Genetics

Adolescent Stress Alters Brain Genes, Affecting Adult Behavior – Neuroscience News

Summary: A new study reveals that excessive stress during adolescence can lead to long-lasting changes in gene expression in the brain, particularly those related to bioenergy functions.

This research indicates that such alterations may disrupt cell respiration and contribute to behavioral issues and psychiatric disorders in adulthood. Using a rat model, the study showed that stressed adolescent rats exhibited anxiety, reduced sociability, and cognitive impairments, linked to changes in genes controlling mitochondrial function in the prefrontal cortex.

These findings underscore the critical impact of adolescent stress on adult brain function and behavior.

Key Facts:

Source: FAPESP

Excessive stress during adolescence can cause alterations in the profile of genes expressed in the brain, especially those associated with bioenergy functions.

These alterations may affect cell respiration, resulting in behavioral problems and psychiatric disorders in adulthood, according to a study in rats conducted by researchers at the University of So Paulos Ribeiro Preto Medical School (FMRP-USP) in Brazil.

The results are reported in an articlepublishedin the journalTranslational Psychiatry.

It is no secret that many changes occur in our bodies and behavior during adolescence when the brain undergoes structural and functional alterations shaped both by neurobiological and social factors.

Like the human brain, the brain of an adolescent rat is highly plastic. This plasticity is seen at the molecular level and in terms of behavior. Changes in the expression profiles of specific genes in different brain regions lead to alterations in brain cell connectivity, which spread systemically and can produce persistent alterations in adulthood that correlate with psychiatric disorders, said Thamyris Santos-Silva, first author of the article. At the time of the study, she was a PhD candidate in pharmacology at FMRP-USP.

Adolescence is a critical period for brain plasticity, which is significantly influenced by social experience, addedFelipe Villela Gomes, last author of the article and a professor in FMRP-USPs Department of Pharmacology.

Susceptibility to adverse social and environmental factors, such as traumas, insults and abuse, increases during this period, and social experience can influence vulnerability and resilience to stress.

The prefrontal cortex is a brain region that is extremely susceptible to stress during adolescence. When it matures, it is crucial to enhanced cognitive control of emotions normally observed in adulthood. In rats subjected to stress during adolescence, this region displayed lower levels of expression of genes that play a key role in mitochondrial respiration.

Mitochondria are organelles found in most cells of both humans and rats, as well as many other living organisms. Through cell respiration, they are the main source of chemical energy for the functioning of neurons, one of the main types of brain cells. They therefore help regulate social behavior, including the response to stress.

The study, which wassupported by FAPESP, began by analyzing behavioral responses to stress, such as anxiety, social interaction and cognition, in late-adolescent rats. The animals were exposed to a stress protocol for ten consecutive days that coincided with an intense period of brain plasticity. They were then submitted to specific tests to assess their behavior, and the results showed distinct impairment in every case.

We found that stressed animals in this life stage displayed a markedly poor behavioral profile, with anxiety, reduced sociability and impaired cognitive function, Gomes said.

To discover whether these variations were reflected by gene expression, the researchers sent RNA samples to the Behavioral Genetics Laboratory of the Brain Mind Institute (BMI) at the Swiss Federal Institute of Technology in Lausanne (EPFL). The laboratory is led by Carmen Sandi, a professor of neuroscience.

To investigate gene expression in the rats brains, the laboratory sequenced messenger RNA and analyzed the results using bioinformatics tools. This part of the study was funded under a joint institutional internationalization program run by USP and CAPES, the Ministry of Educations Coordination for the Improvement of Higher Education Personnel (PrInt USP/CAPES).

The analysis showed alterations to the genes of the prefrontal cortex in the stressed animals. Among the ten most affected genes, several were associated with pathways linked to oxidative stress and mitochondrial function, a key cellular component of energy production for the brain, Gomes said.

Consumption of oxygen by mitochondria in the brains of these animals was also found to be impaired by stress.

We now have evidence of various kinds pointing to the importance of mitochondrial function in this behavioral profile, Gomes said.

Next steps

Next steps for the researchers will include investigating whether this behavioral profile can serve as a basis for predicting an individuals response to stress, and to what extent this actually does lead to the development of psychiatric disorders.

Another route to advance the study would be to focus on genetic alterations, conducting tests to find out what happens when gene expression diminishes or improves. This could provide more evidence regarding the links between stress and the alterations in question, and even point to ways to combat them, Gomes said.

Author: Heloisa Reinert Source: FAPESP Contact: Heloisa Reinert FAPESP Image: The image is credited to Neuroscience News

Original Research: Open access. Transcriptomic analysis reveals mitochondrial pathways associated with distinct adolescent behavioral phenotypes and stress response by Thamyris Santos-Silva et al. Translational Psychiatry

Abstract

Transcriptomic analysis reveals mitochondrial pathways associated with distinct adolescent behavioral phenotypes and stress response

Adolescent individuals exhibit great variability in cortical dynamics and behavioral outcomes. The developing adolescent brain is highly sensitive to social experiences and environmental insults, influencing how personality traits emerge.

A distinct pattern of mitochondrial gene expression in the prefrontal cortex (PFC) during adolescence underscores the essential role of mitochondria in brain maturation and the development of mental illnesses.

Mitochondrial features in certain brain regions account for behavioral differences in adulthood. However, it remains unclear whether distinct adolescent behavioral phenotypes and the behavioral consequences of early adolescent stress exposure in rats are accompanied by changes in PFC mitochondria-related genes and mitochondria respiratory chain capacity.

We performed a behavioral characterization during late adolescence (postnatal day, PND 4750), including nave animals and a group exposed to stress from PND 3140 (10 days of footshock and 3 restraint sessions) by z-normalized data from three behavioral domains: anxiety (lightdark box tests), sociability (social interaction test) and cognition (novel-object recognition test).

Employing principal component analysis, we identified three clusters: nave with higher-behavioral z-score (HBZ), nave with lower-behavioral z-score (LBZ), and stressed animals. Genome-wide transcriptional profiling unveiled differences in the expression of mitochondria-related genes in both nave LBZ and stressed animals compared to nave HBZ.

Genes encoding subunits of oxidative phosphorylation complexes were significantly down-regulated in both nave LBZ and stressed animals and positively correlated with behavioral z-score of phenotypes. Our network topology analysis of mitochondria-associated genes foundNdufa10andCox6a1genes as central identifiers for nave LBZ and stressed animals, respectively.

Through high-resolution respirometry analysis, we found that both nave LBZ and stressed animals exhibited a reduced prefrontal phosphorylation capacity and redox dysregulation.

Our findings identify an association between mitochondrial features and distinct adolescent behavioral phenotypes while also underscoring the detrimental functional consequences of adolescent stress on the PFC.

Originally posted here:
Adolescent Stress Alters Brain Genes, Affecting Adult Behavior - Neuroscience News

Cell Biology

Scientists uncover a way to "hack" neurons’ internal clocks to speed up brain cell development – News-Medical.Net

The neurons that make up our brains and nervous systems mature slowly over many months. And while this may be beneficial from an evolutionary standpoint, the slow pace makes growing cells to study neurodegenerative and neurodevelopmental diseases -; like Parkinson's disease, Alzheimer's disease, and autism -; in the laboratory quite challenging.

Currently, nerve cells derived from human pluripotent stem cells take months to reach an adultlike state in the lab -; a timeline that mirrors the slow pace of human brain development. ("Pluripotent stem cells" have the potential to develop into many other kinds of cells.)

New research led by Memorial Sloan Kettering Cancer Center (MSK), however, has uncovered a way to "hack" the cells' internal clocks to speed up the process. And the work is shedding new light on how cells' developmental timetables are regulated.

"This slow pace of nerve cell development has been linked to humans' unique and complex cognitive abilities," saysLorenz Studer, MD, Director of MSK'sCenter for Stem Cell Biologyand the senior author of two recent studies published inNatureandNature Biotechnology."Previous research has suggested the presence of a 'clock' within cells that sets the pace of our neurons' development, but its biological nature had largely remained unknown -; until now."

Researchers, led by study first authorGabriele Ciceri, PhD, identified an epigenetic "barrier" in the stem cells that give rise to neural cells. ("Epigenetic changes" are ones that don't alter the DNA code.) This barrier acts as a brake on the development process and determines the rate at which the cells mature. By inhibiting the barrier, the scientists were able to speed up the neurons' development,they reported January 31 inNature.

While studying brain development in mice, I was struck by how neurons progress through a series of steps in a very precise schedule. But this schedule creates a big practical challenge when working with human neurons -; what takes hours and days in the mouse requires weeks and months in human cells."

Dr.Gabriele Ciceri,a senior research scientist in the Studer Lab at MSK'sSloan Kettering Institute

Furthermore, the team showed that this rate-setting epigenetic barrier is built into neural stem cells well before they differentiate into different types of neurons. They also found higher levels of the barrier in human neurons compared with mouse neurons, which may help explain differences in the pace of cell maturation in different species.

That such discoveries were made at a cancer center isn't as surprising as it might seem at first blush. The Studer Lab has long focused on harnessing advances in stem cell biology to develop new therapies for degenerative diseases and cancer -; both of which are strongly associated with aging.

Moreover,MSK has long been a leader in "basic science" research-; that is, science that seeks to build fundamental understanding of human biology.

About half of the National Institutes of Health (NIH) budget goes to funding basic science research. And the vast majority of drugs approved bythe Food and Drug Administration in recent years involved publicly funded basic research,according to the NIH.

"All of the major advances in cancer treatment in recent years -;immune checkpoint inhibitor therapy,CAR T cell therapy,cancer vaccines-; they're all rooted in basic research," saysJoan Massagu, PhD, Director of the Sloan Kettering Institute and MSK's Chief Scientific Officer. "Sometimes it can take years for the medical relevance of a particular discovery to become clear."

A second study, led by Studer Lab graduate studentsEmiliano HergenrederandAndrew Minottiand published January 2 inNature Biotechnology, identified a combination of four chemicals that together can promote neuronal maturation. Dubbed GENtoniK, the chemical cocktail both represses epigenetic factors that inhibit cell maturation and stimulates factors that promote it.

Along with helping to bring neurons to an adultlike state faster in the lab, the approach holds promise for other cell types, the researchers note.

Not only was GENtoniK shown to speed the maturation of cortical neurons (involved in cognitive functions) and spinal motor neurons (involved in movement), but the chemicals were also able to accelerate the development of several other types of cells derived from stem cells, including melanocytes (pigment cells) and pancreatic beta cells (endocrine cells).

"The generation of human neurons in a dish from stem cells provides a unique inroad into the study of brain health and disease," the journal editors note in aresearch briefingthat accompanied the study. "A major obstacle in the field arises from the fact that human neurons require many months to mature during development, making it difficult to recapitulate the process invitro. The authors provide a valuable research tool by developing a simple drug cocktail that speeds up the maturation timeframe."

The findings could be particularly helpful in modeling disorders like autism that involve problems with synaptic connectivity, Dr. Studer says.

Still, he notes, additional research is needed to develop models of neurodegenerative disorders that don't occur until very late in life, such as Parkinson's disease, which haslong been a focus of Studer's research.

"Typically, a person is 60 to 70 years old when the disease begins. No baby gets Parkinson's," he says. "So, for those diseases, we need to be able to put the cells not just into an adult state but into an aged-like state. That's something we're continuing to work on."

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Scientists uncover a way to "hack" neurons' internal clocks to speed up brain cell development - News-Medical.Net

Cell Biology

Singapore scientists uncover a crucial link between cholesterol synthesis and cancer progression – EurekAlert

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A study led by scientists at Duke-NUS Medical School has identified the pivotal but previously unknown role of an enzyme, called FAXDC2, that is suppressed in cancers with hyperactive Wnt signalling. FAXDC2 regulates the production of cholesterol and cell signalling molecules, and its suppression causes abnormal cell growth. Restoring FAXDC2 function could potentially normalise cell behaviour in these cancers.

Credit: Babita Madan

SINGAPORE, 2 February 2024 Scientists led by a team at Duke-NUS Medical School have made a breakthrough in understanding the mechanisms that influence cancer cell growth and development. Publishing in theJournal of Clinical Investigation, the researchers illuminate the previously hidden role of a novel enzyme, called fatty acid hydroxylase domain containing 2 (FAXDC2), revealing its pivotal role in cholesterol synthesis and cancer progression.

The study details the cascade of molecular events beginning from the suppression of FAXDC2 to the disruption of normal cholesterol synthesis to altered cancer fates, highlighting a potential vulnerability in cancer cells that could be targeted for therapeutic intervention.

Our journey into the cellular drivers of cancer started with an exploration of the Wnt signalling pathway, a crucial player in cell growth and development, explainedAssistant Professor Babita Madan, first author of the study from Duke-NUSCancer & Stem Cell Biology(CSCB) Programme. It was during these studies that we stumbled upon the enzyme FAXDC2, which emerged as a central figure in controlling cancer and stem cells. Our discovery suggests that FAXDC2's activity, or its suppression, has profound implications for cellular growth and differentiation, painting a complex picture of the relationship between cancer biology and cholesterol synthesis.

The research began with a deep dive into the Wnt signalling pathway, known for its critical role in the regulation of both normal and cancer cell growth. Wnt signalling is a key signalling pathway that regulates growth and development and maintaining brain, skin, hair and intestinal cells. However, hyperactive Wnt signallingpresent in the cancer models employed in the studyimpairs cell differentiation and keeps the cancers in a stem cell-like state. These undifferentiated cancer stem cells proliferate rapidly and uncontrollably, promoting faster tumour progression, and are resistant to anti-cancer therapies.

Employing cutting-edge genomic technologies to unravel this complex biological process, the scientists attention was drawn to the enzyme FAXDC2 when they found it increased dramatically after pancreatic cancer models were treated with amade-in-Singapore Wnt inhibitor, ETC-159. In-depth analyses of colorectal cancer tissue samples corroborated this finding, showing a consistent pattern of FAXDC2 suppression and subsequent buildup of cholesterol precursors, including a building block of cholesterol called lophenol. The lower the FAXDC2 expression, the higher the level of lophenol.

FAXDC2 is a previously unknown enzyme that helps make cholesterol from the precursor lophenol. Importantly, how much FAXDC2 you have in your cells changes the amount of lophenol you have, explainedProfessor David Virshup, Director of the CSCB Programme and the senior author of the study. Lophenol appears to modulate the activity of the differentiation pathway and, therefore, we think it helps to keep cancer cells in a more stem cell-like state.

Prof Virshup emphasised the broader implications of these insights, saying, This study provides a fascinating glimpse into the molecular machinery of cancer cells. The role of FAXDC2 in regulating cholesterol synthesis opens new pathways for future therapies. Understanding these complex mechanisms paves the way for innovative approaches to combat cancer, emphasising the importance of cholesterol biosynthesis intermediates as important signalling molecules and potential drugs.

The discovery of FAXDC2s role in cancer biology marks just the beginning of a longer scientific journey. Further research is necessary to fully understand how the suppression of FAXDC2 and the resulting changes in cholesterol metabolism can be leveraged to develop new cancer therapies. The research team is keen on exploring the therapeutic potential of targeting FAXDC2 in cancer treatment, considering it as a possible avenue for the development of drugs that could inhibit cancer growth by modulating cholesterol synthesis pathways.

Additionally, the findings spur interest in preventative strategies that could mitigate the risk of cancer development by maintaining the balance of cholesterol precursors in the body. Understanding the triggers that lead to the suppression of FAXDC2 in cancer cells could pave the way for novel prevention methodologies, potentially offering new hope in the fight against cancer.

"These findings resonate with our unwavering commitment to improving patient care through pivotal discoveries, commentedProfessor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS. The road ahead involves rigorous research and collaboration across various disciplines, all aimed at translating these fundamental insights into tangible medical breakthroughs that could one day transform cancer treatment and prevention strategies.

Journal of Clinical Investigation

Experimental study

Cells

The cholesterol biosynthesis enzyme FAXDC2 couples Wnt/-catenin to RTK/MAPK signaling

23-Jan-2024

Babita Madan and David Virshup have a financial interest in ETC-159.

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.

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Singapore scientists uncover a crucial link between cholesterol synthesis and cancer progression - EurekAlert

Cell Biology

First atomic-scale ‘movie’ of microtubules under construction, a key process for cell division – EurekAlert

image:

scar Llorca is standing in the center; Marina Serna is first from the right.

Credit: Laura M. Lombarda/CNIO.

Researchers at the Centre for Genomic Regulation (CRG) , the Spanish National Cancer Research Center (CNIO) and the IBMB-CSIC solve a key problem in biology: how human cells build their microtubules

During cell division, microtubules function as nanometer-thick long ropes' inside cells that pull chromosomes apart so that each daughter cell receives a copy of the genetic material

The work published in Science lays the groundwork for future breakthroughs in the treatment of diseases ranging from cancer to neurodevelopmental disorders

Cells in the human body are constantly dividing. With each division the genetic information contained in the chromosomes is duplicated, and each daughter cell receives a complete copy of the genetic material. It is a sophisticated process, a clockwork mechanism that involves refined and fast changes within the cell. To make this possible, the cell relies on microtubules, tiny structures that are indeed tube-shaped. Understanding how they start forming is a long-standing question.

Now, for the first time, researchers at the Centre for Genomic Regulation (CRG), the Spanish National Cancer Research Center (CNIO) and the Spanish National Research Council (IBMB-CSIC) have succeeded in making the equivalent of a film showing how human cells initiate the construction of their microtubules.

The findings, published today in the journal Science, solve a problem brought up years ago and thus lay the groundwork for future breakthroughs in the treatment of diseases ranging from cancer to neurodevelopmental disorders.

Long ropes that pull chromosomes apart

scar Llorca, director of the Structural Biology Program at the CNIO and co-lead author of the study, describes what happens inside the cell when cell division begins: "The chromosomes, once they have duplicated genetic information, move to the center of the cell and the cell, in a very remarkable way, quickly sprouts from its two ends large tubes that hook the chromosomes and pull each of the copies towards the two poles of the cell. Only then is it possible to encapsulate a copy of all our genetic material in each daughter cell."

The structures that are launched "like long ropes that reach the chromosomes to divide them," explains Llorca, are the microtubules. "That's why we say that microtubules play a key role in cell division. We need to understand very well the mechanisms that trigger the formation of these microtubules, at the right place and at the right time."

They are also 'cellular highways'

Microtubules are tubes with a length of thousandths of a millimeter and a diameter of nanometers [millionths of a millimeter]. In addition to being key to cell division, they act as highways for moving cellular components between different areas of the cell. They are also structural elements that shape the cell itself, among other tasks. A good understanding of their formation has implications for multiple areas of biomedicine.

"Microtubules are critical components of cells. Here we capture the process in action inside human cells. Given the fundamental role of microtubules in cell biology, this could eventually lead to new therapeutic approaches for a wide range of disorders," explains ICREA Research Professor Thomas Surrey, CRG researcher and co-lead author of the paper in Science.

Molecular ring triggers microtubule formation

The high-resolution images now obtained answer a question that has been hanging in the air for years: how microtubule formation begins in the early stages of cell division.

We now know that it all starts when a complex structure made up of several proteins, and called g TuRC (pronounced 'gammaturc'), closes, forming a ring.

The shape of g TuRC, its three-dimensional structure, was discovered a few years ago, and it surprised researchers. It was expected that g TuRC would be a closed ring acting as a base mold on top of which the microtubule is built; but g TuRC appeared as an open ring. Its dimensions and shape were incompatible with those of a microtubule mold.

The new CRG and CNIO work unveils the mechanism by which g TuRC closes into a ring and effectively becomes a perfect mold, capable of launching microtubule formation. The closure of g TuRC occurs when the first molecular piece of a microtubule gets attached to it.

"That's the trick the cell uses to close g TuRC," explains Llorca. "As soon as this first brick enters, a region of g TuRC is able to hook it and, like a loop, acts as a latch that pulls the ring closed and launches the process."

Visualizing this process required purifying g TuRC from human cells and reproducing the microtubule initiation process in the test tube. The samples were observed with cryo-electron microscopes and artificial intelligence was used for data analysis.

One million frames in a movie at atomic scale

One of the challenges has been to deal with the high speed of the microtubule construction process. The CRG group succeeded in slowing it down in the laboratory, and also stopping the growth of microtubules in order to better analyze the initial stages of the process.

"We had to find conditions that allowed us to image over a million microtubules in the process of nucleation before they grow too long and obscure the action of -TuRC. We were able to achieve this using the molecular toolbox of our lab and then freeze the microtubule stubs in place," explains Cludia Brito, a postdoctoral researcher at the CRG and first author of the study.

The microtubules under construction were observed at the IBMB-CSIC's Electron Cryomicroscopy Platform, located at the Joint Electron Microscopy Center (JEMCA), inside the ALBA Synchrotron. "They were frozen in a thin layer of ice, preserving the natural shape of the molecules involved," explains Pablo Guerra, head of this Platform. Thats how the best experimental conditions for observing microtubules in formation were determined. The best frozen samples were then sent to BREM (Basque Resource for Electron Microscopy) for imaging, and the resulting images were transferred to Marina Serna and Oscar Llorca at the CNIO for analysis and determination of the three-dimensional structures at atomic resolution.

Artificial intelligence for assembly

In practice, having more than a million microtubules in different stages of growth is equivalent to having many frames of a movie in high resolution. You just have to arrange them in the right order to see the movie in progress. That task fell to the CNIO team, which used artificial intelligence techniques to complete it

Determining the three-dimensional structure of growing microtubules from microscope images has been extremely complex. We needed multiple digital image-processing tools," explains Marina Serna, CNIO researcher.

For Llorca, "the great challenge has been to analyze at high resolution the images of a dynamic process, where we were observing several stages at the same time. This has been possible thanks to the use of neural networks, which have allowed us to organize all this complexity.

The result are three-dimensional structures at atomic resolution that represent the different stages of how the construction of a microtubule begins, and how the -TuRC ring becomes the mold that launches the formation of microtubules.

Implications for health

As Llorca explains, "this finding is relevant because we have addressed a very basic mechanism of cell division, whose process in humans we did not know".

This basic knowledge is useful for learning how to correct errors in the functioning of microtubules, which are associated with cancer, neurodevelopmental disorders and other conditions ranging from respiratory problems to heart disease.

"Some of the drugs used today to treat cancer prevent the formation or dynamics of microtubules," says Llorca. "However, these drugs affect microtubules indiscriminately, both in cancer cells and in healthy cells, leading to side effects. Knowing in detail how microtubules are formed may contribute to the development of more targeted treatments that affect microtubule formation and allow progress in the treatment of cancer and other diseases."

Next step: understanding regulation

Thomas Surrey explains the next steps in understanding microtubules, which involve deciphering how microtubule formation is regulated: "The process of nucleation decides where the microtubules are in a cell and how many you have in the first place. It is likely that the conformational changes we observe are controlled by yet-to-be-found regulators in cells. Several candidates have been described in other studies, but their mechanism of action is unclear."

Further work, "clarifying how regulators bind to -TuRC and how they affect the conformational changes during nucleation, may transform our understanding of how microtubules work, and eventually offer alternative sites that one might want to target to prevent cancer cells from going through the cell cycle," Surrey concludes.

Experimental study

Cells

Transition of human -tubulin ring complex into a closed conformation during microtubule nucleation

1-Feb-2024

The authors declare that they have no competing interests

Originally posted here:
First atomic-scale 'movie' of microtubules under construction, a key process for cell division - EurekAlert

Cell Biology

Small RNAs take on the big task of helping skin wounds heal better and faster with minimal scarring – EurekAlert

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Deposition of laminin into wound bed contributes to blood vessel growth, which in turn, feeds normal skin regeneration. W - wound, BV - blood vessels.

Credit: The American Journal of Pathology

Philadelphia, February 1, 2024 New findings in The American Journal of Pathology, published by Elsevier, report that a class of small RNAs (microRNAs), microRNA-29, can restore normal skin structure rather than producing a wound closure by a connective tissue (scar). Any improvement of normal skin repair would benefit many patients affected by large-area or deep wounds prone to dysfunctional scarring.

Because the burden of non-healing wounds is so significant, it is sometimes called a silent pandemic. Worldwide, costs associated with wound care are expected to reach US$15 to 22 billion per year by 2024, exceeding the cost of managing obesity-related health problems in some parts of the world.

Lead investigator Svitlana Kurinna, PhD, Division of Cell Matrix Biology and Regenerative Medicine, FBMH, University of Manchester, explained, We had data showing that microRNAs can regulate skin growth. microRNAs do not code for proteins, so it wasnt clear exactly how such small molecules can make changes to the skin. We therefore studied underlying mechanisms that could be targeted to improve cutaneous wound healing.

The molecular events during early wound healing stages of inflammation and tissue formation have been well described using single cell sequencing and proteomic approaches. microRNAs are important factors in healing and may regulate functions in skin repair; however, the mechanisms underlying tissue remodeling are unclear. Scientists studying wound healing in microRNA-29 gene knockout transgenic mice suggest that the release of microRNA-29 targets promotes wound healing by regulating skin regeneration by binding long RNAs coding for structural protein laminin C2 (LAMC2) of the skin. This restores the normal skin structure rather than creating a connective tissue scar.

In the current study, researchers noted that wild type wounded mice healed quite well, but the skin of transgenic mice devoid of microRNA-29 regenerated even better. To understand the reasons, they conducted in-depth microscopic analysis of the transgenic wounds. They observed deposition of LAMC2usually found in one of the skin layers in wild micearound blood vessels inside the wounds of microRNA-29deficient transgenic mice. This observation indicates that microRNA-29 may be inhibiting the expression of LAMC2, and deletion in the transgenic mice relieved the inhibition, which resulted in faster wound healing.

Dr. Kurinna noted, These processes are likely mediated by microRNA-29 target microRNAs released upon removal of microRNA-29 to improve cell matrix adhesion. These results further suggest a link between LAMC2, improved angiogenesis, and re-epithelialization. We had expected a different change in skin regeneration; we thought the removal of microRNA-29 would help outer layers of the skin to grow faster, but it was the deep matrix of the wound that showed an improvement.

These findings in both mice and humans demonstrate the role of microRNA-29 in epidermal repair and suggest that the release of microRNA-29 targets, particularly LAMC2, promotes wound healing. The inhibition of microRNA-29 and/or overexpression of LAMC2 may be a new and effective strategy for improving wound healing.

Dr Kurinna concluded, Our findings are of particular interest because they show the mechanism to restore normal skin structure rather than a wound closure by a connective tissue (scar). Any improvement of normal skin repair would therefore help many patients affected by large-area or deep wounds prone to dysfunctional scarring.

American Journal Of Pathology

Observational study

Cells

Release of miR-29 Target Laminin C2 Improves Skin Repair

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.

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Small RNAs take on the big task of helping skin wounds heal better and faster with minimal scarring - EurekAlert

Human Behavior

Overcoming ‘Otherness’ in Scientific Research Commentary in Nature Human Behavior USA – English – USA – PR Newswire

WASHINGTON, Feb. 2, 2024 /PRNewswire/ -- In a provocative commentary in Nature Human Behavior, Dr. Jane L. Delgado of the National Alliance for Hispanic Health and Dr. Rueben C. Warren former Director of the National Center for Bioethics in Research and Health Care at Tuskegee University and now at Meharry Medical College, call for a critical examination of 'otherness' in science to advance the meaningfulness and quality of research and movebeyond health disparities, a sanitized catch-all phrase, that defuses what are more accurately labeled as harmful health outcomes (HHO). They also provide interventions to proactively address otherness to produce better science.

Dr. Delgado explains further, "True scientific excellence requires all voices, and varied experiences and perspectives. To harness the full potential of our society, we must recognize and actively address the biases that 'otherness' introduces into scientific research." Dr. Warren adds, "It's crucial to acknowledge that our collective progress is hindered when research is skewed by the exclusion of significant populations based on gender, race, or other dimensions of identity."

The commentary highlights the detrimental impact of 'otherness' in scientific methodologies and outcomes, particularly in health-related research. They describe how the factors that define a sense of belonging produce the corollary of otherness. These factors include race, ethnicity, sex/gender, religious affiliation, heritage, political association, and other dimensions.The impact is science that is limited by its methods and scope producing adverse health outcomes. Negative otherness distorts all aspects of science from how teams are structured, participants invited, questions asked, answers that are developed, follow-up actions, interpretation of findings, final conclusions, and clinical decision-making."

The commentary makes clear, "Otherness is not a new concept and while the focus on otherness focuses on the negative consequences there are also positive outcomes that may occur. Positive outcomes from otherness occur when there is a recognition of differences that are taken into consideration to tailor actions to the individual to produce positive outcomes." A good example of positive otherness is the movement for precision or tailored medicine.

The authors call for a recalibration of the scientific enterprise by building diverse teams, encouraging multiple perspectives, improving AI algorithms with comprehensive data sets, and leveraging 'otherness' to foster innovation rather than division. The authors conclude that individual actions and leadership are paramount to overcoming the entrenched biases of 'otherness' and achieving a future where scientific discovery is unbounded and all-inclusive.

For the full commentary, please visit Nature Human Behavior: https://www.nature.com/articles/s41562-024-01821-y

About the National Alliance for Hispanic Health(The Alliance) The Alliance is the nation's foremost science-based source of information and trusted advocate for the health of Hispanics in the United States with a mission to achieve the best health for all. For more information visit us atwww.healthyamericas.org

About Meharry Medical College (Meharry) Meharry is one of the nation's oldest and largest historically black academic health science center and includes amedical school,dental school,graduate school,applied computational sciences school, and theCenter for Health Policy. For more information visit Meharry at: https://home.mmc.edu

SOURCE National Alliance for Hispanic Health

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Overcoming 'Otherness' in Scientific Research Commentary in Nature Human Behavior USA - English - USA - PR Newswire

Human Behavior

What Is Organizational Behavior? Everything You Need To Know – MarketWatch

The role of a companys human resources department is to cultivate a healthy and productive workplace. HR can use the insights from an OB study to do this by making improvements in the following areas.

The Big Five is a widely recognized framework that categorizes personality traits into five dimensions: Openness, Conscientiousness, Extraversion, Agreeableness and Neuroticism (OCEAN). The idea is that every person has a little or a lot of each trait. Once you know where your employees personalities fall along the OCEAN spectrum, you can determine how they work and how they interact with coworkers.

Leadership requires specific skills that managers learn and hone throughout their careers. For instance, they need emotional intelligence, teamwork, adaptability, communication, collaboration and other soft skills. After conducting an OB study, you can see how managers interact with their employees, which tells you what skills they still need to work on.

Effective teams go through four stages of development: forming, storming, norming and performing. During forming, the focus is on building relationships. Storming involves dealing with conflicts and power struggles that arise. Norming is about establishing norms and best practices within the team. Performing is when the team reaches its peak performance level. OB can tell you if youre spending too much time or not enough time on forming, storming and norming, preventing you from reaching performing.

OB can help you determine if you have a tall or flat organizational structure and if that structure is right for how your company operates.

A tall structure has multiple hierarchical levels with narrow spans of control, meaning there are several managers that each oversee only a few employees. This type of structure has a clear line of authority, but it can lead to slower decision-making because the decision has to get passed up the chain through several levels.

By contrast, flat structures have fewer levels of hierarchy and wider spans of control, allowing for quicker decision-making and more direct communication. However, flat structures may need help maintaining clear lines of authority and control.

There are several human motivation theories out there, but one popular one is Abraham Maslows Hierarchy of Needs. It begins with basic physiological needs, such as food, shelter and water. Once those needs are met, a person can concentrate on their psychological needs, such as self-esteem and self-actualization.

In practice, employees at the top and bottom of the pyramid both want to be successful at work. However, the why behind this want for success differs. An employee whose motivation is survival wants to perform well so that they have steady income coming in to pay for food and shelter. In contrast, an employee whose basic needs are met wants to find meaning in their life, so they may search for a career that they love and invest in growing in that field.

At the end of the day, both types of employees are hard workers and worth having on your team. However, you want to do whatever you can, such as adjusting pay based on cost of living, to help more of your employees reach the latter stage. That way, they get a better quality of life because they dont have to worry about living paycheck to paycheck, and you get a workforce that is invested in growing with you.

There are several dimensions to communication. Here are some definitions to keep in mind as you study how your employees communication with one another:

Once you know what communication methods your employees use, you can decide if that aligns with how you want your company to operate. For example, maybe you picked up on a lot of crossed arms and frowns during your research, which would indicate unhappiness. You would want to reinforce a work culture of open communication so that employees feel comfortable telling their managers about challenges that are making them unhappy.

There are two approaches to decision-making: rational and intuitive. Rational decision-making is when you thoroughly analyze the situation, including all of the potential solutions, before choosing a path forward. With intuitive decision-making, you make a spontaneous decision based on what your gut tells you.

Employees within your team likely use different decision-making methods. You want to use OB to determine what works best for each person so that the team can meet in the middle to avoid conflict.

Change is unavoidable as a business. It can happen for internal or external reasons. External pressures are beyond the companys control (e.g., economic downturn or market competition). By contrast, internal factors, such as releasing a new product or losing key clients, can necessitate change from within.

Kurt Lewins Model of Change Theory provides a framework for handling both types of change. Its a three-step process that starts with unfreeze. Unfreeze is when you prepare your employees for change by communicating what necessitated the change and what the change will be. Change is the actual implementation of the changes, and refreeze is about solidifying the changes and making them a permanent part of the organization.

By studying your workplace, you can determine if your employees are comfortable with change. If you see them struggling, you can put them at ease and prepare them for the next change by educating them on Lewins theory.

There are two types of conflict: constructive and destructive. Constructive conflict, characterized by using open communication and diverse perspectives to find a solution, can stimulate creativity, foster innovation and improve decision-making. On the other hand, destructive conflict is marked by hostile exchanges and personal attacks, which can disrupt teamwork, damage morale and impede progress.

If you notice characteristics of deconstructive conflict appearing within your team, you may want to implement a mediation system. You act as the mediator as each party explains their side. You can then come to a compromise that addresses both parties concerns.

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What Is Organizational Behavior? Everything You Need To Know - MarketWatch

Internal Medicine

New Professors in the Department of Internal Medicine – Yale School of Medicine

Education:

BS, Pennsylvania State University

MD, Sidney Kimmel Medical College at Thomas Jefferson University

This is truly an honor and a culmination of decades of work dedicated to advance the field of cancer genetics. To have this appointment at an esteemed place such as Yale is even more meaningful, which has global reach and impact. I think the work I have done in collaboration with so many colleagues nationally and globally regarding cancer genetics, cancer disparities, and access to genetics care is critical at this time in oncology. Having the appointment based on this work really feels fulfilling and inspiring to continue this important work.

I contacted my husband, young adult kids, and parents who all congratulated me. Having that level of appreciation from my family, especially my children, was so moving.

I have been blessed to work with so many expert colleagues this really is a team approach to advance cancer care! I am honored to have mentored and continue to mentor the next generation of physicians and physician-scientists. Ultimately, I am deeply grateful to all of my patients who inspire my work. When I hear of even one patient who has been touched by my work, that is all I need to feel that it is all worth it.

I truly enjoy the opportunities to work with colleagues across disciplines, geographic regions, and expertise. I appreciate the ability to have creative freedom to explore new lines of research based on patient needs, which have led to some of the most impactful contributions. I also enjoy teaching and mentorship to build a legacy to carry forward for generations.

My high school mascot was the bulldog and now my career mascot is also the bulldog! I have come full circle here at Yale.

BA, BS, Trinity University

MD, PhD, University of Texas Southwestern Medical School

It is helpful to contextualize the promotion by placing it into a sequence of ~100-month blocks from (1) grade school through middle school, (2) high school and college, (3) MD-PhD education, (4) internship, residency, and fellowship training into K08 award, (5) first R01 grant through associate professorship, and (6) tenure until professorship. It is with a gentle sigh of relief, as I approach my 660th month on this planet, that I have at long last completed my "official" training. It is with much excitement, humility, and sentimentality that I look forward to the centennial blocks to follow this time without training wheels or institutionalized goals. It is in these segments where I hope finally to perform what I have been educated to do. I am told it is during these times when wisdom starts to engraft. Fingers crossed.

It still hasnt quite hit that I have been promoted. Seriously. I am actually a bit afraid to do or say anything for fear that it is just a dream and will disappear when I awake. While I had a perfect evening getting takeout with my lovely wife, Ania (I got to choose the pizza toppings!), I wont let loose until after learning the secret handshake and receiving the key to the clubhouse. That said, we did pop some bubbly with our neighbor Katie, who, coincidentally, was promoted to professor the same day big news for our block!

An awkward and stubborn persistence. Somewhere along the way, my great discovery was an internal doggedness that was supported by a loving family and absolutely amazing team. This doggedness was woven into a network of remarkable colleague-friends and sustained by sage mentors, serene gurus, and sentient leaders. Everything else follows.

The science, equations, and relationships.

Both my parents have full heads of hair.

The Department of Internal Medicine at Yale School of Medicine is among the nation's premier departments, bringing together an elite cadre of clinicians, investigators, educators, and staff in one of the world's top medical schools. To learn more, visit Internal Medicine.

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New Professors in the Department of Internal Medicine - Yale School of Medicine

Internal Medicine

McLaren Port Huron to launch internal medicine resident physician program – The Times Herald

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McLaren Port Huron to launch internal medicine resident physician program - The Times Herald

Internal Medicine

Department of Internal Medicine Grand Rounds – The University of Arizona College of Medicine Phoenix

Sean Wharton, MD, FRCPC, PharmD Adjunct Professor McMaster University, York University, University of Toronto Medical Director Wharton Medical Clinic

This session will be open to clinicians, residents, students and all others. It will be hosted virtually via Microsoft Teams. For access to the Teams feed, please email Veronica Nundahl.

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of The University of Arizona College of Medicine Tucson and UArizonaCollege of Medicine Phoenix. TheCollege of Medicine Tucson is accredited by the ACCME to provide continuing medical education for physicians anddesignates this live activity for a maximum of 1.0AMA PRA Category 1 Credit(s)TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

All Faculty, CME Planning Committee Membersand the CME Office Reviewers have disclosed that they have no financial relationships with commercial interests that would constitute a conflict of interest concerning this CME activity.

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Department of Internal Medicine Grand Rounds - The University of Arizona College of Medicine Phoenix