Tag Archives: Basic Sciences

Clues to lung damage in preterm infants | VUMC Reporter

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by Leigh MacMillan

Bronchopulmonary dysplasia (BPD) — a type of power lung illness — is a number one complication of preterm beginning affecting infants born earlier than 32 weeks gestation. Publicity to excessive ranges of oxygen (hyperoxia) performs a task in BPD pathogenesis, however the exact molecular mechanisms stay unsure.

Jennifer Sucre, MD, and colleagues beforehand demonstrated a sample of elevated Wnt signaling in human BPD tissue and hyperoxia fashions of BPD. They’ve now used three totally different mannequin methods — 3D human organoids, mouse lung slices and a mouse in vivo mannequin — to outline mediators of activated Wnt signaling after hyperoxia damage.

They found that elevated expression of Wnt5A in lung connective tissue cells contributes to the impaired alveolarization (alveoli are the websites of gasoline trade) and septal thickening noticed in BPD.

The findings, reported within the American Journal of Respiratory and Important Care Drugs, recommend that exact concentrating on of Wnt5A within the lungs of preterm infants could stop or reverse BPD.

This analysis was supported by the Nationwide Institutes of Well being (grants HL143051, CA218526, GM108807, HL101794, HL122626, HL129907, HL133536, HL092870, HL085317, HL128996, HL127173, HL116263, GM122516, HL141380), Division of Veterans Affairs, Francis Household Basis and Julia Carell Stadler Chair in Pediatrics.

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Faculty named to Global Voices Fellowship for fall 2020 |

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Erin Calipari (photo by Joe Howell/Vanderbilt University)
Erin Calipari (Joe Howell/Vanderbilt University)

Erin Calipari, Kelly Haws and Marybeth Shinn have been selected as Global Voices Fellows for the fall 2020 semester.

The Global Voices Fellowship expands Vanderbilt’s national and international recognition by amplifying the reach and impact of faculty research through enhanced strategic communications training and support. The fellowship, previously known as the Chancellor’s Public Voices Fellowship, was recently renamed to reflect its emphasis on supporting the mission of the Global VU initiative, which encourages the Vanderbilt community’s international research and engagement.

“The Global Voices Fellowship combines our commitment to faculty development with our mission to communicate with society on a truly international scale,” said Interim Chancellor and Provost Susan R. Wente. “I’m excited to see the impact of this next cohort of fellows, as they use this platform to share their work with more people and in new ways.”

Each new fellow will work with the Division of Communications to develop a highly tailored communications and promotion plan that builds national and international recognition for their scholarship and public profile, and connects their work to new audiences around the world. Fellows receive training in particular skills, such as media interviews; guidance in development of companion products that include opinion pieces and messaging; and assistance with using distribution channels for their research that include web and social media.

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Kelly Haws (Vanderbilt University)

“This signature fellowship shines a light on Vanderbilt’s deep commitment to the idea that academic collaboration and research excellence can address the world’s most pressing challenges,” said Steve Ertel, vice chancellor for communications. “It provides us with another platform to work together to bring stories of research and discovery to broader audiences.”

Calipari, assistant professor of pharmacology at the School of Medicine Basic Sciences, will enhance her communication skills for building awareness for her research—the neural basis of substance use disorder and the implications for understanding the opioid epidemic and other substance use disorders. A large focus of her work is on how sex differences in behavior and neural function interact with environmental factors to make women differentially vulnerable to psychiatric disease states. Calipari has a strong commitment to educating general audiences about her findings to reduce the incidence of substance use disorders, prevent overdose deaths and encourage treatment.

Haws, the Anne Marie and Thomas B. Walker Jr. Professor of Marketing at the Owen Graduate School of Management, will seek to expand attention for her research on food decision-making. She studies consumer behavior, with an emphasis on food decision-making and health-related issues and the underlying decision-making processes involved. Her research has significance for obesity-related health conditions, such as heart disease, stroke, type 2 diabetes and certain types of cancer. Haws hopes to respond to this medical crisis by increasing the public’s understanding of underlying consumer decision-making processes related to food.

portrait of Marybeth Shinn (Vanderbilt University photo)
Marybeth Shinn (Vanderbilt University)

Shinn, Cornelius Vanderbilt Professor of Human, Organizational and Community Development at Peabody College of education and human development, will promote ways to prevent and end homelessness. Shinn’s research is the focus of her new book, In the Midst of Plenty: Homelessness and What to Do About It, in which she draws on three decades of her work. Areas she has written about include the causes of the rise in modern homelessness, programs to restore people to housing, prevention programs for people at high risk, and the broader societal changes necessary to reduce the number of people living on the streets.

The spring 2020 Global Voices Fellows, who are currently undergoing media training and strategy development, are Lisa Fazio, assistant professor of psychology and human development, and Renä A.S. Robinson, associate professor of chemistry. Hiba Baroud, Jeffrey Bennett and Suzana Herculano-Houzel were selected for the first cohort in fall 2019.

This fellowship was the key recommendation of the 2018 report of the Committee for Enhancing Faculty Voices in the Public Sphere.

Fellows must have a project of body of work that is at (or nearing) a stage for promotion to the broader public. Questions regarding the application process for the fellowship can be addressed to Schyler Turrin.

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A key to calcium signaling | VUMC Reporter

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by Sanjay Mishra

IP3 receptors (IP3Rs) are calcium channels found in all animal cells. By mediating calcium ion release, IP3Rs integrate signals from different cellular pathways and metabolic states. Not surprisingly, deregulation of IP3Rs causes many diseases.

In mammals, there are three subtypes of IP3Rs, of which the type 3 receptor is found predominantly in rapidly proliferating cells including several cancers. However, due to their large size and subunit diversity, the structure of IP3Rs has not yet been fully characterized.

Now, in a study published in the Journal of Biological Chemistry, Erkan Karakas, PhD, and colleagues present a structure of the human IP3R type 3 in its ligand-free state.

Their structure, discovered through cryo-electron microscopy, identified previously unresolved local structures, the location of lipid biding sites and the presence of a self-binding peptide (SBP) that occupies the IP3 binding site and competitively inhibits IP3 binding.

The researchers concluded that the SBP could be a key molecular determinant of subtype-specific calcium signaling in IP3Rs.

This research was supported by the National Institutes of Health (grants DK020593, HD061543, GM008320) and by Vanderbilt University.

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Microscopic spines join worm neurons | VUMC Reporter

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by Leigh MacMillan

Dendritic “spines” — small protrusions on the receiving aspect of the connection (synapse) between two nerve cells — are acknowledged as key purposeful elements of neuronal circuits in mammals. The shapes and numbers of spines are regulated by neuronal exercise and correlate with studying and reminiscence.

Though spine-like protrusions have been reported within the nervous system of the invertebrate worm C. elegans, it isn’t identified if these buildings share purposeful options with vertebrate dendritic spines.

Now, Andrea Cuentas-Condori, Sierra Palumbos, David Miller, PhD, and colleagues have used super-resolution microscopy, electron microscopy, live-cell imaging and genetics to characterize spine-like buildings on C. elegans motor neurons. They report within the journal eLife that C. elegans spines are dynamic buildings that sense and reply to neuronal exercise, like their mammalian counterparts.

The research set up the genetically tractable and clear C. elegans as a mannequin organism for the research of dendritic backbone formation and performance. Reside-cell imaging research and unbiased genetic screens ought to pace the invention of genes that regulate backbone biology.

This analysis was supported by the Nationwide Institutes of Well being (grants NS081259 and NS106951), the American Coronary heart Affiliation, the Nationwide Science Basis and the Canadian Institute of Well being Analysis.

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Wente and Macara named American Society for Cell Biology Fellows | Vanderbilt Information

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Interim Chancellor and Provost Susan R. Wente (Vanderbilt University)
Interim Chancellor and Provost Susan R. Wente (Vanderbilt College)

Interim Chancellor and Provost Susan R. Wente and Louise B. McGavock Professor of Cell and Developmental Biology Ian Macara have been elected 2019 Fellows of the American Society for Cell Biology.

“It is a great honor for our colleagues and for Vanderbilt,” mentioned Lawrence J. Marnett, dean of Fundamental Sciences and the Mary Geddes Stahlman Professor of Most cancers Analysis. “Each Susan and Ian have elevated the extent of scholarship on this campus with their internationally acknowledged analysis packages and play important management roles at Vanderbilt, of their self-discipline and past. We’re very lucky to have them as school members and are happy by this genuinely-earned recognition.”

Wente and Macara are amongst 16 internationally acknowledged cell biologists chosen by their friends this yr for lifetime recognition of their efforts to advance cell biology and/or its purposes and for his or her engagement and dedication to the society.

“By means of the ASCB Fellows program, we acknowledge the scope and variety of the society’s membership,” mentioned Erika Shugart, chief government officer for ASCB. “Our fellows symbolize not solely an elite group of scientists who’ve contributed considerably to the physique of data about cell biology and to the neighborhood of scientists learning the cell, but additionally people who’ve demonstrated all through their careers their dedication to the mission of the society.”

“I’m so honored to obtain this recognition from my fellow cell biologists, and to affix such a distinguished group of ASCB scientists devoted to advocating for excellence in analysis,” Wente mentioned. “I’m additionally grateful to my modern colleagues at Vanderbilt the place collectively, our tradition of collaboration helps us all make new insights into cell organic processes and, extra broadly, throughout the sciences.”

Wente, who was appointed interim chancellor in August and has served as provost since 2014, is a biomedical scientist and professor of cell and developmental biology. She has held a number of key roles in analysis, administration and management, and continues to run the Wente Lab, an internationally revered analysis program that has made groundbreaking discoveries concerning the trade of proteins and RNA between the nucleus and cytoplasm, enabling alternatives for additional insights into the organic mechanics of various human developmental illnesses.

All through her profession, she has obtained many honors and awards, together with the coveted MERIT award from the Nationwide Institutes of Well being (2010 – 2020), the Ladies in Cell Biology Senior Profession Award from the ASCB (2011), and the John H. Exton Award for Analysis Resulting in Revolutionary Organic Ideas (2008). Moreover, she is an elected fellow of the American Affiliation for the Development of Science.

Wente was recruited to Vanderbilt from Washington College in St. Louis as professor of cell and developmental biology and division chair in 2002. Wente earned her bachelor of science in biochemistry from the College of Iowa and her doctorate in biochemistry on the College of California, Berkeley.

Ian Macara (photo by Vanderbilt University)
Louise B. McGavock Professor of Cell and Developmental BIology Ian Macara (Vanderbilt College)

Macara serves as chair of his division and can be the co-leader of the Sign Transduction and Chemical Biology Analysis Program at Vanderbilt-Ingram Most cancers Middle. He has made main contributions to understanding mechanisms driving cell polarity and aberrant cell signaling in breast most cancers.

“It’s actually an honor to have been chosen as a fellow of the ASCB, which has been my society of selection since I used to be a graduate scholar,” mentioned Macara. “I’ve at all times admired the dedication of ASCB to all points of range on the annual assembly, in committees and in public coverage initiatives, and its promotion of transparency in society governance.”

The creator of greater than 190 analysis publications, Macara is the recipient of an Excellent Investigator Award from the Nationwide Most cancers Institute and the Worldwide Most cancers Analysis prize, and is a fellow of the American Affiliation for the Development of Science. An editor of the Journal of Cell Biology, Macara additionally has served on the NCI Fundamental Sciences Council and ASCB Council.

He was recruited to Vanderbilt in 2012 from the College of Virginia. Macara earned his doctorate in biochemistry from the College of Sheffield in the UK and did postgraduate work at Brandeis and Harvard universities.

The ASCB will formally acknowledge the brand new cohort of fellows earlier than the keynote speech on the 2019 ASCB|EMBO assembly in Washington, D.C., Dec. 7.

Kate Derrick contributed to this story.

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A catalog of DNA replication proteins | VUMC Reporter

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by Leigh MacMillan

Upkeep of genome integrity — and prevention of ailments corresponding to most cancers — requires full and trustworthy replication of the genome each cell division cycle.

To totally perceive how genome integrity is maintained, David Cortez, PhD, and colleagues have generated a “catalog” of the proteins current at websites of DNA duplication (replication forks) and chromatin packaging of newly synthesized DNA.

The investigators used a way they developed known as iPOND (isolation of proteins on nascent DNA) mixed with quantitative mass spectrometry in a number of cell sorts to determine 593 proteins which might be enriched at replication forks and nascent chromatin. Utilizing loss-of-function genetic analyses and a evaluation of present research, they discovered that 85% of the proteins had actions in line with a operate in DNA and chromatin replication or replication stress responses.

They demonstrated the worth of their catalog by figuring out a job for BET household proteins in controlling DNA replication. The useful resource was revealed within the Sept. 24 difficulty of Cell Studies.

This analysis was supported by the Nationwide Institutes of Well being (grants GM116616, CA239161, CA009582, GM126646), Breast Most cancers Analysis Basis and Vanderbilt-Ingram Most cancers Heart, and by a Susan G. Komen fellowship.

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Crew discovers yet another piece to the autism puzzle | VUMC Reporter

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by Invoice Snyder

Mutations in a subunit of a receptor that binds the foremost inhibitory neurotransmitter GABAA within the mind have been linked, by means of a standard mechanism, to epilepsy, autism and mental incapacity, researchers at Vanderbilt College Medical Middle and colleagues report.

The workforce’s discovery, reported final month within the journal Mind, supplies extra proof that autism and mental incapacity noticed in some sufferers with extreme seizure issues are usually not brought on by the seizures themselves however come up independently from receptor mutations.

Jing-Qiong Kang, MD, PhD

“This work represents a vital piece in the entire puzzle we’re engaged on, the impaired GABAergic pathway in epilepsy, autism and mental incapacity,” stated the paper’s corresponding creator, Jing-Qiong “Katty” Kang, MD, PhD, affiliate professor of Neurology and Pharmacology at Vanderbilt College College of Drugs.

Kang stated she hopes these insights will assist advance improvement of recent, mechanism-based therapies for epilepsy and autism.

Gamma-Aminobutyric acid sort A (GABAA) is an inhibitory neurotransmitter that performs an vital function in mind improvement. Mutations within the gene for the beta3 subunit of the GABAA receptor (GABRB3), by means of which the neurotransmitter acts, are often related to genetic epilepsy syndromes and neurodevelopmental issues.

Mutations in the identical gene have been linked to a large spectrum of epilepsy phenotypes (traits). Some sufferers solely have delicate seizures throughout childhood that may be simply handled whereas others have extreme epilepsy that’s usually refractory (doesn’t reply) to a number of drugs and has a poor consequence.

The molecular mechanisms chargeable for completely different types of epilepsy are usually not identified. It’s additionally not clear why mutations in the identical gene can produce such broadly various phenotypes.

Working with a number of teams all over the world, Kang and her Vanderbilt colleagues have in contrast the pathophysiology of a number of mutations in several subunits in GABAA receptors.

The group beforehand developed a mannequin of extreme genetic epileptic encephalopathy, based mostly on a mutation in one other GABAA receptor subunit, GABRG2, and confirmed that it additionally causes widespread, age-dependent neurodegeneration.

Lately the researchers recognized a mutation in a GABA transporter protein, GAT-1, that causes an identical phenotype to what’s noticed in sufferers with GABRB3 mutations.

On this paper, they used high-throughput screening to check a number of mutations after which centered on two novel mutations in GABRB3 which might be related to completely different epilepsy severities.

They examined variations of the mutations in non-neuronal cells and rat cortical neurons and in a mouse mannequin with GABRB3 deficiency and recognized a standard mechanism related to impairment of the beta3 subunits that occurred in several epilepsy syndromes.

Kang stated her group’s work contributes to understanding the pathophysiology of genetic epilepsy on account of an impaired GABAergic pathway and why mutations give rise to completely different epilepsy syndromes.

Whereas future research are wanted to make clear the influence of those mutations on mind improvement, the researchers concluded that impaired activation of the GABAA receptor could contribute to irregular improvement of the synapses, the advantageous useful models between nerve cells that transmit chemical or electrical indicators.

“Impaired GABAA receptor operate brought on by mutations … thus (might) end in complicated neurodevelopmental issues together with epilepsy, autism and mental incapacity,” they wrote.

The following part of the analysis will handle the right way to design therapy to rescue/reverse illness signs at an early age and enhance outcomes.

The scientific data of two sufferers with GABRB3 mutations was contributed by colleagues at Guangzhou Medical College in Guangzhou, China. All of the useful research had been carried out at VUMC with help from the Nationwide Institutes of Well being and different funding sources.

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Microvilli in movement | VUMC Reporter

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by Anivarya Kumar

The Sept. 9 difficulty of Developmental Cell featured the analysis of Matthew Tyska and colleagues on the duvet. The picture reveals microvillar actin protrusions with colours indicating depth relative to the cell floor.

Microvilli are protrusions on the floor of epithelial cells which can be devoted to mechanosensation within the inside ear, and chemosensation and solute uptake within the lungs, intestine, gut and urinary tract. Epithelial cells assemble dense arrays of microvilli known as “brush borders” that defend towards infections and harm.

Leslie Meenderink, MD, PhD, Matthew Tyska, PhD, and colleagues used reside cell imaging to visualise early steps of brush border formation.

They discovered that particular person microvilli exhibit persistent lively motility. Pushed by actin meeting on the barbed ends of core bundles, microvilli motility permits the protrusions to collide and cluster into extremely organized arrays.

The analysis, featured on the duvet of the Sept. 9 difficulty of Developmental Cell, factors to microvillar motility as a beforehand unrecognized driving pressure for apical floor reworking and maturation throughout epithelial differentiation. These findings present additional perception into the morphogenesis of a number of organ programs.

This analysis was supported by the Nationwide Institutes of Well being (grants AI007474, GM008554, HD007502, GM008320, DK111949, DK095811).

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A “rheostat” for most cancers alerts | VUMC Reporter

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by Sanjay Mishra

WNT signaling pathways play necessary roles in cell development, improvement and most cancers.The classical or “canonical” WNT pathway and its atypical, “non-canonical” counterpart share a protein referred to as DVL2 that “transduces” or converts one form of sign to a different.

Now Jason MacGurn, PhD, and colleagues have proven that two different proteins, USP9X and WWP1, act on DVL2 to control each WNT signaling pathways.

Whereas WWP1 suppresses DVL2 by tagging it with a protein referred to as ubiquitin that marks it for degradation, USP9X promotes WNT activation by releasing DVL2 from ubiquitin and rescuing it from degradation.

These antagonistic interactions set up a ubiquitylation “rheostat” on DVL2 that may be a important regulator of WNT pathway specification in human breast most cancers cells, and which directs its participation in both WNT pathway, the researchers reported within the journal Cell Experiences.

These findings have necessary implications for therapeutic concentrating on of WNT pathways in human most cancers.

This analysis was supported by the Nationwide Institutes of Well being (grants GM101077 and CA095103).

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The plus and minus of microtubules | VUMC Reporter

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by Bill Snyder

The September issue of the Journal of Cell Biology featured the research of Marija Zanic and colleagues on the cover. The image is a montage of dynamic microtubule extensions (teal) grown in vitro from stabilized microtubule seeds (red).

Microtubules are protein polymers that assemble into dynamic structures, essential for cell division, shape, motility, and transport of intracellular cargos.

Proteins that regulate microtubule function and activity have been implicated in disorders ranging from Alzheimer’s disease to cancer. By learning how microtubules work, scientists hope to find new ways to treat these diseases.

The “plus” and “minus” ends of microtubules switch between growing and shrinking, a phenomenon known as “dynamic instability.” Now Marija Zanic, PhD, and colleagues have discovered that the distinct rate at which tubulin protein subunits dissociate (the tubulin “off-rate”) underlies key dynamic differences between the two ends.

The researchers also found that a minus-end directed motor protein, the human kinesin-14 HSET, promotes minus-end stability by suppressing the minus-end tubulin “off-rate,” even when challenged by the de-stabilizing kinesin-13 MCAK motor.

Their report, published in the September issue of the Journal of Cell Biology and featured on the cover, suggests that regulation of both the plus and minus microtubule ends is integrated to form the basis for the dynamic architecture of cellular microtubules.

This research was supported by the National Institutes of Health (grants GM119552, GM086610, GM008554), the Human Frontier Science Program and the Searle Scholars Program.

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