steven Boyd, PhD, is a professor at the Cumming School of Medicine (CSM) in the Department of Radiology and holds a joint position at the Schulich School of Engineering and the Faculty of Kinesiology. He is the director of the McCaig Institute for Bone and Joint Health at the CSM, and the Bob and Nola Rintoul Chair in Bone and Joint Research, as well as the McCaig Chair in Bone and Joint Health.

Story Source:

Materials provided by University of Calgary. Original written by Gillian Edwards. Note: Content may be edited for style and length.

Journal Reference:

  1. Leigh Gabel, Anna-Maria Liphardt, Paul A. Hulme, Martina Heer, Sara R. Zwart, Jean D. Sibonga, Scott M. Smith, Steven K. Boyd. Incomplete recovery of bone strength and trabecular microarchitecture at the distal tibia 1 year after return from long duration spaceflight. Scientific Reports, 2022; 12 (1) DOI: 10.1038/s41598-022-13461-1

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Immune cells in brain could be possible new drug targets for ASD and intellectual disability

 University at Buffalo scientists have discovered a convergent mechanism that may be responsible for how two top-ranked genetic risk factors for autism spectrum disorder/intellectual disability (ASD/ID) lead to these neurodevelopmental disorders.

While ASD is distinct from ID, a significant proportion -- approximately 31% -- of people with ASD also exhibit ID. Neither condition is well-understood at the molecular level.

"Given the vast number of genes known to be involved in ASD/ID and the many potential mechanisms contributing to the disorders, it is exciting to find a shared process between two different genes at the molecular level that could be underlying the behavioral changes," said Megan Conrow-Graham, PhD, first author and an MD/PhD candidate in the Jacobs School of Medicine and Biomedical Sciences at UB.

Published today in the journal Brain, the paper focuses on ADNP and POGZ, the two top-ranked risk factor genes for ASD/ID. The research demonstrates that mutations in these genes result in abnormal activation and overexpression of immune response genes and genes for a type of immune cell in the brain called microglia.

"Our finding opens the possibility of targeting microglia and immune genes for treating ASD/ID, but much remains to be studied, given the heterogeneity and complexity of these brain disorders," said Zhen Yan, PhD, senior author and SUNY Distinguished Professor in the Department of Physiology and Biophysics in the Jacobs School.

The UB scientists found that mutations in the two genes studied activate microglia and cause immune genes in the brain to be overexpressed. The hypothesized result is the abnormal function of synapses in the brain, a characteristic of ASD/ID.

The research involved studies on postmortem brain tissue from humans with ASD/ID, as well as studies on mice in which ADNP and POGZ were silenced through viral delivery of small interference RNA. These mice exhibited impaired cognitive task performance, such as spatial memory, object recognition memory and long-term memory.

Weakening a repressive function

"Under normal conditions, cells in the central nervous system should not express large quantities of genes that activate the immune system," said Conrow-Graham. "ADNP and POGZ both work to repress these genes so that inflammatory pathways are not continuously activated, which could damage surrounding cells. When that repression is weakened, these immune and inflammatory genes are then able to be expressed in large quantities."

The upregulated genes in the mouse prefrontal cortex caused by the deficiencies in ADNP or POGZ activated the pro-inflammatory response.

"This is consistent with what we see in upregulated genes in the prefrontal cortex of humans with ASD/ID," said Conrow-Graham. The prefrontal cortex is the part of the brain responsible for executive function, such as cognition and emotional control.

The mutated genes also activate the glial cells in the brain called microglia, which serve as support cells for neurons and have an immune function in the brain; they comprise 10-15% of all brain cells.

Sensitive microglia

"Microglia are very sensitive to pathological changes in the central nervous system and are the main form of active immune defense to maintain brain health," explained Yan. "Aberrant activation of microglia, which we demonstrate occurs as a result of deficiency in ADNP or POGZ, could lead to the damage and loss of synapses and neurons."

The researchers are hopeful that future research will determine whether chronic neuroinflammation could be directly contributing to at least some cases of ASD/ID, in which targeting microglia or inflammatory signaling pathways could prove to be a useful treatment.

The researchers pointed out that the clinical presentation of both ASD and ID is incredibly varied. Significant variation also likely is present in the kinds of mechanisms responsible for the symptoms of ASD and/or ID.

"We found that changes in two risk genes lead to a convergent mechanism, likely involving immune activation," said Conrow-Graham. "However, this probably isn't the case for all individuals with ASD/ID. When designing clinical trials to evaluate treatment effectiveness, I think our research underscores the importance of considering the genetic factors involved in an individual's ASD/ID."

The research is the culmination of Conrow-Graham's PhD work; she has now returned to complete the last two years of the MD degree in the Jacobs School. She described her experience pursuing both an MD and a PhD as extremely complementary.

The immune system has a role

"My training at each level was super helpful to supplement the other," she said. "When I began my PhD, I had completed two years of MD training, so I was familiar with the basics of physiology, anatomy and pathology. Because of this, I was able to bring a broader perspective to my neuroscience research, identifying how the immune system might be playing a role. Prior to this, our lab had not really investigated immunology-related pathways, so having that background insight was really beneficial."

She added that she learned so much from all of her colleagues in Yan's lab, including faculty members, lab technicians and other students. "I learned so many technical skills that I had never used before joining the lab, thanks to the dedication of lab co-workers for my training," she said.

Her experience at the lab bench working on the basic science underlying neuropsychiatric disorders will definitely influence her work as a clinician.

"I plan to pursue a career as a child and adolescent psychiatrist, so I may be able to work directly with this patient population," she said. "We're learning now that better care may be able to be provided by taking a personalized medicine approach, taking into account genetics, psychosocial factors and others. Being able to take a very deep dive into the field of psychiatric genetics was a privilege that I hope will help me to provide the best care for patients."

The research was funded by the Nancy Lurie Marks Family Foundation and by a National Institutes of Health Ruth L. Kirschstein Individual Predoctoral NRSA for MD/PhD F30 fellowship for Conrow-Graham.

In addition to Conrow-Graham and Yan, co-authors are Jamal B. Williams, PhD, former graduate student; Jennifer Martin, PhD, former postdoctoral fellow; Ping Zhong, PhD, senior research scientist; Qing Cao, PhD, postdoctoral fellow; and Benjamin Rein, PhD, former graduate student.

All are current or former members of Yan's lab.

Story Source:

Materials provided by University at Buffalo. Original written by Ellen Goldbaum. Note: Content may be edited for style and length.

Journal Reference:

  1. Megan Conrow-Graham, Jamal B Williams, Jennifer Martin, Ping Zhong, Qing Cao, Benjamin Rein, Zhen Yan. A convergent mechanism of high risk factors ADNP and POGZ in neurodevelopmental disorders. Brain, 2022; DOI: 10.1093/brain/awac152

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