All posts by medical

Neuropathology

What happens in your brain when your head gets hit? – Cosmos

When you hit your head or when something hits it your brain is going to feel it.

While that thud might trigger a pain response (we all know what its like to stand up and suddenly strike your head against something), inside your skull, your brain is probably rattling around.

But it isnt just a strike to the cranium that causes your grey matter to rock back and forth: concussions occur when the body anywhere on the body is impacted such that the head, and the brain within it, suddenly moves.

If the effect of this biomechanical force is enough to cause the brain to hit against the skull, or twist, physical and chemical damage may occur to the neurons brain cells that are essential to its normal, healthy function. Thats when a concussion or mild traumatic brain injury is likely.

Everyone talks about concussion in sport, but theres more to it than that

Even if theres no clinical diagnosis of concussion, the potential for subtle, silent, mild TBI remains.

We know from accelerometer data that the head undergoes quite a lot of significant acceleration/deceleration events [in sport], says Dr Michael Buckland, the head of the neuropathology department at the Royal Prince Alfred Hospital and Executive Director of the Australian Sports Brain Bank at Sydney Universitys Brain and Mind Centre.

Only a small minority of those lead to clinical signs and symptoms that would be diagnosed as concussion the vast majority appear to be clinically silent.

But there is evidence, if you look at circulating biomarkersimaging, [and] advanced MRI studies after a game of sport, that there is actually a subtle traumatic brain injury or settled damage to the brain from those events, even though you feel completely fine.

Its all about how much exposure your brain is getting to these acceleration and rotational forces over short periods of time.

A concussion or mild TBI might be accompanied by a range of symptoms, from headaches, nausea and sensitivity to sound or light, to memory problems, brain fog, sleep problems and heightened emotions.

Sometimes theres a loss of consciousness, sometimes there isnt.

Perhaps the greatest diagnostic challenge for both clinicians and patients is that symptoms vary between people.

Diagnosing concussion isnt as straightforward as you might think, says Dr Sarah Hellewell, a neurotrauma researcher from the Peron Institute and Curtin University, in Perth.

There are various guidelines, but mostly diagnosis is based on reports from patients themselves or people around them at the time of injury. Most guidelines or tests include criteria such as presence of symptoms, alterations in mental state, the time of loss of consciousness or amnesia, if any.

In the simplest terms, neurodegeneration occurs when neurons in the brain deteriorate. Repeated concussions without adequate recovery might play a major role in this process.

Too much cell death and dysfunction could lead to any of several pathologies, including Alzheimers, Parkinsons, Huntingtons, motor neurone diseases, and amyotrophic lateral sclerosis (ALS).

CTE or chronic traumatic encephalopathy is in there too, and that has captured the concerns of the sporting community in recent years.

Mostly diagnosis is based on reports from patients themselves or people around them at the time of injury.

CTE is remarkably like Alzheimers. Both show shrinkage in the hippocampus, which plays a crucial role in learning and processing information as part of short and long-term memory formation. Change to the hippocampus is associated with a range of neurodegenerative and psychiatric disorders.

Both CTE and Alzheimers appear to share a common problem: toxic tau. Tau proteins play an important structural role in stabilising microtubules in brain axons the long cable-like structures of neurons that extend away from the cell body, ending in the synapses used to communicate with other brain cells.

Trauma to the brain causes tau proteins to clump together in tangled masses and alter normal brain functioning.

Get an update of science stories delivered straight to your inbox.

At a molecular level, tau tangles appear in different layers of the brain and may have different folded structures between CTE and Alzheimers.

But while Alzheimers might be triggered by several age, genetic, environmental and lifestyle factors, CTE is found in those with histories of repeated impacts to the head.

Tau is actually a normal, cellular protein. Its found in all neurons in the brain and it serves to stabilise their long outward projections called axons, says Buckland.

Its all about how much exposure your brain is getting to these acceleration and rotational forces over short periods of time.

Within those axons is whats called microtubule associated protein tau or MAPT [pronounced Map-Tee], and the tau stabilises the microtubules to give structural integrity to that axon.

In CTE, as in Alzheimers disease, the tau takes on an abnormal shape, gets abnormally modified chemically a lot of phosphorylation is added to it and it tends to move out of the axon and clump in the nerve cell body.

Buckland explains that many neurodegenerative diseases appear to be characterised by this abnormal accumulation of wrongly folded proteins.

Its not unlike a blood clot obstructing blood flow, except we have neural proteins crammed together in nerve cells.

Technically, both CTE and Alzheimers can only be conclusively diagnosed after death, that is, via a post-mortem examination of a persons brain (although Alzheimers has many clinical symptoms which enables a pre-death diagnosis).

The term mild is attached to TBIs and concussions, but its deceptive no brain injury is truly mild and there is need for close monitoring of the individual athlete.

A tennis player enduring their first nausea-inducing head hit might be fit and firing after two weeks, but a footballer placed on their fifth concussion stretcher might need much, much longer to heal properly. The brain can recover, but subsequent trauma which occurs before that process has been completed is what worries scientists: does repeat injury before recovery compound the problem?

If you subject your head to repeated concussion, you increase the chances that you might have a long-term brain disease. Thats not rocket science, says Emeritus Professor Robert Vink, a neuroscientist from UniSA.

Risk reduction in the immediate aftermath of a mild TBI or concussion is, therefore, crucial not just for short-term recovery but to reduce long-term risk.

For example, Vink warns about post-concussion drug and alcohol consumption.

Drugs worsen the CTE pathways. So, lets say youve initiated CTE by some event take alcohol, that worsens the pathway the chances of developing CTE go up, its another insult to the brain on top of the head knock, Vink says.

48 hours abstaining from drug and alcohol consumption, rest and monitored sleep, and avoiding strenuous activities like reading, television and screen use are among the current best practice care recommendations from Connectivity, a leading brain injury awareness organisation in Australia.

Understanding the physical and chemical changes that take place within the brain is crucial in the quest to provide clarity and information to communities around mild TBI and concussion: what it is, how to manage it, and when a person can return to participate in the activities they love.

When it comes to the sudden impact of biomechanical force on the brain, few, if any, sports are spared. Now science is revealing the potential extent of repeat head injury, codes are mobilising to respond.

But athletes, and the communities around them, also need definitive diagnosis of brain injuries, their seriousness, and to be given clearer management plans to ensure safe recovery.

To achieve this, neuroscientists are chasing elusive but hugely powerful biomarkers that could make the diagnosis and management much, much more effective.

Next week: The hunt for brain injury biomarkers

Continued here:

What happens in your brain when your head gets hit? - Cosmos

Neuropathology

Bioengineered Protein May Prevent COVID Infections and Improve … – Feinberg News Center

A novel ACE2 protein developed by Northwestern Medicine investigators improved survival and prevented brain infection in mice infected with SARS-CoV-2 when administered intranasally, according to a recent study published in the journal Life Science Alliance.

SARS-CoV-2, the virus that causes COVID-19, uses the angiotensin converting enzyme 2 (ACE2) protein as a main receptor to infect healthy cells. Since the discovery of this mechanism in early 2020, the use of soluble ACE2 proteins to neutralize SAR-CoV-2 infection has been investigated as a novel therapeutic approach.

Over the last three years, investigators led by Daniel Batlle, MD, the Earle, del Greco, Levin Professor of Nephrology/Hypertension, developed a bioengineered soluble ACE2 protein and have been studying its therapeutic potential in reducing infection first in human organoids and later in mice infected with SARS-CoV-2.

The soluble protein, called ACE2 618-DDC-ABD, intercepts the spike of the SARS-CoV-2 virus before it can attach to the ACE2 receptor, preventing SARS-CoV-2 from entering and infecting healthy cells.

The natural ACE2 protein circulates in a small amount and cannot do much to really prevent the virus from attaching to the cell membrane receptor, so the cell membrane ACE2 receptor always wins. If you provide, however, enough amounts of an adequate soluble ACE2 protein at the right time, you can intercept the virus from attaching to the cell membrane receptor and getting inside the cells; this is whats known as the decoy action of soluble ACE2, Batlle said.

In previous work published in the Journal of the American Society of Nephrology, Batlles team found that when their decoy protein was administered both intranasally and intraperitoneally to mice inoculated with a lethal dose of SARS-CoV-2 virus, the mice experienced near 100 percent survival and reduced lung damage.

Our protein has the property of increased duration of action. That alone is an advantage because the virus is not going to take a holiday break and you want something that stays around for days. Moreover, we modified it further so that the binding power for the virus is enhanced, Batlle said.

In the current study, Batlles team studied the efficacy of this treatment approach by administering their decoy protein, comparing intranasal administration to intraperitoneal (by injection) administration to mice, either before or after infection with SARS-COV-2.

Overall, five-day survival rates were zero percent in the untreated mice, 40 percent in the mice treated intraperitoneally before SARS-COV-2 inoculation, and 90 percent in the mice treated intranasally before SARS-COV-2. Additionally, in the mice treated intranasally, the investigators found the mice had undetectable viral presence in the brain and reduced viral presence and pathology in the lungs.

We expected a difference between intranasal and systemic administration, better by the nasal route, but perhaps not of the magnitude observed, Batlle said.

In the future, Batlle said that ideally their protein could be developed into an anti-viral nasal spray that could be used by patients and healthcare providers the moment they test positive for SARS-CoV-2 or after exposure to infected individuals.

This study demonstrates that soluble ACE2 protein is most effective against the SARS-CoV-2 virus when administered by the intranasal route. We envision that intranasal inhalation of soluble ACE2 could become a new anti-viral strategy, especially when given topatients at risk and medical personnel in hospitals who are constantly exposed to the virus or to people recently infected, said Jan Wysocki, MD, PhD, research associate professor of Medicine in the Division of Nephrology and Hypertension and a co-author of the study.

Luise Hassler, a former research scholar in the Division of Nephrology and Hypertension, was the lead author of the study. Jared Ahrendsen, MD, PhD, assistant professor of Pathology in the Division of Neuropathology, was also a co-author.

This work was supported by the National Institutes of Health grant 1R21 AI166940-01, a gift from the Joseph and Bessie Feinberg Foundation, and the Biomedical Education Program.

See the article here:

Bioengineered Protein May Prevent COVID Infections and Improve ... - Feinberg News Center

Neuropathology

My Fathers Brain: Life in the Shadow of Alzheimers – Next Big Idea Club Magazine

Sandeep Jauhar is a New York Times bestselling author and a practicing cardiologist. He writes regularly for the New York Times and has appeared on National Public Radio and MSNBC. His essays have been published in The Wall Street Journal, Time, and Slate.

Below, Sandeep shares five key insights from his new book, My Fathers Brain: Life in the Shadow of Alzheimers. Listen to the audio versionread by Sandeep himselfin the Next Big Idea App.

My father became cognitively impaired in what has been called a hypercognitive world. In this world, swirling with information, we prioritize intellect and reason as predominant virtues. If you do not possess these virtues, you are marginalized. If you cant follow or add to the endless conversation, you are rendered invisible. So, when my fathers cognition degenerated, he became largely invisible to the outside world.

This happened to my father in his own family, too. I wish I could say that we were more patient than the world outside, but we werent. The Etch-a-Sketch that was his Alzheimers mind trapped him in a perpetual present, and his children in perpetual frustration. He is helpless. He wont remember. He is like a child now. We would say those things in front of him, sometimes even to him. There was little to deter us, even as we regretted it, again and again, after the fact. We knew that our father was more than just his damaged brain, we knew it, but we struggled to believe it.

The risk of Alzheimers is twice as high in the loneliest persons as compared with those who have the most social support. Even after controlling for other factors, such as cognitive and physical activity, neuropathology is not the sole driver of clinical dementia.

Moreover, brain damage and the degree of clinical dementia are not as strongly correlated as one might expect. Patients with only a small amount of brain damage often have excess disability out of proportion to their neurological impairment. The converse is also true: Patients with an excess of brain damage may be surprisingly cognitively intact. The usual explanation for this discrepancy is cognitive reserve or higher educational levels, prior intelligence, and so on. However, what is rarely acknowledged is the vital role of psychosocial reserve, relationships, environment, and family support. Studies have shown that this may be just as important in Alzheimers disease as neuropathology.

When our parents got sick, my siblings and I joined the ranks of the 15 million or so unpaid (and untrained) family caregivers for older adults in this country. The busiest half of this largely invisible workforce spends, on average, nearly 30 hours a week providing care to relatives. Many of these relatives have dementia and it amounts to more than $400 billion worth of annual unpaid time. The work takes its toll and these relatives are at increased risk of developing depression, as well as physical and career difficulties, including loss of job productivity. Being sick and elderly in this country can be terrifying, and having a sick and elderly loved one is a full-time job.

In the U.S., government support for dementia care is largely nonexistent. Of the $200 billion in total annual costs for dementia care, Medicare pays only $11 billion. The shortfall is covered by families, to the tune of $80,000 per family per yearalmost double the outlay for cancer or heart disease. Long-term care insurance may help with this burden; however, most Americans dont own, or cannot afford such policies. Therefore, most of the burden of elder care ends up being borne by family caregivers, unless families can afford to hire private help.

When my father was declining from Alzheimers disease, one of the things my siblings and I used to argue about was how much to correct or accommodate his confusions. For example, my father, in his impaired state, expected his live-in aide to work for free and would lash out at her (and us) whenever he learned that she had been paid. My siblings tended to think that it was fine to lie to him and tell him she was receiving no money from us. More pragmatic than I, they had no reservations about employing deception to help our father (and themselves) get through one of his rancorous moods.

I fought against this practice as a matter of principle. To me, a healthy relationship with our father, even in his debilitated state, could only be based on truth and trust. Little lies, even if told with the best of intentions, would erode what little connection we had left with him.

However, while doing the hard work of caring for my father, I came to learn that truth-telling can be a double-edged sword. I came to understand that the relationship between ethics and treatment in dementia is a complicated one. The demands of truth-telling exist in tension with other moral imperatives, such as a sons obligation to do the best for his declining father. Personal ethics, I discovered, may come into conflict with the reality of caregiving.

I remember one day after my father kicked his caregiver out of the house, I took her back to him. I knew that if she left, that would surely be the end of my fathers independent living. He would undoubtedly end up in a locked memory unit like so many dementia patients.

Look, Dad, Harwinder came back, I said. He eyed her suspiciously.

She says she is sorry, I said. She told me she will work for free. No money. Just food and shelter.

His face relaxed, and I discerned a faint smile. Okay, he said, Please come in.

I remember so many details from our first year in America, nearly five decades ago, when I was just eight years old. There was a lawn mower in the backyard whose engine imprinted a coin-sized burn on my thigh. There was a small woodshed that housed shovels, gardening tools, and various rusted hulks. In the middle of the yard was a grand oak tree with a tire swing. I can still see my father sitting on a lawn chair under that tree, his fingers caked with soil, his cold beer trickling condensation, predicting how bountiful the harvest would be that fall.

But did it all really happen this way? Was the garden really visible through the kitchen window? Was that window really framed by frilly white curtains? Memory construction, psychologists say, involves a tension between two opposing principles. Correspondence tries to force our memories to agree with the original event that we experienced. It is how most of us view memory: as a true reproduction of something that occurred in the past.

The principle of coherence, on the other hand, transforms our memories to make them consistent with the way we see ourselves and the world in the present. Through coherence, our memories are reconstructed to support our current values or beliefs and these beliefs may not allow us to see things the way they really happened. Those kitchen curtains may now be white to reflect the nostalgia with which I reflect, 45 years later, on my familys first year in America. Hence, autobiographical memories involve a balance of two conflicting forces, one aiming to represent the past the way it was, the other aiming to reconstruct the past in the way that we need to see it today.

To listen to the audio version read by author Sandeep Jauhar, download the Next Big Idea App today:

Excerpt from:

My Fathers Brain: Life in the Shadow of Alzheimers - Next Big Idea Club Magazine

Neuropathology

Scholarship for the PhD in Medical Sciences in the field of Pathology … – Times Higher Education

The PhD in Medical Sciences:

The University of Nicosia Medical School offers the degree PhD in Medical Sciences. The degree is awarded to students who successfully complete an independent research programme leading to novel findings in the chosen field of study. The PhD programme aspires to empower students to become independent researchers, thus advancing innovation and development.

The Research Project:

We are currently inviting application through a competitive process for high calibre candidates to apply for one PhD Scholarship in the fields of Pathology of Neurodegenerative Diseases. The successful candidate will enrol in the PhD programme in Medical Sciences and will work under the Supervision of Professor Dimitrios Kanakis with expertise in the fields of Pathology and Neuropathology at the University of Nicosia Medical School.

Project Description:

Code and Title of research project: PHD-2023-A2: Investigating the possible association of NRG1 and tau, in the development of Alzheimer s Disease (AD).

Background and Rationale:

Neurodegenerative disorders constitute a major problem for the health care system globally. The number of newly diagnosed patients suffering from one of the known neurodegenerative diseases increases dramatically. Finding a treatment or even a preventative measure against such disorders is one of the major challenges of modern science. However, these scientific efforts, though intensive, have not yet achieved the expected result, that is the development of efficacious therapeutic schemes. The reason for this is the absence of sufficient knowledge of the pathogenesis of each of the various degenerative diseases. It is therefore of utmost importance to understand comprehensively the pathology of this category of diseases in order to focus our research explicitly.

Alzheimer s disease (AD) is the commonest age-related neurodegenerative disorder, affecting millions of people worldwide. It is a progressive neurological disorder that drives to the irreversible loss of neurons, primarily in the entorhinal cortex and hippocampus. The amyloid- plaques and the neurofibrillary tangles (NFTs) are the main histopathological hallmarks of the disease.

The amyloid hypothesis suggests that the abnormal cleavage of Amyloid Precursor Protein (APP) and the subsequent deposition of toxic amyloid peptides are a predominant step in the pathogenesis of the disease. However, tau hyperphosphorylation and neurofibrillary tangle (NFT) formation is a direct epiphenomenon of this abnormal deposition suggesting the close association of APP and MAPT (Microtubule Associated Protein Tau) genes.

Neuregulins (NRG) are a family of growth and differentiation factors involved in neuronal differentiation and migration, oligodendrocyte development, N-methyl-D-aspartate (NMDA) receptor function, myelination, neurite extension and arborization, synapse formation and neurotransmitter release.

There are four different neuregulin types: NRG1, NRG2, NRG3, and NRG4. NRG1 is the most widely studied growth factor of the neuregulin family. There are three NRG1 isoforms, namely NRG1 type I, NRG1 type II and NRG1 type III. NRG1 protein has been shown to be important in the development of the CNS, the circulatory system and accessory reproductive organs like the mammary glands. NRG1 plays a pivotal role in neurogenesis and neural differentiations (i.e. neural crest cell differentiation into Schwann cells). Its function is mediated by transmembrane tyrosine kinase receptors of the ErbB family, inducing receptor heterodimerization, which in turn initiates a signal transduction cascade.

A close association of Neuregulin-1 (NRG1), BACE1 and APP genes exists that suggest a potential link between NRG1 and Alzheimer s disease, as the last two factors (i.e. BACE and APP) have been implicated in the development of this condition. NRG1 is a major physiological substrate of -site amyloid precursor protein cleaving enzyme 1 (BACE1), which is cleaved within its ectodomain allowing the exposure of the EGF-like domain for ErbB signaling. In other words, NRG1 activation is mediated by the enzymatic cleavage of BACE1, a rate limiting enzyme for APP proteolysis and amyloid production.

Double immunofluorescence and electron microscopy analysis demonstrated that ErbB4 antibodies co-localized with hyper-phosphorylated tau inclusions and NFTs, proving the relationship between the neuregulin receptor ErbB4 and protein hyper-phosphorylated protein tau. The importance of ErbB/neuregulin signaling in AD pathogenesis, APP processing and tau hyper-phosphorylation has also been shown.

In vitro experiments demonstrated further that NRG1 eliminated the effect of amyloid beta-induced decrease in dendritic spine density in rat primary hippocampal neurons, and improved neural cell differentiation in mouse fetal neuronal stem cells. These results render Neuregulin-1 a potential therapeutic agent for Alzheimer s disease.

It is therefore evident that the exact role of NRG1 is quite enigmatic, so there is an urgent need to solve the puzzle and understand the exact role of NRG1 in AD pathogenesis. Additionally, there is a missing link between NRG1 gene and tau hyper-phosphorylation. The main aim of the study is to elucidate the possible role of NRG-1 type III gene in the pathogenesis of Alzheimer s disease, through direct or indirect MAPT interaction leading to tau hyper-phosphorylation and NFT formation.

Aims and Objectives:

The current Research Proposal has the following aims and objectives:

1. To examine the possible association of NRG1 with tau protein, tau hyper-phosphorylation and the development of toxic NFTs in AD mice.

2. To examine the potential co-localization of the NRG1 protein with the hyper-phosphorylated protein tau.

3. In a later stage, the association of NRG1 with BACE1 will be examined too, through RNAi technology. BACE1 inhibition will be performed on NRG1 transfected cells, in order to assess the possible change in NRG1 normal processing.

The Scholarship:

The Scholarship will have a duration of three to four years and will cover:

The tuition fees for the PhD programme which are 15,000 in total for the first 3 years and 2,000 for year 4.

Requirements and Qualifications:

Eligible Candidates should hold (or hold by the time that the programme is expected to commence i.e. October 2023) a recognised degree (BSc or a degree equivalent for entry to a Master s Degree) and a Master s degree (MSc) in the field(s) of Molecular Biology or a Doctor of Medicine degree (e.g. MBBS or MD degree).

Expertise in a variety of laboratory (e.g. immunohistochemistry and immunofluorescence in paraffin fixed mouse brain samples) and specific molecular biology methods (e.g. Western blotting, in vitro experiments with different cell lines) is a prerequisite for carrying out the experiments of the PhD project.

Application for the PhD Scholarship:

Candidates should submit an online application through this link and upload the following supporting documents:

A cover letter clearly stating that they apply for the PhD Scholarship in the field of Pathology of Neurodegenerative Diseases for the PhD Research Project PHD-2023-A2: Investigating the possible association of NRG1 and tau, in the development of Alzheimer s Disease (AD) .

Copies of the applicant s qualifications/degree(s) the application can be assessed with scanned copies, but certified true copies must be provided if the candidate is successful and prior to enrolment on the PhD programme.

Copies of the applicant s transcript(s) - the application can be assessed with scanned copies, but certified true copies must be provided if the candidate is successful and prior to enrolment on the PhD programme.

Proof of English language proficiency such as IELTS with a score of 7 overall and with a minimum score of 7 in writing or TOEFL iBT with a score of 94 overall and a minimum score of 27 in Writing. Other internationally recognized English language qualifications might be considered upon review. Students from the UK, Ireland USA, Canada (from English speaking provinces), Australia and New Zealand are exempt from the English language requirement.

Two reference letters, of which at least one should be from an academic.

A full Curriculum Vitae (CV)

Once you complete your application please send an email to admissions@med.unic.ac.cy expressing officially your interest in the PhD Research Project PHD-2023-A2: Investigating the possible association of NRG1 and tau, in the development of Alzheimer s Disease (AD) and also attaching all the required documents.

Applications should be submitted by Friday, June 2, 2023 at 5pm. Only fully completed applications, containing all necessary supporting documents will be reviewed.

Only candidates who are shortlisted will be contacted and invited to an interview.

Follow this link:

Scholarship for the PhD in Medical Sciences in the field of Pathology ... - Times Higher Education

Neuropathology

Variation along P2RX7 interacts with early traumas on severity of … – Nature.com

Bandelow, B. & Michaelis, S. Epidemiology of anxiety disorders in the 21st century. Dialogues Clin. Neurosci. 17, 327335 (2015).

Article PubMed PubMed Central Google Scholar

Pereira, V. S. et al. Antidepressant- and anticompulsive-like effects of purinergic receptor blockade: Involvement of nitric oxide. Eur. Neuropsychopharmacol. 23, 17691778. https://doi.org/10.1016/j.euroneuro.2013.01.008 (2013).

Article CAS PubMed Google Scholar

Murrough, J. W., Yaqubi, S., Sayed, S. & Charney, D. S. Emerging drugs for the treatment of anxiety. Expert Opin. Emerg. Drugs 20, 393406. https://doi.org/10.1517/14728214.2015.1049996 (2015).

Article CAS PubMed PubMed Central Google Scholar

Mechawar, N. & Savitz, J. Neuropathology of mood disorders: do we see the stigmata of inflammation?. Transl. Psychiatry 6, e946. https://doi.org/10.1038/tp.2016.212 (2016).

Article CAS PubMed PubMed Central Google Scholar

ngr, D., Bechtholt, A. J., Carlezon, W. A. & Cohen, B. M. Glial abnormalities in mood disorders. Harv. Rev. Psychiatry 22, 334337. https://doi.org/10.1097/HRP.0000000000000060 (2014).

Article PubMed PubMed Central Google Scholar

Bhattacharya, A. & Jones, D. N. C. Emerging role of the P2X7NLRP3IL1 pathway in mood disorders. Psychoneuroendocrinology 98, 95100. https://doi.org/10.1016/j.psyneuen.2018.08.015 (2018).

Article CAS PubMed Google Scholar

Rahimian, R., Wakid, M., OLeary, L. A. & Mechawar, N. The emerging tale of microglia in psychiatric disorders. Neurosci. Biobehav. Rev. 131, 129. https://doi.org/10.1016/j.neubiorev.2021.09.023 (2021).

Article PubMed Google Scholar

Fekri, K., Nayebi, A. M., Sadigh-Eteghad, S., Farajdokht, F. & Mahmoudi, J. The neurochemical changes involved in immobilization stress-induced anxiety and depression: Roles for oxidative stress and neuroinflammation. Neurochem. J. 14, 133149. https://doi.org/10.1134/S181971242002004X (2020).

Article Google Scholar

Hanisch, U. K. Microglia as a source and target of cytokines. Glia 40, 140155. https://doi.org/10.1002/glia.10161 (2002).

Article PubMed Google Scholar

Bollinger, J. L. & Wohleb, E. S. The formative role of microglia in stress-induced synaptic deficits and associated behavioral consequences. Neurosci. Lett. 711, 134369. https://doi.org/10.1016/j.neulet.2019.134369 (2019).

Article CAS PubMed PubMed Central Google Scholar

Lehmann, M. L., Weigel, T. K., Poffenberger, C. N. & Herkenham, M. The behavioral sequelae of social defeat require microglia and are driven by oxidative stress in mice. J. Neurosci. 39, 55945605. https://doi.org/10.1523/JNEUROSCI.0184-19.2019 (2019).

Article CAS PubMed PubMed Central Google Scholar

Du Preez, A. et al. The type of stress matters: Repeated injection and permanent social isolation stress in male mice have a differential effect on anxiety- and depressive-like behaviours, and associated biological alterations. Transl. Psychiatry 10, 325. https://doi.org/10.1038/s41398-020-01000-3 (2020).

Article CAS PubMed PubMed Central Google Scholar

Tynan, R. J. et al. Chronic stress alters the density and morphology of microglia in a subset of stress-responsive brain regions. Brain Behav. Immun. 24, 10581068. https://doi.org/10.1016/j.bbi.2010.02.001 (2010).

Article CAS PubMed Google Scholar

Meyer, J. H. et al. Neuroinflammation in psychiatric disorders: PET imaging and promising new targets. Lancet Psychiatry 7, 10641074. https://doi.org/10.1016/S2215-0366(20)30255-8 (2020).

Article PubMed PubMed Central Google Scholar

Sperlgh, B. & Illes, P. P2X7 receptor: An emerging target in central nervous system diseases. Trends Pharmacol. Sci. 35, 537547. https://doi.org/10.1016/j.tips.2014.08.002 (2014).

Article CAS PubMed Google Scholar

Cortese, B. M. & Phan, K. L. The role of glutamate in anxiety and related disorders. CNS Spectr. 10, 820830. https://doi.org/10.1017/s1092852900010427 (2005).

Article PubMed Google Scholar

Simon, A. B. & Gorman, J. M. Advances in the treatment of anxiety: Targeting glutamate. NeuroRx 3, 5768. https://doi.org/10.1016/j.nurx.2005.12.005 (2006).

Article CAS PubMed PubMed Central Google Scholar

Skolnick, P., Popik, P. & Trullas, R. Glutamate-based antidepressants: 20 years on. Trends Pharmacol. Sci. 30, 563569. https://doi.org/10.1016/j.tips.2009.09.002 (2009).

Article CAS PubMed Google Scholar

Zarate, C. et al. Glutamatergic modulators: the future of treating mood disorders?. Harv. Rev. Psychiatry 18, 293303. https://doi.org/10.3109/10673229.2010.511059 (2010).

Article PubMed PubMed Central Google Scholar

Machado-Vieira, R., Ibrahim, L., Henter, I. D. & Zarate, C. A. Novel glutamatergic agents for major depressive disorder and bipolar disorder. Pharmacol. Biochem. Behav. 100, 678687. https://doi.org/10.1016/j.pbb.2011.09.010 (2012).

Article CAS PubMed Google Scholar

Sanacora, G., Treccani, G. & Popoli, M. Towards a glutamate hypothesis of depression: An emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 62, 6377. https://doi.org/10.1016/j.neuropharm.2011.07.036 (2012).

Article CAS PubMed Google Scholar

Li, N. et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329, 959964. https://doi.org/10.1126/science.1190287 (2010).

Article ADS CAS PubMed PubMed Central Google Scholar

Hong, S. et al. The P2X7 receptor in activated microglia promotes depression- and anxiety-like behaviors in lithium -pilocarpine induced epileptic rats. Neurochem. Int. 138, 104773. https://doi.org/10.1016/j.neuint.2020.104773 (2020).

Article CAS PubMed Google Scholar

Mantere, O. et al. Neuroticism mediates the effect of P2 RX7 on outcomes of mood disorders. Depress. Anxiety 29, 816823 (2012).

Article CAS PubMed Google Scholar

Soronen, P. et al. P2RX7 gene is associated consistently with mood disorders and predicts clinical outcome in three clinical cohorts. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156B, 435447. https://doi.org/10.1002/ajmg.b.31179 (2011).

Article CAS PubMed Google Scholar

Hejjas, K. et al. Association between depression and the Gln460Arg polymorphism of P2RX7 gene: A dimensional approach. Am. J. Med. Genet. B Neuropsychiatr. Genet. 150, 295299. https://doi.org/10.1002/ajmg.b.30799 (2009).

Article CAS Google Scholar

Nagy, G. et al. P2RX7 Gln460Arg polymorphism is associated with depression among diabetic patients. Prog. Neuropsychopharmacol. Biol. Psychiatry 32, 18841888. https://doi.org/10.1016/j.pnpbp.2008.08.021 (2008).

Article CAS PubMed Google Scholar

Liu, J. et al. Genome-wide Mendelian randomization identifies actionable novel drug targets for psychiatric disorders. Neuropsychopharmacology 48, 270280 (2023).

Article PubMed Google Scholar

Howard, D. M. et al. Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nat. Neurosci. 22, 343352. https://doi.org/10.1038/s41593-018-0326-7 (2019).

Article CAS PubMed PubMed Central Google Scholar

Luo, X.-J. et al. Cross-ancestry genome-wide association study and systems-level integrative analyses implicate new risk genes and therapeutic targets for depression. medRxiv 2023.2002. 2024.23286411 (2023).

Kristof, Z. et al. P2RX7 gene variation mediates the effect of childhood adversity and recent stress on the severity of depressive symptoms. PLoS ONE 16, e0252766. https://doi.org/10.1371/journal.pone.0252766 (2021).

Article CAS PubMed PubMed Central Google Scholar

Kendall, P. C. & Watson, D. E. Anxiety and Depression: Distinctive and Overlapping Features (Academic Press, 1989).

Google Scholar

Eysenck, M. W. & Fajkowska, M. Anxiety and Depression: Toward Overlapping and Distinctive Features. Vol. 32. 13911400 (Taylor & Francis, 2018).

Fajkowska, M. Personality Coherence and Incoherence: A Perspective on Anxiety and Depression (Eliot Werner Publications, 2013).

Google Scholar

Fajkowska, M., Domaradzka, E. & Wytykowska, A. Types of anxiety and depression: Theoretical assumptions and development of the Anxiety and Depression Questionnaire. Front. Psychol. 8, 2376 (2018).

Article PubMed PubMed Central Google Scholar

Andrejew, R. et al. The P2X7 receptor: Central hub of brain diseases. Front. Mol. Neurosci. 13, 124. https://doi.org/10.3389/fnmol.2020.00124 (2020).

Article CAS PubMed PubMed Central Google Scholar

Purcell, S. M. et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748752. https://doi.org/10.1038/nature08185 (2009).

Article ADS CAS PubMed Google Scholar

Shi, S. Q. et al. Molecular analyses of circadian gene variants reveal sex-dependent links between depression and clocks. Transl. Psychiatry 6, e748. https://doi.org/10.1038/tp.2016.9 (2016).

Article CAS PubMed PubMed Central Google Scholar

North, R. A. Molecular physiology of P2X receptors. Physiol. Rev. 82, 10131067. https://doi.org/10.1152/physrev.00015.2002 (2002).

Article CAS PubMed Google Scholar

Erhardt, A. et al. Association of polymorphisms in P2RX7 and CaMKKb with anxiety disorders. J. Affect. Disord. 101, 159168. https://doi.org/10.1016/j.jad.2006.11.016 (2007).

Article CAS PubMed Google Scholar

Jiang, L.-H., Roger, S. & Baldwin, S. Insights into the molecular mechanisms underlying mammalian P2X7 receptor functions and contributions in diseases, revealed by structural modeling and single nucleotide polymorphisms. Front. Pharmacol. 4, 55 (2013).

Article CAS PubMed PubMed Central Google Scholar

Wei, L. et al. ATP-activated P2X7 receptor in the pathophysiology of mood disorders and as an emerging target for the development of novel antidepressant therapeutics. Neurosci. Biobehav. Rev. 87, 192205. https://doi.org/10.1016/j.neubiorev.2018.02.005 (2018).

Article CAS PubMed Google Scholar

Kim, J. et al. A double-hit of stress and low-grade inflammation on functional brain network mediates posttraumatic stress symptoms. Nat. Commun. 11, 1898. https://doi.org/10.1038/s41467-020-15655-5 (2020).

Article ADS CAS PubMed PubMed Central Google Scholar

Horti, A. G. et al. PET imaging of microglia by targeting macrophage colony-stimulating factor 1 receptor (CSF1R). Proc. Natl. Acad. Sci. U S A 116, 16861691. https://doi.org/10.1073/pnas.1812155116 (2019).

Article ADS CAS PubMed PubMed Central Google Scholar

Lord, B. et al. A novel radioligand for the ATP-gated ion channel P2X7: [3H] JNJ-54232334. Eur. J. Pharmacol. 765, 551559. https://doi.org/10.1016/j.ejphar.2015.09.026 (2015).

Article CAS PubMed Google Scholar

He, Y., Taylor, N., Fourgeaud, L. & Bhattacharya, A. The role of microglial P2X7: Modulation of cell death and cytokine release. J. Neuroinflamm. 14, 135. https://doi.org/10.1186/s12974-017-0904-8 (2017).

Article CAS Google Scholar

Adinolfi, E. et al. The P2X7 receptor: A main player in inflammation. Biochem. Pharmacol. 151, 234244. https://doi.org/10.1016/j.bcp.2017.12.021 (2018).

Article CAS PubMed Google Scholar

Bhattacharya, A. & Biber, K. The microglial ATP-gated ion channel P2X7 as a CNS drug target. Glia 64, 17721787 (2016).

Article PubMed Google Scholar

Falzoni, S., Donvito, G. & Di Virgilio, F. Detecting adenosine triphosphate in the pericellular space. Interface Focus 3, 20120101 (2013).

Article PubMed PubMed Central Google Scholar

He, Y., Taylor, N., Fourgeaud, L. & Bhattacharya, A. The role of microglial P2X7: Modulation of cell death and cytokine release. J. Neuroinflamm. 14, 113 (2017).

Article Google Scholar

Bhattacharya, A. et al. Neuropsychopharmacology of JNJ-55308942: Evaluation of a clinical candidate targeting P2X7 ion channels in animal models of neuroinflammation and anhedonia. Neuropsychopharmacology 43, 25862596 (2018).

Article CAS PubMed PubMed Central Google Scholar

Read more here:

Variation along P2RX7 interacts with early traumas on severity of ... - Nature.com

Neuropathology

How to Treat Dementia No Matter What Age You Are – DISCOVER Magazine

Search the term preventing dementia online, and a list of possible precautions pop up. One story describesa new studythat finds older Americans who used the Internet but not too much have a lower risk of dementia. Other stories suggest that taking vitamin D, getting a good nights sleep or learning a second language are key to combating dementia.

Scientists dont fully understand what causes dementia, a degenerative neurological condition that impacts memory, speech and basic functioning. But they do know thatas many as 40 percentof cases could be slowed or prevented by making certain lifestyle changes.

In 2020,The LancetCommission on Dementia identified 12 risk factors. Although some of these factors, like air pollution, are out of a persons control, there are many lifestyle changes a person can make to reduce their risk. Problematically,studies find that mostpeople arent aware of the risk factors and what they can do to protect themselves.

As more people live longer, the threat of developing this condition increases. By 2050, an estimated 135 million peoplewill be living with dementia. The bulk of these diagnoses, about 71 percent, will come from lower and middle-income countries where education and healthcare are more limited.

Scientists have learned that preventing dementia is a lifelong process that begins in childhood with access to education.The LancetCommission identified not having an educationbeyond age 12as an important risk factor.

Lack of education is a widespread problem as many people worldwide cannot read or have a limited education.About 14 percentof the worlds population aged 15 and over are illiterate, and although younger generations are becoming more literate, young girls are less educated than their male peers.

Literacy is increasing, but access to education past age 12 is not. Dropout rates were made worse during the COVID-19 pandemic whenmore older children left school, particularly girls.

Reading and engaging in intellectual challenges can reduce a persons risk for dementia later in life. Scientists believe education helps build apersons cognitive reserve, allowing the brain to endure neuropathology. A stronger cognitive reserve can mean a persons dementia is less noticeable or progresses more slowly.

Maintaining a cognitive reserve starts early in life but has to be worked at over the years. This is why studies suggest a person who challenges themselves mentally through puzzles or language learning could stave it off.

Social ties are also a way to maintain a persons cognitive reserve.The LancetCommission noted that hearing loss typically begins in middle age (after age 45) and can threaten a persons interest in socializing and, in turn, minimize their cognitive reserve but more on that later.

During the middle years, a person can also start to develop other dementia risk factors related to vascular brain damage. Having diabetes, high cholesterol, hypertension, and obesity all create the potential for vascular brain damage. Similarly, smoking and drinking alcohol excessively also risk brain damage associated with the condition.

The Lancetcategorized the above conditions asmodifiable factorsthat could be changed through interventions. Exercising, eating aMediterranean diet, getting hearing aids if needed, managing cholesterol and hypertension, drinking in moderation and not smoking can all help reduce or prevent dementia.

There were other identified risk factors. However, the commission identified that a person could likely not control, including head injury and vascular damage from air pollution.

As people enter later life (after age 65), dwindling social contact and depression can be painful risk factors for dementia. Researchers havelinked social isolationto a decline in cardiovascular health and an increase in depression and dementia.

Social isolation increases a persons risk for dementia because it limits how they engage with others and maintain their cognitive reserve. Similarly, as mentioned above, hearing loss can also stop older adults from socializing or challenging themselves mentally.About one-thirdof U.S. adults have hearing loss, which makes it difficult for them to speak on the phone, follow conversations or enjoy listening to the TV or radio.Only about one-fifthof older adults with hearing loss actually have a pair of hearing aids.

Interventions like hearing aids, exercise and community-supported social events can help older people get the socialization they need to maintain their cognitive reserve and fend off dementia. Such interventions demonstrate how managing modifiable factors is a lifelong need that follows a person from their earliest to their oldest years.

Read More: The 4 Main Types of Dementia

Read more:

How to Treat Dementia No Matter What Age You Are - DISCOVER Magazine

Neuropathology

UC Irvine study shows traffic-related air pollution in Irvine weakens … – EurekAlert

Irvine, Calif., May 11, 2023 Researchers from the University of California, Irvine have found that exposure to traffic-related air pollution in Irvine led to memory loss and cognitive decline and triggered neurological pathways associated with the onset of Alzheimers disease.

The link between air pollution and Alzheimers disease is concerning, as the prevalence of toxicants in ambient air is not just on the rise globally, but also hitting close to home here in Irvine, said corresponding and senior author Masashi Kitazawa, Ph.D., associate professor of environmental and occupational health in UCIs Program in Public Health. Our findings are just one example of what particulate matter can do to brain function.

The studys results are published in the journal Toxicological Sciences.

Alzheimers disease is the most common cause of dementia among the elderly and is a growing public health crisis in the U.S. as well as several other countries. Despite extensive research on all aspects of Alzheimers disease, its exact origins remain elusive. Although genetic predispositions are known to play a prominent role in disease progression, growing bodies of evidence suggest that environmental toxicants, specifically air pollution, may cause the onset of Alzheimers disease.

Kitazawa and his team compared mouse models at two ages. Researchers exposed a group of 3- and 9-month-old mouse models to ultrafine particulate matter for 12 weeks via ambient air collected in Irvine. A second group was exposed to purified air. The differing ages were used to determine the potential impact of particulate matter exposure during highly vulnerable life stages: developing youth and the elderly.

Researchers conducted testing related to memory tasks and cognitive function and found that both benchmarks were impaired by exposure to particulate matter. Notably, they also discovered that their older models (12 months at the time of analysis) showed brain plaque build-up and glial cell activation, which are both known to increase inflammation associated with the onset of Alzheimers disease.

Air pollution is one of the very few prominent, modifiable environmental risk factors in Alzheimers disease, said co-author Michael Kleinman, Ph.D., adjunct professor of environmental and occupational health in UCIs Program in Public Health. Public and environmental regulatory agencies need to accelerate efforts to reduce particulate matter levels in order to reduce the risk of Alzheimers disease and other serious health conditions.

Kitazawa added, This evidence is alarming, and its imperative that we take action to adopt effective and evidence-based regulations, spread awareness on lifestyle changes and work together to improve our air quality.

This study was supported by the National Institutes of Health under awards R21 ES028496 and RF1 NS130616 and by UCI MINDs Womens Alzheimers Movement Womens Initiative grant.

Additional authors include Jason G. Kilian, Marina Mejias-Ortega, Heng-Wei Hsu, David A. Herman, Janielle Vidal, Rebecca J. Arechavala, Samantha Renusch, Hansal Dalal, Irene Hasen, Amanda Ting, Carlos J. Rodriguez-Ortiz, Siok-Lam Lim, Xiaomeng Lin and Joan Vu, all currently or formerly with the UCI Program in Public Healths Department of Environmental and Occupational Health; professor Takashi Saito of Japans Nagoya City University; and team leader Takaomi C. Saido of the RIKEN Center for Brain Science in Wako, Japan.

About the University of California, Irvine:Founded in 1965, UCI is a member of the prestigious Association of American Universities and is ranked among the nations top 10 public universities byU.S. News & World Report. The campus has produced five Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UCI has more than 36,000 students and offers 224 degree programs. Its located in one of the worlds safest and most economically vibrant communities and is Orange Countys second-largest employer, contributing $7 billion annually to the local economy and $8 billion statewide.For more on UCI, visitwww.uci.edu.

Media access: Radio programs/stations may, for a fee, use an on-campus ISDN line to interview UCI faculty and experts, subject to availability and university approval. For more UCI news, visit news.uci.edu. Additional resources for journalists may be found at communications.uci.edu/for-journalists.

Toxicological Sciences

Exposure to quasi-ultrafine particulate matter accelerates memory impairment and Alzheimers disease-like neuropathology in the AppNL-G-F knock-in mouse model

19-Apr-2023

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

Go here to read the rest:

UC Irvine study shows traffic-related air pollution in Irvine weakens ... - EurekAlert

Biology

Bringing the power of molecular biology to environmental science – Science Business

A first-of-a-kind research expedition is pioneering the use of mobile laboratories to understand how Europes coastal ecosystems are impacted by environmental factors such as pollution, loss of biodiversity, and climate change.

The mobile truck laboratories will bring state of the art equipment and technologies to over 100 locations along the coast in 24 countries, where scientists will collect samples and analyse them directly on site. This will be the first time researchers have been able to carry out such detailed molecular biology research in the field.

Studying the ocean has always been more difficult than studying the land. Some of the challenges include a lack of visibility, pressure changes, salinity that can wreak havoc with equipment, and tides. Compounding this is a lack of standardisation of hardware, surveying methodologies and systems for recording data.

Carrying out molecular biology research in coastal ecosystems is even more challenging. Organisms die in transit to central laboratories, and thats why the Traversing European Coastlines (Trec) project has developed mobile laboratories to take the complex technology needed to analyse samples into the field.

We realised that today we have the technologies and the power to explore these land/water interface ecosystems in a completely new way, said Edith Heard, director general of the European Molecular Biology Laboratory (EMBL), which is coordinating Trec with Frances Tara Ocean Foundation and the European Marine Biological Resource Centre.

We are bringing technologies to where life is happening, and where the scientists want to use them, as opposed to always having to rely on shipping things back to some place that has the right material, the right machines, Heard said.

The project, which stated last month, involves 120 different sampling stops along the EU coastline, starting at Roscoff in France. At each site, the team will lay transects from the Tara foundations schooner at anchor, to the shore. A variety of soil, sediment, and water samples will be taken.

These will be analysed in mobile labs equipped with microscopes, freezers, and equipment to prepare samples for imaging, genomic and metabolomic analysis, which will travel between sites.

Protein complexes

The approach is already delivering results. We can see the ultrastructure of dinoflagellates as never seen before, with many new organelles not known before, for which it will take us years to unravel their functions, said Detlev Arendt, senior scientist at EMBL. We also expect that new protein complexes will be described in the next couple of years thanks to the field data that is being generated.

While in fields such as healthcare, mobile labs are becoming commonplace, they are not yet mainstream in environmental science. One aim of Trec is that this way of working will become the standard amongst molecular biologists working in the field.

Based on first experiences, mobile laboratories can make a very important contribution to data collection methodologies, especially in implementing quality assurance and quality control protocols, says Giuseppe Manzella, co-founder of OceanHis, a company that manufactures mobile mini-labs that collect ocean data in real-time.

The mini-labs can be installed on different kinds of boats, and use a range of sensors to collect physical, geochemical and biological data, such as temperature, salinity, chlorophyll levels, blue algae, oxygen levels, conductivity and turbidity.

The method is completely different from the classic method of collecting samples and analysing them in the laboratory, Manzella said.

The research being carried out by the Trec project will add to knowledge about the sections of the European coastline that will be surveyed, said Kate Larkin, head of the European Marine Observation and Data Network. By combining the Trec data with the wide range of data available in existing European Marine Observation and Data Network (Emodnet) datasets, new insights will be unlocked.

This type of data is valuable, but if you imagine lots of different point data being put together, you suddenly start getting a real picture, Larkin said.

Although originally focused on physical and chemical data, work is ongoing to incorporate more biological and genetic information into Emodnets vast databases.

Joining up the dots between the different forms of data is essential to give researchers a clear picture of whats going on, notes Larkin. People dont just want to know the spatial distribution of killer whales. They also want to know whats in the water column and whats on the seafloor, she said.

EMBL hopes the mobile labs will set a new standard for environmental molecular biology and that the results of the TREC expedition will become a reference point for other researchers.

Were not just doing experiments in our research. Were providing infrastructure. And we provide all our data resources openly, said Heard. As a research infrastructure, we have to rise up to the next challenges. We need to do [this] now because climate change is hitting fast.

The Trec project is not part of the Horizon Europe Oceans Mission, but it is complementary, Heard said. There will be cross-benefits between Trec and a project that is part of the Oceans Mission that EMBL is also involved in, called BIOOcean5D, which will investigate marine biodiversity on a large scale. BIOOCean5D is working on the standardisation of protocols for environmental data collection, which will feed into Trec.

See the original post here:

Bringing the power of molecular biology to environmental science - Science Business

Biology

The new human pangenome could help unveil the biology of everyone – Science News Magazine

More than 20 years after people got a peek at the first draft of the human genome, our genetic instruction book, researchers have unlocked the next level: the human pangenome.

In four studies published May 10 in Nature, researchers describe the achievement, how the pangenome was built and some of the new biology scientists are learning from it.

The more complete reference book, which includes almost all the DNA of 47 people, will allow researchers to explore types of variation that could never be examined before, such as large chunks of duplicated, lost or rearranged DNA. That work could possibly reveal more details about the genetic underpinnings of heart diseases, schizophrenia and various other diseases and disorders.

The pangenome adds 119 million DNA bases the information-carrying units of DNA not present in the existing human genome, called the reference genome. Much of that DNA is in never-before-explored parts of the genome containing multiple copies of genes that are duplicated from originals elsewhere in the DNA.

Those duplicated parts are changing faster than nonduplicated portions of the genome, says Evan Eichler, a human geneticist at the University of Washington in Seattle and one of the leaders of the Human Pangenome Reference Consortium. Whats more, when Eichler and colleagues examined the types of variants that arise in these duplicated regions, they found a very strong signal that the mutations that are occurring are fundamentally different from [mutations in] the rest of the genome, he says.

Some of these duplicated regions include ones implicated in humans large brains relative to other species and other traits that set humans apart from other primates. Others have been implicated in certain traits or diseases.

Conversely, another study found that the very short arms of certain chromosomes, including chromosomes 13, 14 and 21, are becoming more like each other as they swap DNA. Those short arms are important because they contain genes for making ribosomal RNAs, which serve as the scaffolds for ribosomes, the machinery responsible for building every protein in the body.

But perhaps the biggest achievement of the pangenome project is that it is finally giving researchers a more complete look at the full spectrum of human genetic diversity.

The roughly two-decade-old human reference genome derives mostly from one man, but is a patchwork quilt of more than 60 peoples DNA (SN: 3/4/21). It has been restitched and added to over the years but still has holes.

Last year, the first fully complete human genome was announced (SN: 3/31/22). That genome contains all of the DNA from tip to tip, or telomere to telomere, of each human chromosome. Except that genome wasnt from a person. It came from a type of tumor known as a hydatidiform mole. These unusual tumors result when a human sperm fertilizes an empty egg and the fathers chromosomes are duplicated.

The genetic information from such tumors represents not even one individual. Its from one half of one individual, says human geneticist Timothy OConnor of the University of Maryland School of Medicine in Baltimore who was not involved in either project.

The new pangenome draft is from actual people and contains almost complete DNA from 47 anonymous individuals from different parts of the world. That diversity is important because it helps us to understand ourselves as a single human species, as a single human race, OConnor says.

Past genetics research has been criticized for relying too heavily on DNA from people of European heritage. Studying just one population of people could mean missing genetic variants that have arisen in specific populations, OConnor says. Having a pangenome reference allows us to assess that population-specific variation in a much more detailed way. And hopefully, that will then lead to greater insight into the biology of everyone.

While the pangenome is a great first step to better represent all human genetic diversity, OConnor says, it still is missing key groups in the world. Its still underrepresenting Latin Americans and Indigenous Americans, and theres nobody included from Oceania. Theres still a lot more variation that needs to be added to the pangenome to really, truly be representative of everyone.

Added diversity is coming, human geneticist Karen Miga of the University of California, Santa Cruz said during a May 9 news conference. The consortium plans to complete a total of 350 genomes, including these 47, by mid-2024. The first phase of the project was aimed at developing the technology to build the pangenome.

Now, the consortium is in talks with Indigenous groups and scientists from around the world about trying to develop a shared framework, so that its not the U.S. trying to set the table. Its really providing a table and inviting other stakeholders who see the value in creating this type of reference resource to join us, said Miga, who helped lead the pangenome project.

Having a more complete understanding of human genetic diversity could help researchers begin to unravel the genetic underpinnings of various diseases and disorders.

Whats more, new DNA deciphering technologies have allowed pangenome researchers to examine types of genetic variants that have been difficult to study before.

In particular, duplicated regions of the genome were hard to study because researchers previously could read only short pieces of DNA. There was no way to tell where in the vast puzzle of the human genome those nearly identical pieces fit. Newer long-read DNA deciphering, or sequencing, technology makes it possible to read stretches of DNA many thousands of bases long (SN: 2/22/21).

Being able to assess where some people have extra DNA and others are missing DNA, called structural variants, adds a more nuanced view of human genetics, OConnor says, revealing more of its complexity (SN: 4/10/09).

For instance, researchers used the pangenome map to trace how chromosomes fold up so that different parts are touching each other. Scientists could see some folds and chemical marks in structural variants that may affect how genes are turned on and off. That could affect traits or health. Eichlers group also mapped one version of a gene that has converted another copy into its own image. These gene conversions were surprisingly common with each person having, on average, more than 2,000 instances of them.

With this more nuanced and complex view of human genetics comes a promise for improved genetics-based medicine. But it may take a while before the pangenome makes a difference in medical clinics, Eichler says.

Researchers hope the pangenome will help them more easily diagnose the genetic changes that contribute to rare diseases and find treatments for common disorders, he says. Once that happens, clinicians may start incorporating data from the pangenome in their practices.

See the original post here:

The new human pangenome could help unveil the biology of everyone - Science News Magazine

Biology

Warren High biology teacher accused of inappropriate relationship – San Antonio Express-News

A Warren High School biology teacher is accused of having an inappropriate relationship with a student.

Stephanie Woods, 28, turned herself in Thursday and was charged with improper relationship between educator and student. She was released Friday after posting bail, which was set at $50,000.

READ ALSO: Teachers child sex case all over Snapchat months after OConnor HS decided not to tell parents

Principal Melissa Hurst said in a letter that Woods was placed on administrative leave when the allegation was brought to district officials attention. The principal said there is limited information to share as the investigation continues, adding that investigators have no reason to suspect that other students are involved.

The relationship came to light when the student involved, a 17-year-old girl, told a therapist about the matter, an affidavit supporting Woods arrest states.

On Wednesday, the teen told police that she was afraid to speak because Woods would get in trouble. She said their relationship started in December and that she spent nights with Woods.

READ ALSO: San Marcos teacher arrested, accused of inappropriate relationship with student

The teen would tell her parents that she was going to a friends house, but she was at Woods place, according to police.

Hurst said that incidents involving the safety of the school, students or staff may be reported via theNorthside Independent School Districts safeline at 210-397-7233.

jbeltran@express-news.net

Go here to read the rest:

Warren High biology teacher accused of inappropriate relationship - San Antonio Express-News