Tag: Medicine

Posted on by

Study provides new understanding of the earliest molecular events in Type 1 Diabetes pathogenesis

Study provides new understanding of the earliest molecular events in Type 1 Diabetes pathogenesis

For the first time, researchers have revealed that during the development of Type 1 Diabetes (T1D), when insulin-producing cells in the pancreas are under attack from T lymphocytes, the cells lining the pancreatic duct reprogram themselves in an attempt to suppress autoimmune T cell responses. This study is published today in Nature Metabolism.

The first events that occur in a patient heading towards Type 1 Diabetes, the events that trigger autoimmunity, have been difficult for researchers to pin down because of our inability to biopsy the pancreas, and the fact that clinical diagnosis is only made once massive beta cell destruction has occurred. That is why it is so important to develop a better understanding of the earliest molecular events in T1D pathogenesis, so we can uncover more about biomarker identification and disease prevention.”


Golnaz Vahedi, PhD, senior author, associate professor of Genetics and member of the Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine at the University of Pennsylvania

Autoimmune diseases, which affect as many as 23.5 million Americans, occur when the body’s immune system attacks and destroys healthy organs, tissues and cells. There are more than 80 types of autoimmune diseases, including rheumatoid arthritis, inflammatory bowel disease, and T1D. In T1D, immune cells called T lymphocytes attack and destroy insulin-secreting pancreatic beta cells and the pancreas stops producing insulin, the hormone that controls blood sugar levels.

“Although it might be an ultimately unsuccessful attempt of the pancreas to limit the adaptive T cell response responsible for destroying beta cells, this finding that the ductal cells are capable of playing this suppressive role towards autoimmune T cell responses is unprecedented,” said co-senior author Klaus Kaestner, PhD, the Thomas and Evelyn Suor Butterworth Professor in Genetics. “Our study shows that these cells, which had never previously been linked to immunity, may change themselves to protect the pancreas.”

Established in 2016, the Human Pancreas Analysis Program (HPAP) is supported by a $28 million grant from the National Institutes of Health with major contributions from Penn, the University of Florida and Vanderbilt University. The HPAP, which is co-directed by Kaestner and Ali Naji MD, PhD, the J. William White Professor of Surgical Research, started collecting pancreatic tissues from hundreds of deceased organ donors diagnosed with T1D. Because many T1D patients harbor beta cell autoantibodies called Glutamic Acid Decarboxylase (GAD) in their bloodstream years before clinical diagnosis, HPAP also collects samples from autoantibody-positive donors, who are at risk for developing T1D but have not received that diagnosis.

“Our study took those quality tissue samples and created high-resolution measurements of millions of cells from patients at various stages of T1D progression, resulting in a single-cell atlas of pancreatic islets,” said co-senior author R. Babak Faryabi, PhD, an assistant professor of Pathology and Laboratory Medicine and a core member of Epigenetics Institute at Penn.

Blood tests to check for levels of GAD are common for patients with, or at risk for, T1D, and doctors use it as a diagnostic tool. Another finding of this study is the new understanding of what is happening on a molecular level in the pancreas and how it correlates to the findings of the GAD test.

“Our study is the first to show that even when a person is not clinically considered to have T1D, high levels detected in their GAD test indicate large-scale transcriptional remodeling of their beta cells,” said Naji, a study co-senior author. “It solidifies to clinicians to closely monitor patients with increasing levels of GAD, as we now know what cellular and molecular changes are in motion in relation to those levels.”

Although researchers do not yet know whether these transcriptional changes are contributing to or are consequences of disease pathogenesis, the discovery of molecular phenotypic changes in pancreatic cells of autoantibody-positive individuals advances the understanding of early pancreatic changes occurring in T1D, and sets the course for continued research in this area.

Source:

University of Pennsylvania School of Medicine

Journal reference:

Fasolino, M., et al. (2022) Single-cell multi-omics analysis of human pancreatic islets reveals novel cellular states in type 1 diabetes. Nature Metabolism. doi.org/10.1038/s42255-022-00531-x.

Posted on by

Cell stress-related biochemical events may be partly driving Parkinson’s disease

Cell stress-related biochemical events may be partly driving Parkinson's disease

Parkinson’s disease may be driven in part by cell stress-related biochemical events that disrupt a key cellular cleanup system, leading to the spread of harmful protein aggregates in the brain, according to a new study from scientists at Scripps Research.

The discovery, published in The Journal of Neuroscience in February 2022, offers a clear and testable hypothesis about the progression of Parkinson’s disease, and may lead to treatments capable of significantly slowing or even stopping it.

We think our findings about this apparent disease-driving process are important for developing compounds that can specifically inhibit the process of disease spread in the brain.”


Stuart Lipton, MD, PhD, study senior author, Step Family Endowed Chair, founding co-director of the Neurodegeneration New Medicines Center, and professor in the Department of Molecular Medicine at Scripps Research

Parkinson’s disease affects roughly one million people in the United States. Its precise trigger is unknown, but it entails the deaths of neurons in a characteristic sequence through key brain regions. The killing of one small set of dopamine-producing neurons in the midbrain leads to the classic Parkinsonian tremor and other movement impairments. Harm to other brain regions results in various other disease signs including dementia in late stages of Parkinson’s. A closely related syndrome in which dementia occurs early in the disease course is called Lewy Body Dementia (LBD), and affects about 1.4 million people in the U.S.

In both diseases, affected neurons contain abnormal protein aggregations, known as Lewy bodies, whose predominant ingredient is a protein called alpha-synuclein. Prior studies have shown that alpha-synuclein aggregates can spread from neuron to neuron in Parkinson’s and LBD, apparently transmitting the disease process through the brain. But precisely how alpha-synuclein aggregates build up and spread in this way has been unclear.

One clue, uncovered by Lipton’s lab and others in prior research, is that the Parkinson’s/LBD disease process generates highly reactive nitrogen-containing molecules including nitric oxide. In principle, these reactive nitrogen molecules could disrupt important cellular systems, including “housekeeping” systems that normally keep protein aggregates under control.

In the new study, the Scripps Research team demonstrated the validity of this idea by showing that a type of nitrogen-molecule reaction called S-nitrosylation can affect an important cellular protein called p62, triggering the buildup and spread of alpha-synuclein aggregates.

The p62 protein normally assists in autophagy, a waste-management system that helps cells get rid of potentially harmful protein aggregates. The researchers found evidence that in cell and animal models of Parkinson’s, p62 is S-nitrosylated at abnormally high levels in affected neurons. This alteration of p62 inhibits autophagy, causing a buildup of alpha-synuclein aggregates. The buildup of aggregates, in turn, leads to the secretion of the aggregates by affected neurons, and some of these aggregates are taken up by nearby neurons.

“The process we observed seems very similar to what is seen in Parkinson’s and LBD brains,” says study first author Chang-Ki Oh, PhD, a staff scientist in the Lipton laboratory.

The researchers also tested postmortem brains of LBD patients, and again found that levels of S-nitrosylated p62 were abnormally high in affected brain areas-;supporting the idea that this process occurs in humans.

Lipton and Oh say that S-nitrosylation of proteins becomes more likely in many situations of cellular stress, including the presence of protein aggregates. Thus, this chemical modification of p62 could be a key factor in a self-reinforcing process that not only stresses brain cells beyond their limits, but also spreads the source of stress to other brain cells.

The team is now working to develop drug-like compounds that specifically inhibit the S-nitrosylation of p62. Although it would take years to develop such compounds as potential commercial drugs, they could, in principle, slow the Parkinson’s/LBD disease process or prevent its further spread in the brain after it begins, Lipton says.

Source:

Scripps Research Institute

Journal reference:

Oh, C., et al. (2022) S-Nitrosylation of p62 Inhibits Autophagic Flux to Promote α-Synuclein Secretion and Spread in Parkinson’s Disease and Lewy Body Dementia. Journal of Neuroscience. doi.org/10.1523/JNEUROSCI.1508-21.2022.

Posted on by

Indigenous duo aims to create good medicine and good vibes only with online dating event | CBC News

Indigenous duo aims to create good medicine and good vibes only with online dating event | CBC News

Dating can feel daunting but when you add the impacts of intergenerational trauma into the mix it can become exhausting, say two friends who are trying to eliminate all that stress with a virtual snag fest. 

The cheeky title implies that the upcoming Zoom sessions are meant to be fun. The concept started as a joke between Deanna StandingCloud and Victoria Marie but as they thought about Indigenous networking, the talks became serious. 

“It’s such a hard time to get out there and meet new people,” said Marie, who is a tribal member of Sisseton-Wahpeton Oyate and lives in Minnesota.

The pair met when they were both pregnant and developed a friendship while they organized an Indigenous wellness retreat together. Both work in the Indigenous wellness field and organize other events centred on Indigenous healing. 

StandingCloud, a citizen of Red Lake Nation in Minnesota, is a powwow MC, a bingo caller and a wellness advocate for Indigenous communities. 

She said dating is yet another task on an already long list that includes child-rearing and healing from her own hurts and said a lot of single Indigenous women can understand that. Then when you have a partner who wants help dealing with their own trauma, it can be exhausting.

“I get tired of holding it all together, so I would love for men to be medicine for their communities,” said StandingCloud.

Marie’s company, Indigenous Lotus, is hosting the event on Zoom. There will be two 90-minute sessions where participants will break out into speed dating rounds and will play connection games, like the old-time dating game shows.

Victoria Marie is the owner of Indigenous Lotus, which is hosting the Indigenous speed-dating event. (Submitted by Victoria Marie)

Jane Meader, a Mi’kmaw grandmother from Unama’ki, said in dating, Indigenous people are asked to be good medicine to one another because of a responsibility to the community. Ensuring women feel safe in dating has always been a part of Mi’kmaw culture, she said. 

“Women were very helpful to one another and treated each other with kindness,” said Meader. 

She said today’s sexual objectification of Indigenous women is a foreign concept and that traditionally in Mi’kmaw families, women held the power. They chose who they wanted to marry and a potential partner would have to prove to her and her family that he was worth marrying. When they married, he was committing to the woman’s language, culture, clan and family, and it was also within her power to decide if she wanted a divorce. 

Mi’kmaw grandmother Jane Meader says Mi’kmaw women always cared for one another and their safety was always important. (Tom Ayers/CBC)

Meader said anyone considering dating should ask if their potential partner loves, honours and respects themselves, other genders and Creator.

“It’s about us being better human beings, first before anything else,” said Meader. 

Marie said she hopes Indigenous women can have fun at their online connection event and that for men, being in a circle with healthy Indigenous women will encourage them to seek healing for intergenerational trauma.

“I believe in bringing people together with the same intention of having fun, and connecting is expanding our ability to heal one another,” said Marie.

The online event will also centre on creating new friendships and participants can either hold a yellow ribbon for friendship or a red ribbon for romantic interests. 

Posted on by

Biological events occurring during puberty trigger sex differences in learning and memory

Biological events occurring during puberty trigger sex differences in learning and memory

New research from the University of California, Irvine reveals that sex differences in learning and memory mechanisms are triggered by biological events occurring during puberty. Findings show prepubescent female rodents have much better hippocampal long-term potentiation (LTP) and spatial learning than same-age males, but puberty has opposite consequences for synaptic plasticity in the two sexes.

The study, titled “Prepubescent female rodents have enhanced hippocampal LTP and learning relative to males, reversing in adulthood as inhibition increases” was recently published in Nature Neuroscience.

Since the late 19th century, the general consensus in the scientific community has been that men outperform women on spatial tasks, while women excel in learning tasks involving verbal material, while the general debate has been about why there is a difference.

The surprising conclusion from our results is that the polarization of sex differences in hippocampal synapses and related learning reverses in females and males from before to after puberty. This occurs because of distinct developmental changes. Thresholds for plasticity and encoding spatial information increase in females and decease in males.”


Christine Gall, PhD, co-corresponding author, and distinguished professor and chair of anatomy and neurobiology at the UCI School of Medicine

Puberty is a critical landmark in brain maturation and results in a wide variety of sex differences in behavior, but little is known about how it affects the substrates for memory encoding. Researchers identified a female-specific mechanism that increases the LTP threshold and decreases spatial memory from before to after puberty. Sex differences were demonstrated for hippocampus-dependent processes and driven by different underlying mechanisms.

In females only, inhibitory synapses in the CA1 field of the hippocampus exhibit an increase in levels of GABAA receptors containing the α5 subunit; this increase is associated with greater inhibition of synaptic activity critical for synaptic plasticity and memory. The α5 receptors have been linked to anxiety which also undergoes changes at the onset of the estrous cycle. Researchers found that pharmacological suppression of α5-GABAA receptors restored LTP and memory encoding in females to levels observed before puberty.

“Our team proposes that the emergent female pattern may favor learning in complex circumstances while the emergent male pattern favors rapid acquisition of simpler material. This idea suggests that optimal teaching strategies need to reflect previously unsuspected brain differences between the sexes and how these are dramatically adjusted during puberty,” Gall said. “The vast majority of studies have begun with analyses of young adult male rodents. Females use somewhat different memory mechanisms than do males and therefore may respond differently to drugs and gene mutations. This new research demonstrates the need for new sexually differentiated approaches for the development of therapeutic treatments and their applications at different life stages.”

Further research will be conducted to determine if the sex-specific LTP threshold changes identified in hippocampus during the transition to postpubertal life are evident in other brain areas and influence the encoding of different types of memories.

Source:

University of California, Irvine

Journal reference:

Le, A.A., et al. (2022) Prepubescent female rodents have enhanced hippocampal LTP and learning relative to males, reversing in adulthood as inhibition increases. Nature Neuroscience. doi.org/10.1038/s41593-021-01001-5.