bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypersialylation of Tumor Cells Promotes Pancreatic Cancer Progression
Authors: Bellis Susan , Bhalerao Nikita , Chakraborty Asmi , Marciel Michael
Published: May 2022

Tumor cells are well‐known to have elevated levels of sialylated surface glycoproteins. The addition of sialic acid (a negatively‐charged sugar) to select surface receptors modulates the structure and function of such receptors, leading to changes in intracellular signaling and gene expression. Increased tumor cell sialylation occurs, in part, through the upregulation of sialyltransferases such as ST6GAL1, an enzyme that adds an α2‐6 linked sialic acid to N‐glycosylated proteins. ST6GAL1 is overexpressed in numerous malignancies, including pancreatic ductal adenocarcinoma (PDAC), and high expression correlates with a poor prognosis. Prior work from our group revealed that ST6GAL1 confers a cancer stem cell phenotype, typified by invasiveness and apoptosis‐resistance, through the sialylation‐dependent activation of receptors such as EGFR. In the current investigation we used human Suit2 PDAC cells, as well as two metastatic Suit2 subclones, to show that ST6GAL1 activity promotes tumor progression and metastasis in tumor xenograft models. Moreover, high ST6GAL1 expression in this isogenic cell series induces EGFR activation and epithelial to mesenchymal transition. To complement tumor xenograft experiments, we developed a genetically‐engineered mouse (GEM) model with conditional ST6GAL1 expression in the pancreas (termed, “SC” mice) and crossed this line to the “KC” PDAC model, which expresses oncogenic Kras (KrasG12D) in the pancreas. Mice with dual expression of ST6GAL1 and KrasG12D (”KSC” mice) exhibit greatly accelerated PDAC initiation, progression, and mortality when compared with KC mice. In light of ST6GAL1's known role in conferring stem/progenitor properties, we hypothesized that ST6GAL1 activity contributes to PDAC initiation by fostering acinar to ductal metaplasia (ADM). During ADM, pancreatic acinar cells de‐differentiate into ductal‐like, progenitor cells and acquire greater proliferative potential as well as apoptosis resistance. Cells undergoing ADM are particularly vulnerable to oncogenic transformation. To interrogate whether ST6GAL1 promotes ADM, we compared SC mice with control, wild‐type littermates. Using a variety of analyses and model systems including RNA‐Seq of GEM pancreata, organoid lines derived from GEM pancreata, the canonical 266‐6 ADM cell model, and in vivo model of inflammation‐induced ADM, we determined that high expression of ST6GAL1 in acinar cells imparts an ADM‐like phenotype, as evidenced by the upregulation of stem and ductal genes and downregulation of genes associated with differentiated acinar cells. Furthermore, GEM tissues and organoids with ectopic ST6GAL1 expression display strikingly elevated levels of activated EGFR. Given that activation of EGFR is one the major drivers of ADM, these data suggest a potential mechanism by which ST6GAL1‐mediated sialylation facilitates ADM. Collectively these results point to a critical role for ST6GAL1 in both early and late stages of pancreatic malignancy.
Modeling the mucinous glycocalyx to unravel receptor pattern recognition by influenza A viruses
Authors: Godula Kamil
Published: May 2022

Influenza A viruses (IAVs) exploit host glycans in airway epithelial mucosa for entry and infection. Rapid detection of changes in IAV glycan‐binding phenotype can provide early indication of virus transmissibility and infection potential. IAVs use hemagglutinins (HAs) to bind sialic acids, and a switch in HA specificity is considered a prerequisite for transmission from birds to humans. Likewise, understanding the molecular mechanisms used by the viruses to overcome the mucin barrier may guide the development of more effective antiviral therapies. This presentation will describe the development of a glycan array platform, which uses synthetic mimetics of mucin glycoproteins to model how receptor presentation in the mucinous glycocalyx (i.e., glycan type, valency of the glycoconjugates, and their surface density) may impact IAV recognition. This platform utilizes machine learning to identify preferred receptor displays in the mucinous glycocalyx for adhesion of H1N1 and H3N2 viruses. Intriguingly, the arrays revealed a change in receptor pattern recognition by H1N1 upon transition from avian to mammalian cell culture. Without altering its HA affinity, the mammalian cell‐produced virus showed reduced sensitivity to surface crowding of the mucin mimetics. Using our mucin mimetics, we have also evaluated the physical protective functions of the glycocalyx on viral adhesion to cells. We found that bulky mucin mimetics lacking sialoglycan receptors inhibited the rate of H1N1 adhesion in a size‐ and density‐dependent manner, consistent with current view of the mucins as providing a protective shield against pathogens. Counterintuitively, increasing density of the mucin mimetics enhanced the retention of bound viruses. Careful characterization of SNA behavior at the RBC surface using a range of biophysical and imaging techniques revealed lectin‐induced crowding and reorganization of the glycocalyx with concomitant enhancement in lectin clustering, presumably through the formation of a more extensive glycan receptor patch at the cell membrane. Our findings indicate that glycan‐targeting pathogens may exploit the biophysical and biomechanical properties of mucins to overcome the mucosal glycocalyx barrier.
What makes a competitive applicant? Assessing students for graduate/professional school applications
Authors: Sayer Erin M.
Published: May 2022

Whether a faculty member is asked to write one letter or several dozen letters of recommendation/reference, the process can be reflective or challenging for the writer as we support our undergraduate students applying to graduate or professional schools. What makes us “qualified” to assess students for these important letters? What process do we use to be sure we provide the schools/programs with the information they need to make an informed decision? In addition, there are recent challenges we face as letter writers when we are asked by students we barely know due to COVID‐capped in person classes or faceless Zoom sessions required by synchronous learning requirements.

This presentation will discuss the difference between a “good/strong” letter of reference and a balanced letter of evaluation. We will consider what content makes a good letter of reference, what a writer can and cannot discuss in the letter, and what process a writer can use to collect relevant information to write a well‐rounded, factual letter that presents an accurate reflection of the student.
The tiny pharmacists within: How the microbiome impacts the treatment of human disease
Authors: Turnbaugh Peter J.
Published: May 2022

Although the importance of human genetic polymorphisms and drug‐drug interactions in precision medicine is increasingly understood, the role of specific genotypic variants and products elaborated by our “second genome” (the microbiome) has been largely overlooked. In this presentation I will describe a microbiome‐centric approach to pharmacology, working to elucidate the direct and indirect mechanisms through which the human microbiome shapes the efficacy and toxicity of small molecule and biologic therapies. For example, recent research in my laboratory has revealed a complex interplay between human drug transporters in the intestine and commonly used excipients prevalent in foods and many drug products. This interplay is mediated by gut microbes which metabolize excipients leading to unexpected effects on drug absorption. We are also working on the metabolism of drugs used to treat heart disease, cancer, rheumatoid arthritis, and Parkinson’s Disease by human gut bacteria. Collectively, attendees will learn about exciting new research at the interface between pharmacology and the human microbiome.
Phase behavior of intrinsically disordered prion‐like domains
Authors: Mittag Tanja , Bremer Anne , Farag Mina , Borcherds Wade M. , Pappu Rohit V.
Published: May 2022

Phase transitions underlie cellular compartmentalization and mediate fundamental biological processes. How they are encoded in the protein sequence is therefore important. Here, we use biophysical experiments, theory, and simulations to generate a conceptual stickers‐and‐spacers framework to understand phase behavior of intrinsically disordered prion‐like low‐complexity domains (PLCDs) of RNA‐binding proteins. Stickers form non‐covalent inter‐ and intramolecular crosslinks, whereas spacers enable or suppress the formation of these crosslinks. We have previously shown that aromatic residues are the stickers in the PLCD of hnRNPA1. Here, we demonstrate that tyrosine is a stronger sticker than phenylalanine and account for interactions of charged residues. Negatively charged residues are solubilizing spacers. Arginines act as stickers through pairwise interactions with aromatic residues, while lysines weaken sticker‐sticker interactions. Low or high values of the net charge per residue weaken phase separation via mean‐field electrostatic effects, while a net charge per residue close to zero minimizes solubility and is optimal for phase separation. We further characterize the function of spacer residues, particularly that of the two most frequent spacer types glycine and serine, to ask whether serine acts as a weak sticker via its side chain. Instead, we find that increasing serine contents decreases the driving force for phase separation in agreement with the higher effective solvation volume of serine vs glycine. Our analytical and coarse‐grained models accurately predict PLCD phase behavior.
Domain stacking enables a limb enhancer to act across multiple TAD boundaries
Authors: Boettiger Alistair
Published: May 2022

Many developmentally important genes have their promoter and enhancers within different TADs. Although there are hypotheses about molecular mechanisms enabling such cross‐TAD interactions between these cis‐elements, but they remain to be assessed. To test these hypotheses, we use Optical Reconstruction of Chromatin Architecture (ORCA) to characterize the conformations of the Pitx1 locus on thousands of single chromosomes in developing mouse limbs. Our data supports a model in which cis‐elements adjacent to TAD boundaries are collected in transient hub‐like structures when neighboring boundaries are stacked with each other as a result of loop‐extrusion. Through molecular dynamics simulations, we further propose that increasing boundary strengths (eg. by increasing CTCF occupancy) facilitates the formation of the stacked boundary conformation. This work provides a revised view of the TAD borders’ function both facilitating as well as preventing cis‐regulatory interactions and introduces a framework to distinguish border‐crossing from border‐respecting enhancer‐promoter pairs.
The interconnected dynamics of ribonucleoprotein condensates and the endoplasmic reticulum
Authors: Lee Jason E.
Published: May 2022

A hallmark of eukaryotic cells is the ability to compartmentalize essential reactions into membrane‐bound and membrane‐less organelles. Membrane‐bound organelles work together through transport vesicles and membrane‐to‐membrane organelle contact sites to traffic cargo and distribute lipids throughout the cell. Conversely, many membrane‐less organelles are condensates of messenger RNAs and proteins (RNPs), which participate throughout the mRNA life cycle. Our recent work uncovered that these two classes of organelles – membranous and membrane‐less – join forces to potentially shunt mRNAs between the endoplasmic reticulum and RNP condensates involved in mRNA silencing, degradation and sequestration in response to stress. We use two model RNP condensates, processing (P)‐bodies and stress granules, to dissect the relationships between the endoplasmic reticulum and RNP condensate biogenesis, composition, and disassembly.
Uncovering conditional vulnerabilities in human cancer cells
Authors: Cantor Jason R.
Published: May 2022

Forward genetic screens based on either RNAi or CRISPR make it possible to systematically identify genes required for the survival and growth of mammalian cells, and thus offer a powerful approach to characterize protein function and identify potential cancer vulnerabilities. Nonetheless, fitness genes can be context‐dependent, and indeed, CRISPR screens across hundreds of human cell lines have revealed that genetic dependencies can vary with natural cell‐intrinsic diversity. However, while the impact of environmental factors on cell physiology has become better appreciated, there has been little investigation into how nutrient availability affects gene essentiality and, further, most forward genetic screens are performed in vitro using culture media with little relevance to human physiology. We previously developed Human Plasma‐Like Medium (HPLM) – the first systematically designed physiologic medium, which contains over 60 components at concentrations that reflect their average values in human blood. To test the hypothesis that medium composition influences gene essentiality, we performed CRISPR‐based loss‐of‐function screens of blood cancer lines HPLM versus traditional media. Analysis of these data revealed that sets of conditionally essential genes are involved in several biological processes and can vary with both cell‐intrinsic diversity and the combination of basal and serum components that comprise typical media. Moreover, our approach allows for the downstream identification of gene‐nutrient interactions that underlie conditional CRISPR phenotypes, which can in turn uncover conditionally essential protein roles.

Additionally, most preclinical therapies fail to achieve translation – a major problem attributed in part to the limited physiologic relevance of existing models. Nonetheless, there has been similarly little systematic investigation into how the composition of culture media might affect drug efficacy. Further, virtually all drug screens, initial hit validation efforts, and studies of drug activity are performed in vitro using traditional media as well. Therefore, we with collaborators at NCATS used a library of approved and (pre)‐clinical drugs to screen blood cancer lines in HPLM versus conventional media. Remarkably, we identified many whose killing activity varied with medium composition, including drugs approved for non‐oncology indications. Indeed, neither the drug‐nutrient interaction nor the mechanism of drug activity in cancer cells is immediately apparent in many such cases.
The genetics of tumor suppression by p53
Authors: Murphy Maureen , Leung Jessica , Leu Julia , Indeglia Alexandra , Clarke Nicole , Kannan Toshitha , Kirven Nicole , Barnoud Thibaut , Kossenkov Andrew , George Donna L.
Published: May 2022

Mutational inactivation of TP53 occurs commonly in cancer. In addition to mutation, there are over two hundred germline genetic variants in the TP53 coding region; some of these produce partially functional (hypomorphic) protein. Presently the impact of hypomorphic p53 variants on cancer risk is unknown. Also missing is a test to distinguish hypomorphs from benign variants and/or wild type p53. We report that two African‐centric hypomorphs of TP53, Pro47Ser and Tyr107His, share common activities. Specifically, these variants share an increased propensity to misfold into a conformation specific for mutant, misfolded p53, and to activate NF‐kB. These hypomorphs also increase migration and invasion, and share common impact on metabolism and drug resistance. RNA sequencing data reveals a gene signature that is predictive of hypomorphic p53 from wild type or benign variants. These data support a role for misfolding of hypomorphic p53 on cancer risk and the efficacy of cancer therapy. They also suggest that a predictive gene signature could have profound impact on the over 4 million individuals in the United States with germline coding region variants of p53.
The phase of fat: Mechanisms and physiology of lipid storage
Authors: Farese Robert V. , Walther Tobias C.
Published: May 2022

The synthesis and storage of neutral lipids, such as triglycerides, are crucial for both cellular and physiological energy homeostasis. When fuels are abundant, triglycerides are synthesized in the ER by DGAT enzymes and subsequently stored in cytosolic organelles called lipid droplets. In the Farese & Walther laboratory, we study the molecular processes that govern the synthesis of energy storage lipids as well as their storage in and mobilization from lipid droplets. We will discuss our studies on genetic factors controlling triglyceride synthesis, lipid droplet formation and growth, lipid droplet protein targeting, and relevant aspects of the physiology of lipid storage and lipid excess.
PI 3‐Kinase signaling: A journey in three AKTs
Authors: Toker Alex
Published: May 2022

The PI 3‐kinase (PI3K) and AKT signaling pathway plays a critical role in regulating all aspects of normal cellular physiology, and is also frequently deregulated in human pathophysiologies, most evidently in cancer and diabetes. Growth factors and hormones stimulate PI3K leading to the biosynthesis of the lipid‐derived second messenger PIP3. In turn, PIP3 elicits the membrane recruitment of the protein kinase AKT, originally discovered in 1987 by Staal and colleagues as v‐Akt, a transforming oncogene. In the early 1990s, three independent groups cloned and described the cellular homolog c‐AKT, a serine/threonine protein kinase with a high degree of homology to other AGC family protein kinases. In the ensuing three decades, the mechanisms by which AKT transduces signals to cell growth, proliferation, motility and metabolism were uncovered. Three AKT isoforms exist in humans encoded by distinct genes (AKT1, AKT2, AKT3), and although originally thought to function redundantly, many studies have shown that AKT isoforms have non‐overlapping and unique roles in both normal physiology and disease. Similarly, genetic lesions in the PI3K and AKT oncogenes have been described, and many of the genes that contribute to PI3K/AKT pathway activation and also signal termination have been found to be altered in human cancers. Numerous drugs that inhibit PI3K as well AKT have been developed for therapeutic use in patients, and many of these are being evaluated in late‐stage clinical trials. During the lecture, I will highlight the major advances in PI3K and AKT field over the past 30 years, with a focus on mechanistic insight into this ubiquitous lipid signaling pathway. Genetic lesions in the PI3K/AKT pathway in human cancers will also be discussed, as well as efforts to target this pathway therapeutically. The second part of the lecture will focus on recent efforts in our laboratory to uncover novel mechanisms of AKT signaling and biology, with an emphasis on breast cancer and with a focus on metabolic reprogramming mediated by AKT. I will also present recent efforts aimed at targeting AKT with novel therapies, including degrader technologies and how these have illuminated novel aspects of AKT biology. I will conclude with some personal thoughts and future perspectives as to where the field is going, gaps in knowledge and what studying AKT for 30 years has taught me.
Tissue stem cells: survival of the fittest
Authors: Fuchs Elaine
Published: May 2022

Barrier epithelial tissues such as the skin, lung and gut are the first line of defense between our body and the outside world. As such, their stem cells must continually generate and rejuvenate their tissue, but also self‐renew to maintain the reservoir of stem cells. When the barrier has been breached, for example by wounding, the stem cells must not only repair the damaged tissue but also call to the immune system to help guard against pathogen entry. All the while the stem cells must protect themselves from a variety of assaults, including not only injury but also mechanical stress, noxious chemicals, ultraviolet radiation, and allergens that stimulate an inflammatory response. How do stem cells equip themselves to respond to these different stresses? My laboratory uses mice as a model organism and the skin epithelium as our tissue to explore the molecular mechanisms involved. We use high throughput genetic and genomic approaches to learn at a molecular level how the stem cells balance growth and differentiation in normal tissue homeostasis, and how they change their behavior and interactions with their neighbors (the stem cell ‘niche’) in response to changes in their environment. Our global objective is to apply our knowledge of the basic science of epithelial stem cells to unfold new avenues for therapeutics to treat inflammatory conditions and cancers.
Hyperbolic Geometry in Biological Systems
Authors: Sharpee Tatyana
Published: May 2022

Across different scales of biological organization, biological networks often exhibit hierarchical tree‐like organization. For networks with such structure, hyperbolic geometry provides a nnatural metric because of its exponentially expanding resolution. In this talk, I will describe how the use of hyperbolic geometry can be helpful for visualizing and analyzing high‐dimensional datasets. Our examples will include data from plant and animal volatiles that serve as input for the sence of smell (Zhou et al Science Advances 2018) and patterns of gene expression in diverse mammalian cell types (Zhou and Sharpe, iScience 2021). We find that local noise causes data to exhibit Euclidean geometry on small scales, but that at broader scales hyperbolic geometry becomes visible and pronounced. The hyperbolic maps are typically larger for datasets of more diverse and differentiated cells, e.g. with a range of ages. We find that adding a constraint on large distances according to hyperbolic geometry improves the performance of t‐SNE algorithm to a large degree causing it to outperform other leading methods, such as UMAP and standard t‐SNE. I will conclude with a discussion of new opportunities for identifying age‐ and disease‐related factors afforded by hyperbolic maps.
My Journey with cAMP‐dependent Protein Kinase
Authors: Taylor Susan
Published: May 2022

I was first introduced to cAMP‐dependent protein kinase (PKA) when I was just a young scientist at the beginning of my career, and it has remained as a lifelong companion. PKA has taken me from protein chemistry to atomic structures to brain imaging, and the quest for new knowledge is still ongoing. PKA was the second kinase to be discovered, and we solved the first protein kinase structure in 1991. In the subsequent decades we have come to appreciate the highly dynamic features that drive this molecular allosteric switch. In cells the activity of the PKA catalytic subunit is typically packaged as a holoenzyme complex with functionally non‐redundant cAMP‐binding regulatory (R) subunits, and the holoenzymes are localized to specific sites in the cell in close proximity to dedicated substrates. Many dedicated “cAMP signaling islands” exist within one cell, some at the plasma membrane but others at organelles such as the mitochondria and Golgi and in the nucleus, and each is tightly regulated. Nowhere is PKA signaling more complex than in the brain. PKA is ubiquitous in every mammalian cell, and in so many ways has served as the “poster child” for the kinome that contains over 500 proteins. How then can we explain why the Cb subunit lies near the bottom of the Dark Kinome where important protein kinase are buried but not yet studied? The Cb family contains several isoforms that all differ in only their first exon and includes many splice variants. While Cb1 is expressed ubiquitously in most cells at low levels, Cb2 is expressed in lymphoid tissues while the Cb3/4 isoforms are expressed almost exclusively in brain. Indeed ~50% of PKA signaling in the brain is mediated by Cb isoforms. Using the retina with its well‐organized and terminally differentiated neurons as a “window into the brain” we find that Cb isoforms are highly expressed and that Cb is localized differently from Ca. In addition, we find that Cb is localized to mitochondria in contrast to Ca, RIIa, and RIIb, which are all excluded from mitochondria. Four distinct mutations in Cb lead to a complex phenotype that includes cardiac and skeletal defects as well as a polydactyl presentation. These mutations also inhibit Sonic hedgehog (Shh) signaling adding further support to the importance of Cb in neuronal signaling and development. We are our interdisciplinary strategy to explore this new frontier for PKA signaling in the brain.
Chromatin‐based modulations underlying gene regulation and pathogenesis
Authors: Wang Greg G.
Published: May 2022

Our research programs focus on mechanistic understanding of how chemical modifications of chromatin (including methylations of DNA and histone tails) regulate gene expression and cell fate determination during development, and how their deregulations lead to diseases such as cancer. We have recently identified and characterized novel proteins that specifically bind to histone lysine methylations. These histone methylation ‘readers/effectors’ are crucially involved in gene and genome regulation, cell lineage specification and/or cancerous transformation. In addition, we studied phase separation of transcription factor, which is critically involved in organization of three‐dimensional chromatin structure during pathogenesis. Lastly, we aim to developing inhibitor of epigenetic factors as new therapeutics. During this meeting, we will report our progress along these lines. Addition information can be found at our lab Website: https://www.gregwanglab.com/.
Back to Basics: Qualitative Research and Methodologies in Anatomy Education
Authors: Dueñas Angelique N.
Published: May 2022

The spectrum of quantitative and qualitative research methodologies can be a divisive one. Particularly in scientific fields such as anatomy and anatomy education, there can be misunderstandings about what exactly qualitative research is, its purpose, and the rigorous nature of good qualitative inquiry. This presentation aims to elucidate some of these points, by first well defining qualitative research and its core tenants. Major forms of qualitative methodologies, including ethnography, phenomenology, and grounded theory, will be outlined, focusing on their potential use in the anatomical sciences. For further consideration of qualitative research, and to aid in clear communication of qualitative research goals, an introduction to paradigmatic discussions will also be introduced. This will highlight the legacy of positivism and post‐positivism in anatomy, but also encourage attendees to reflect on their own true research beliefs. By understanding (and clearly defining) axiological, ontological, and epistemological positions, all researchers can pick the methodology best suited for them and their research, ultimately aiding the advancement of the field.
Do you trust me? Rigor and Information Power in Qualitative Research
Authors: Byram Jessica
Published: May 2022

Qualitative researchers employ a variety of strategies to demonstrate the legitimacy of their work from the viewpoint of positivist scholars. While the traditional concepts of validity and reliability cannot be addressed the same way in qualitative as they are in quantitative research, qualitative researchers have established frameworks to ensure the rigor of qualitative work. In this talk, the qualitative trustworthiness criteria of credibility, transferability, dependability, and confirmability will be compared to their positivist counterparts of validity, generalizability, reliability, and objectivity, respectively. An additional threat to the legitimacy and perceived rigor of qualitative research is that many studies can have a small sample size. The concept of information power has been used in contrast to the quantitative sample size appropriation of power calculations and has recently been promoted as an alternative to saturation which is fundamentally a positivistic concept. This talk will provide practical advice for demonstrating the trustworthiness and rigor of qualitative research while maintaining the theoretical underpinning that drive qualitative studies in anatomy education.
The Ethics of Sourcing a Cadaver Population–A Perspective from South Africa
Authors: Kramer Beverley
Published: May 2022

We cannot deny the early, turbulent unethical history of the sourcing of human bodies for dissection during the 18th and 19th Centuries, but we most certainly can learn from the past. While the International Federation for the Associations of Anatomists (IFAA) has recommended ethical guidelines for the sourcing of bodies from donors only (IFAA, 2021), many institutions around the world have not been able to fulfil these recommendations. In South Africa, as an ethical imperative, most departments of anatomy have converted from the use of unclaimed bodies (although legal by South African law) to body donor programs which are founded on ethics and informed consent. South Africa has a diverse multicultural population derived from four main population groups (Black, Coloured, White and Indian) with health sciences classes being made up of predominantly Black students. As a consequence of the transformation from the use of unclaimed bodies to donor programs, the population diversity of the more recent cadaver populations has been impacted and White bodies now predominate. This transformation of the cadaver population will in time also impact the large skeletal collections in South Africa which are used for teaching and research by both local and international researchers. The change in the cadaver population with respect to population affinity particularly, may also impact our students and how they view the body they dissect. In South Africa and Africa, a number of factors including religious and cultural practices have a bearing on the diversity of the donors in donor programs. Donor programs are extremely important from the ethical perspective, and so too is the informed consent aligned to registration for these programs. In considering establishing diversity in the cadaver population of our donor programs for the future, some of the questions which should be pondered by South African anatomists and anatomists in general are: Is it important to have a body donor cohort that is representative of the demographics of the student population? How do we overcome the religious and cultural challenges which are prevalent in some of the population in order to maintain a donor program that is based on sound ethical behaviour and which is representative of the population at large? In addition, will anatomists be able to maintain ethical standards of sourcing bodies in the light of unexpected crises such as the recent pandemic? There is no doubt that in South Africa, widespread communication, educational programs and community outreach, particularly through the traditional leaders of each community, would assist with increasing the diversity of the donors.

Reference

IFAA. 2012. International Federation of Anatomical Associations. Federative International Committee on Ethics and Medical Humanities (FICEM). Recommendations of good practice for the donation and study of human bodies and tissues for anatomical examination. Plexus 2012: 4‐5.
A Transcriptional Switch Governs Fibroblast Activation in Heart Disease
Authors: Alexanian Michael
Published: May 2022

In diseased organs, stress‐activated signalling cascades alter chromatin, thereby triggering maladaptive cell state transitions. Fibroblast activation is a common stress response in tissues that worsens lung, liver, kidney and heart disease, yet its mechanistic basis remains unclear. Pharmacological inhibition of bromodomain and extra‐terminal domain (BET) proteins alleviates cardiac dysfunction, providing a tool to interrogate and modulate cardiac cell states as a potential therapeutic approach. We used single‐cell epigenomic analyses of hearts dynamically exposed to BET inhibitors to reveal a reversible transcriptional switch that underlies the activation of fibroblasts. Resident cardiac fibroblasts demonstrated robust toggling between the quiescent and activated state in a manner directly correlating with BET inhibitor exposure and cardiac function. Single‐cell chromatin accessibility revealed previously undescribed DNA elements, the accessibility of which dynamically correlated with cardiac performance. Among the most dynamic elements was an enhancer that regulated the transcription factor MEOX1, which was specifically expressed in activated fibroblasts, occupied putative regulatory elements of a broad fibrotic gene program and was required for TGFβ‐induced fibroblast activation. We identified MEOX1 as a central regulator of fibroblast activation associated with cardiac dysfunction. Our ongoing work focus on further elucidating the molecular mechanism of fibroblast activation and exploring cellular cross‐talk between fibroblast and other cardiac cell populations in heart disease.
IMPROVing Communication about Diversity, Equity, and Inclusion in Health Professions Education
Authors: Muldoon Kathleen M.
Published: May 2022

There has never been a stronger call for authenticity in health professions education than this moment in time. The health inequities laid bare by the COVID‐19 syndemic (a concept that describes the clustering of SARS‐CoV‐2 infection and disease by political, social and economic factors) compels health professions educators to learn how best to engage in, sustain, and deepen conversations on diversity, equity, and inclusion (DEI) within our learning environments. Health professions curricula should address such concerns through explicit faculty training programs in dialogue models of communication. I propose that medical improv can help refocus health professions training to the humanistic values of empathy for others and respect for multiple viewpoints. Medical improv refers to teaching methods that adapt improvisation principles and exercises to enhance professional competencies in the health professions, such as communication. I describe a training series implemented at one institution to prepare faculty facilitators to engage in conversations about DEI in a discussion‐based core course on the social determinants of health for first year medical students called “Humanity in Medicine”. Key elements of dialogue training, including examinations of identity and positionality, caretaking and team‐making, and conversations with a skeptic, are viewed through the lens of improv exercises as a pedagagy in communication. I report on facilitator and medical students’ positive response to facilitator training and the Humanity in Medicine course. Potential next steps towards a formal evaluation of the method, and outcomes assessments of the use of improv in health professions training are discussed.

The IRB at MWU (Glendale, AZ) found that this study did not qualify as human subjects research as defined by 45 CFR 46.102.
Shades of Gray: Teaching Embryology Beyond the Sex Binary
Authors: Moore Kathryn
Published: May 2022

There have been many changes in understanding sex and gender that have driven concurrent change in how we teach reproductive development. Human sex differentiation, like all biological variation, exists on a spectrum, with traits of individuals existing on a continuum beyond static and narrow definitions of “typical male” and “typical female”. Further, these sex‐defining traits are determined at genetic, anatomical and phenotypic levels during development, and may even change postnatally. Importantly, these levels can be discordant within a single level and with one another. As our awareness of biological sex diversity evolves, anatomical science educators should strive to introduce and define basic terms related to sex and gender, present biological sex as a spectrum or continuum of variable characteristics and include discussion of how sex‐defining traits may change over the life of an individual, biologically or through medical interventions. How we teach sex diversity in the anatomical sciences contributes to inclusive education and acknowledges gender‐diverse and intersex persons, who are often marginalized in a binary system. Ultimately, the way in which students learn about sex diversity affects how they conceptualize patients, with a subsequent impact on health care delivery. In this master class, we will discuss teaching the embryology of the reproductive system, including the concept of “differences in sexual development”.
Musculoskeletal Considerations in Pelvic Health
Authors: Snowden Karen
Published: May 2022

Patients seek rehabilitation services for various conditions related to pelvic muscle dysfunction. If not referred by their physician, patients often refer themselves. Healthcare providers treating patients with pelvic concerns must be sensitive and authentic when communicating with patients about their pelvic health and sexuality. Individualized care and respectful interaction are imperative in developing an effective therapeutic relationship. Pelvic health physical therapists evaluate and treat patients of all genders with musculoskeletal conditions related to weakness, overactivity, pain, menopause, following genital surgery, and gender‐affirming surgery. This presentation will highlight the role of pelvic health physical therapy and the bladder, bowel, sexual, and post‐surgical conditions treated. The terminology used when communicating with patients to enhance the therapeutic alliance and treatment outcomes will also be discussed.
Dissecting the Genetic Mechanisms Underlying Congenital Diaphragmatic Hernia
Authors: Sun Xin
Published: May 2022

Congenital Diaphragmatic Hernia (CDH) affects 1 in ~2,500 live birth, and carries a high mortality rate primarily due to cardiopulmonary failure. Variants in a large number of genes have been identified in CDH patients. We have generated mouse mutants carrying mutations in these genes to test if these variants are causal, and use these mouse models to address CDH mechanisms. Our findings indicate complex gene‐specific basis of the disease, suggesting that genetic diagnosis is valuable to link genotype to possible mechanisms, and thereby inform treatment.
Yap/Taz in Foregut Development
Authors: Que Jianwen
Published: May 2022

The lung, trachea and esophagus are the major organs derived from the anterior foregut. The signaling protein Yap is critical for lung morphogenesis. Our recent studies demonstrate that Yap is also required for the development of the esophagus. Conditional deletion of Yap during early esophageal development leads to failed generation of the stratified squamous epithelium. Interestingly, our recent in vivo genetic manipulation shows that Yap deletion prior to trachea‐esophageal separation leads to esophagus agenesis. The underlying molecular mechanism includes the role of Yap in driving the proliferation of esophageal progenitor cells.
Tunnels in the Rock: Mechanobiology of Osteocyte Morphogenesis
Authors: Boerckel Joel D.
Published: May 2022

The year was c.700 BC. King Hezekiah scrambled to prepare his city for a siege. But there was a problem. The Gihon spring that provided water to the hill‐top city was outside the city walls, so Hezekiah devised a last‐ditch plan: dig a tunnel to direct the water into the city. With time slipping away, workers dug from both ends, hoping to meet in the middle. Despite a few changes of direction, the engineers were successful; the pool filled with water, and the city successfully held off the siege. This blind tunneling through rock, from both ends, meeting in the middle, occurs more than a trillion times in each human skeleton in the osteocyte lacunar‐canalicular network. But how do osteocytes accomplish this feat? In this talk, we’ll explore the mechanisms by which osteocytes dig these tunnels, and what this might mean for bone health and disease.
Metaplasia‐induced Epithelial Heterogeneity Directs Pancreatic Injury and Tumorigenesis
Authors: DelGiorno Kathleen , Ma Zhibo , Lytle Nikki , Chen Bob , Jyotsana Nidhi , Weiser Novak Sammy , Cho Charles , Caplan Leah , Ben‐Levy Olivia , Neininger Abigail , Burnette Dylan , Trinh Vincent , Tan Marcus , Manor Uri , Mills Jason , Goldenring James , Lau Ken , Wahl Geoffrey
Published: May 2022

Background and Aims

Despite years of research, mechanisms of pancreatic injury and healing remain poorly understood. Acute pancreatitis is a painful and debilitating condition; chronic pancreatitis may be asymptomatic, but greatly enhances the risk of pancreatic ductal adenocarcinoma (PDAC). Acinar to ductal metaplasia (ADM), or the transdifferentiation of digestive enzyme producing acinar cells to ductal cells, is an early event in both conditions. While ADM is thought to function in healing and regeneration, it also represents a first step in tumorigenesis, demonstrating the duplicitous nature of this inherent plasticity. The goal of these studies was to define the populations arising in ADM, associated transcriptional changes, and their role in disease progression.

Methods

Acinar cells were lineage traced to follow their fate upon injury. Transcripts of more than 13,000 EYFP+ cells were determined using single cell RNA sequencing (scRNA‐seq). Developmental trajectories were generated using several computational biology approaches that rely on non‐overlapping assumptions. Data were compared to scRNA‐seq studies of gastric metaplasia, oncogenic KrasG12D‐induced ADM, and human pancreatitis. Results were confirmed using immunostaining and electron microscopy. Tuft and enteroendocrine cell (EEC) populations were quantified throughout tumorigenesis. KrasG12D was expressed in injury‐induced ADM populations using several inducible Cre drivers.

Results

scRNA‐seq of ADM from chronically injured pancreata revealed emergence of a mucin/ductal population that resembles gastric pyloric metaplasia. Developmental trajectories suggest that some pyloric metaplasia cells generate tuft or EEC populations as distinct lineages. Comparison to KrasG12D‐induced ADM reveals populations associated with disease progression. Immunostaining demonstrates that tuft and EEC formation is an early event in tumorigenesis. Activation of KrasG12D in ADM populations results in neoplastic transformation and the formation of MUC5AC+ pit cells. Human pancreatitis samples reflect a pyloric metaplasia phenotype as well as the formation of tuft and EEC populations.

Conclusions

ADM under conditions of chronic injury results in the formation of a pyloric‐type metaplasia which seeds disparate tuft and EEC lineages. This carefully orchestrated plasticity generates myriad epithelial cell types which likely mitigate injury, providing protection from the formation of pancreatitis and PDAC. KrasG12D expression is sufficient to drive neoplasia when targeted to injury‐induced ADM populations offering an alternative origin for tumorigenesis. This program is conserved in human pancreatitis and provides insight into early events in pancreas diseases.
Molecular basis of neural control of ontogenetic allometric growth in the regenerating Axolotl limb
Authors: McCusker Catherine , Wells Kaylee , Kelley Kristina
Published: May 2022

Urodele amphibians such as the Mexican axolotl have the amazing ability to regenerate missing limbs. Limb regeneration is dependent on the formation of a transient regenerative organ known as the blastema, which is composed of limb progenitor cells that proliferate, pattern, and re‐differentiate into the missing limb tissues. Initially the limb regenerate is small in size and undergoes a period of rapid ontogenetic allometric growth until it reaches the proportionally appropriate size. The underlying mechanisms that regulate this growth in the late staged regenerate are not known. We have recently shown that the limb nerves are required to maintain the growth of the regenerating limb, and that the size of the regenerated limb positively correlates with the abundance of nerves that are connected to it. To identify the molecular signals that could regulate the growth of the regenerate, we evaluated the expression of previously established nerve dependent growth factors in the limb nerves and the regenerating limb tissues during the late stages of limb regeneration. We found that the expression of multiple growth factors including FGFs and BMPs are elevated in both tissues during the stages of regeneration that exhibit the most rapid growth rates. Removing nerve signaling from the late staged regenerate, which attenuates growth, alters the expression of these growth factors in the regenerating tissues. Last, we found that pharmacological inhibition of BMP signaling inhibits the growth of the regenerating limb and mimics the effect of denervation on the expression of some, but not all of the growth factors that we previously evaluated. These studies constitute the first steps in identifying the molecular underpinnings of the neural regulation of ontogenetic allometric growth of the regenerating amphibian limb.
Systemic Cell Cycle Re‐entry Following Amputation in Axolotl: Consequence and Mechanism
Authors: Whited Jessica , Payzin‐Dogru Duygu , Wilson Sarah , Blair Steven , Erdogan Burcu , Hossain Shifa , Cammarata Louis , Velazquez Matos Juan , Wong Alan , Min Sangwon
Published: May 2022

Axolotl salamanders fully regenerate limbs following amputation throughout life. These limbs are anatomically similar to human limbs. Thus, understanding the molecular and cellular biology of axolotl limb regeneration will provide a road map for how tetrapod limbs naturally regenerate, with the hope of spurring future therapeutic approaches in human. Most research has focused on cellular events at the site of amputation since the progenitor cells that are used as building blocks reside nearby. However, we recently discovered a body‐wide cell proliferation, “systemic activation,” response to amputation in axolotl, which is separable from successful regeneration. We will present new experiments demonstrating that amputation primes other limbs for faster future regeneration, representing a possible selective advantage for this process. We will present work implicating the peripheral nervous system, as well as adrenergic and insulin signaling, in transmitting amputation‐injury information to distant tissues. We also show that mTOR signaling is essential for systemic activation in response to amputation in axolotl. We will discuss these findings with respect to known regenerative responses, and more limited injury responses without full appendage regeneration, in other species. Overall, our research supports a two‐step model whereby putative progenitor cells are broadly activated following amputation, but only some highly‐regenerative species go on to refine this response to the local site of injury to enable regeneration of a lost body part.
Remote injury responses during zebrafish heart regeneration
Authors: Poss Kenneth , Sun Fei
Published: May 2022

Acute trauma stimulates local repair but can also affect structures distant from the injury, for instance through the activity of circulating factors. To study the responses of remote tissues to injury and regeneration, we generated genome‐wide profiles from zebrafish brains following experimental cardiac damage. Our findings indicate regulatory mechanisms that distinguish short‐ and long‐range gene expression responses to injury.