bluuebunny/crossref_metadata_2025_split huggingface dataset:
Histone demethylase KDM5B is critical for PI3K‐AKT‐mTOR signaling and stemness of melanoma
Authors: Yan Qin , Zhang Shang‐Min , Meeth Katrina , Micevic Goran , Bosenberg Marcus 
Published: November 2023

Epigenetic states are critical for the maintenance of cancer stem cells, which drive tumor initiation, relapse, and metastasis. Recent studies have suggested histone demethylase KDM5B is crucial for the plasticity of melanoma stem‐cell like subpopulations. Utilizing a series of human‐relevant mouse melanoma models, we previously identified two types of mouse melanoma propagating cells (MPCs). Based on these findings, we hypothesized that KDM5B is critical for the maintenance of MPCs. Indeed, we found that knockdown of KDM5B decreased MPC populations. Consistent with these results, knockdown of KDM5B decreased clonogenicity of these mouse melanoma cells. These phenotypes were linked to decreased PI3K‐AKT‐mTOR signaling. These results strongly suggest that KDM5B regulates melanoma formation and progression, and its inhibition could be combined with immune checkpoint blockade to treat melanoma.Support or Funding InformationDepartment of Defense Peer Reviewed Cancer Research Program Award W81XWH‐13‐1‐0235 and W81XWH‐16‐1‐030, Melanoma Research Foundation Career Development Award, Yale Comprehensive Cancer Center pilot grant, and Yale SPORE in Skin Cancer Developmental Research Award
The Influence of ENPP1 Expression in Mucosal Tissues
Authors: Curtis Valerie , Wang Ruth , Battista Kayla , Lee J. Scott , Colgan Sean 
Published: November 2023

Previous work has established that extracellular adenosine signaling is protective in mucosal inflammation and promotes the resolution of ongoing inflammation. The sources of extracellular adenosine include enzymatic processing from nucleotides, such as ATP and AMP, which can be liberated from a variety of cell types, including leukocytes. Guided by a microarray screen of hypoxia‐inducible genes in mucosal epithelial cells, we identified the strong induction of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) in a time‐dependent manner. ENPP1 is a type II transmembrane glycoprotein that can hydrolyze ATP and diadenosine triphosphate (Ap3A) to AMP and inorganic pyrophosphate. ENPP1, present on the surface of chondrocytes, has been extensively studied for its role in tissue mineralization. Its potential role in the resolution of mucosal inflammation via AMP generation has yet to be determined. Presently, we have established that ENPP1 mRNA is expressed in T84 and Caco‐2 intestinal epithelial cells, and this expression can be upregulated by conditions that drive epithelial metabolism (e.g., exposure to the short chain fatty acid butyrate). Likewise, studies in mouse intestinal epithelial cells lacking the transcription factor HIF‐1a revealed significantly diminished expression of ENPP1. In parallel, it was revealed that activated human neutrophils are a source of Ap3A, previously thought to be made primarily by platelets. These studies indicate that Ap3A and ENPP1 at the mucosal surface may function to provide an additional source of adenosine, sub‐serving its role in inflammatory resolution.Support or Funding InformationThis work was supported by NIH grants DK50189, HL60569 and DK95491 and by grants from the Crohn's and Colitis Foundation of America.
Autophagy regulates hepatocellular senescence
Authors: Huda Nazmul , Khambu Bilon , Chen Xiaoyun , Yin Xiao‐Ming 
Published: November 2023

Autophagy and senescence are two distinct but functionally intertwined stress mediated cellular process. In advanced human liver disease there is widespread senescence in hepatocytes. Several lines of evidence showed that the hepatocyte senescence was associated closely with fibrosis stage and an adverse outcome in chronic liver disease. Mechanism that establishes the relationship between autophagy and senescence in liver is unclear. In this study we have used mice whose hepatocytes lack Atg7 (and thus autophagy) to elucidate the precise trigger that induce senescence and the pathway leading to senescence mechanism. Here we report evidence that autophagy deficient hepatocytes showed higher expression of senescence associated factors including p15, p21, CDKN3, & HP1γ compared to wildtype. Autophagy defects activated the oxidative stress and DNA damage responses in hepatocytes. Moreover, the autophagy deficiency caused significantly increase in β‐galactosidase activity, and SASP phenotype in hepatocytes.ConclusionDysregulation of autophagy causes senescence in hepatocytes, which can contribute to the pathology of the autophagy‐deficient liver.Support or Funding InformationNIH, R21AA 021450 and R01AA021751; Department of Pathology and Laboratory Medicine Indiana University School of Medicine Indianapolis, IN 46202
RNA Granule Organization
Authors: Lehmann Ruth , Trcek Tatjana , Grosch Markus , Shroff Hari , Lionnet Timothée 
Published: November 2023

Germ granules, specialized ribonucleoprotein particles, are a hallmark of all germ cells. In Drosophila, an estimated 200 mRNAs are enriched in the germ plasm, and some of these have important, often conserved roles in germ cell formation, specification, survival and migration. How mRNAs are spatially distributed within a germ granule and whether their position defines functional properties is unclear. We have used single‐molecule FISH and structured illumination microscopy, a super resolution approach, to show that mRNAs are spatially organized within the granule whereas core germ plasm proteins, such as Vasa, Oskar, Tudor and Aubergine are distributed evenly throughout the granule. Multiple copies of single mRNAs self‐organize into “homotypic clusters” that occupy defined positions within the granule. This organization, which is maintained during embryogenesis and independent of the translational or degradation activity of mRNAs, reveals new regulatory mechanisms for germ plasm mRNA‐protein that may be applicable to other mRNA granules.Support or Funding InformationHoward Hughes Medical Institute and NICHD
New insights into intravascular lipolysis and new causes of hypertriglyceridemia
Authors: Young Stephen G. , Beigneux Anne , Fong Loren , Ploug Michael 
Published: November 2023

GPIHBP1, a GPI‐anchored protein of capillary endothelial cells, is crucial for the lipolytic processing of triglyceride‐rich lipoproteins (TRLs). GPIHBP1 binds lipoprotein lipase (LPL) in the interstitial spaces and shuttles the enzyme to its site of action in the capillary lumen. GPIHBP1 is also required for the margination of TRLs along capillaries—so that lipolytic processing can proceed. Finally, the binding of LPL to GPIHBP1 reduces the spontaneous unfolding of LPL's catalytic domain, thereby stabilizing LPL catalytic activity. GPIHBP1 mutations cause severe hypertriglyceridemia; the majority are missense mutations that interfere with the proper conformation of GPIHBP1's LU (Ly6‐uPAR) domain and thereby abolish the capacity of GPIHBP1 to bind and transport LPL. Recent studies have shown that GPIHBP1 is also highly to the pathogenesis of acquired forms of hypertriglyceridemia.Support or Funding InformationLeducq Foundation; National Heart, Lung, and Blood Institute
Geranylgeranyl‐Regulated, ER‐to‐Golgi Transport of UBIAD1: Implications for Cholesterol Homeostasis and Schnyder Corneal Dystrophy
Authors: DeBose‐Boyd Russell A. 
Published: November 2023

Multiple feedback mechanisms converge on the ER (endoplasmic reticulum)‐localized enzyme HMG CoA reductase, which catalyzes a key step in synthesis of cholesterol and essential nonsterol isoprenoids including Fpp (farnesyl pyrophosphate) and GGpp (geranylgeranyl pyrophosphate), which can become attached to many proteins and are utilized in synthesis of dolichol, ubiquinone, heme, and vitamin K2. One mechanism for feedback control of reductase involves sterol‐induced ubiquitination, which marks the enzyme for ERAD (ER‐associated degradation) that is augmented by GGpp, but not by Fpp. Here, we show that sterols trigger binding of a subset of reductase molecules to UBIAD1 (UbiA prenyltransferase domain‐containing protein‐1), a prenyltransferase that utilizes GGpp to synthesize the vitamin K2 menaquinone‐4. Sterol‐induced binding to UBIAD1 protects reductase from accelerated degradation, permitting continued synthesis of nonsterol isoprenoids in sterol‐replete cells. GGpp triggers release of UBIAD1 from reductase, allowing for maximal ERAD of reductase.Mutations in UBIAD1 cause SCD (Schnyder corneal dystrophy), an autosomal dominant eye disease in humans characterized by corneal accumulation of cholesterol. SCD‐associated mutants of UBIAD1 resist GGpp‐induced displacement from reductase and thereby inhibit its sterol‐accelerated ERAD. In the course of our studies, we discovered that GGpp also stimulates translocation of UBIAD1 from the ER to Golgi. SCD‐associated mutants of UBIAD1 are refractory to GGpp‐induced translocation to the Golgi and remain sequestered in ER membranes where they inhibit reductase ERAD in a dominant‐negative fashion. These results support a model that posits upon sensing GGpp depletion in membranes of the ER, UBIAD1 becomes trapped in the organelle and inhibits reductase ERAD so as to stimulate mevalonate synthesis for replenishment of GGpp. This novel sensing mechanism directly controls ERAD of reductase and becomes disrupted in SCD, which likely contributes to the accumulation of cholesterol that characterizes the eye disease.Support or Funding InformationThis work is supported by NIH grants HL20948, GM112409, and GM119180.
Bromodomain and Extraterminal (BET) Proteins Regulate Hepatocyte Proliferation in Hepatocyte‐Driven Liver Regeneration
Authors: Russell Jacquelyn Olivia , Ko Sungjin , Shin Donghun , Monga Satdarshan Paul 
Published: November 2023

Bromodomain and extraterminal (BET) proteins are epigenetic readers capable of binding to the acetylated lysine tails of histones, where they recruit key components of the basic transcriptional machinery to promote transcriptional activation of a wide variety of genes. Aberrant epigenetic gene regulation has been identified in many human malignancies, including genetic mutations in BET proteins. Excitingly, small molecule inhibitors of BET proteins, such as JQ1, have shown efficacy in preclinical models of various hematological and solid tumors without widespread toxicity to normal tissues. Importantly, JQ1 was shown to inhibit cell growth of hepatocellular carcinoma (HCC) cell lines. BET proteins have also been shown to regulate cell proliferation in non‐tumor settings. We recently showed BET proteins regulate biliary‐driven liver regeneration. Therefore, we sought to study the roles of BET proteins in other models of liver regeneration. Since two‐thirds partial hepatectomy (PHx) in rodents and acetaminophen (APAP)‐induced liver injury in both zebrafish and mice are well‐established models to study the mechanisms of hepatocyte proliferation, we set out to determine if JQ1 could inhibit liver regeneration by blocking hepatocyte proliferation in the PHx and APAP‐injury models. We injected mice with JQ1 either 2 or 16 hours post‐PHx in order to determine the kinetics of BET protein activation and harvested animals at approximately 45 hours post‐surgery, as hepatocyte proliferation in mice peaks around 36–48 hours post‐PHx. We demonstrate here that animals treated with JQ1 after PHx display notably increased liver injury with elevated transaminases and a near‐complete inhibition of hepatocyte proliferation. Treatment with JQ1 after sham surgery did not induce liver injury in mice. Levels of Cyclin D1 mRNA and protein were reduced in 16 hour post‐PHx JQ1 injected animals, and were even further reduced if JQ1 was injected 2 hours post‐PHx. Zebrafish larvae treated with JQ1 after APAP‐induced liver injury also displayed impaired hepatocyte proliferation. Therefore our results show that BET proteins regulate hepatocyte proliferation‐driven liver regeneration and establish a model to determine the mechanisms by which BET proteins promote hepatocyte proliferation.Support or Funding InformationFunding was provided via the NIH CATER training grant T32 EB001026. Funding was additionally provided through the NIDDK via 5R01DK062277‐13. Support was provided by the Cellular & Molecular Pathology Graduate Program at the University of Pittsburgh.
Dramatization of Starling Forces: An Interactive Learning Approach
Authors: Connor Brian W , Carvalho Helena 
Published: November 2023

PurposeVTCSOM is a modern hybrid medical school where student learning is facilitated outside of the traditional classroom setting through active learning approaches such as Problem‐Based Learning, hands‐on workshops and lectures. When students are actively engaged during the teaching/learning process, they understand topics in a more comprehensive fashion. As the amount of information which medical students are expected to master grows, it becomes necessary to develop and implement innovative learning methodologies that help students to retain and apply complex physiological topics, rather than rote memorization. Our goal is to use dramatization to interactively teach the effects of Starling forces in the microcirculation.MethodsA brief introduction was given on the topic of Starling forces regulating microcirculation for 23 first year medial students. One half of the group moved to an area representing the lumen of the capillary while the other half moved to an area representing the interstitium. Four to seven other students represented dynamic fluid molecules. They competed to move faster than their peers from circulation (capillary) to the interstitium or vice versa under the influence of hydrostatic and coloidosmotic pressures or a clinical vignette, as they were projected. The task for the students, behaving as fluid, was to move into or out of the space designated as capillary.ResultsIn an anonymous survey, 23 students were evaluated on their knowledge of Starling forces and edema both before and after this kinetic learning approach. The pre and post‐activity surveys, which were evaluated on a 100‐point grading scale, contained the same questions randomized in a different order. An overall improvement was seen from the pre‐activity performance (χ̄ =45.4±sd=25.1; range 9–91%) to the post‐activity performance (χ̄ =77.5±sd=14.1, range 45–100%). Additionally, in a subjective question included in the post‐survey 85% of students found this activity to be an effective way of learning.ConclusionIntegrating interactive approaches into teaching in the context of undergraduate medical education can be helpful in demonstrating challenging yet important concepts, such as fluid exchange in the microcirculation. After the activity, students showed a 32% improvement in their understanding of Starling forces and edema with a substantial decrease in variation between students. Thus, our data coincide with literature that shows active learning approaches can be effective in replacing or complementing passive learning in traditional lectures.
Factors Directing Preclinical Medical Students towards Specialty of Choice
Authors: Shacfe Fathiah Nadine Hasan , Alhomoudi Reham Ibrahim , Peeran Ahmed Aftab , Abdeh Amal Iman , Obad Adam Subait , Shareef Mohammed Abrar 
Published: November 2023

IntroductionChoosing a medical specialty could be difficult and confusing process for medical students. Hence, the aim of this study was to determine the factors and predictors that influence preclinical medical students' specialty preference.MethodsA self‐administered, paper‐based, 19‐item anonymous questionnaire was distributed among preclinical medical student at Alfaisal University. The questionnaire examined factors related to: social life, profession, education, and seniors' advice. Confirmatory factor analysis and cronbach's alpha were used to validate the priori hypothesis and examine the internal consistency of the questionnaire, respectively. Moreover, Kruskal Wallis and Multinomial Logistic Regression tests were used to compare means and determine career choice predictors among medical students.ResultsA total of 306 students completed the questionnaire with highest choices as surgery 34% (n=99), 33% (n=95) “didn't have any idea about their future specialty preference”, and 9.8% (n=30) internal medicine. The least preferred specialty was family medicine (1.3% n=4). The questionnaire showed acceptable validity and good reliability. The four mean rating values for social, professional, educational, and senior's advice domains were 3.47, 3.4, 3.32, 3.4, respectively (5‐strongly agree, 1‐strongly disagree). Having a High GPA was predictive of choosing an academic career (PhD, P <0.001) and internal medicine (P < 0.001). Additionally, social and educational factors were of more concern to females compared to males (P = 0.029, P = 0.001, respectively). Other factors and domain items had variable importance for students' choice of their future specialties.ConclusionStudents' choices were influenced by several social, professional and educational factors. Yet a remarkable number of students were not decisive about their future specialties. Understanding the factors that influence students' preference should prompt the adaptation of plans and curricular modifications to direct students towards highly demanded specialties. An additional emphasis on the importance of family medicine should be adopted by integrating related practical and theoretical activities into the curriculum.
A Mathematical Model of Beaver Incisor Tooth Morphology
Authors: Rinaldi Caroline E , Kuhn‐Hendricks Stephen M , Erickson Gregory M 
Published: November 2023

A key evolutionary innovation of rodents was the development of ever‐growing incisors, characterized by their arc‐shaped form. These teeth grow and erupt throughout the life of the animal at approximately the same rate as wear occurs at their occlusal ends. Fortuitously, daily growth increments are visible on the surfaces of rodent incisors. These structures, known as periradicular bands, provide a moving, or kymographic record of each tooth's growth history. This record can be used to reconstruct tooth growth and wear rates occurring during the period of the animal's life represented by the bands, and the total number days over which the tooth formed. We studied the upper incisors of 18 Florida wild‐caught extant beavers (Castor canadensis) spanning ontogeny to develop a model incorporating gradients in incisor growth rates and form throughout the life of a typical individual. The specimens were digitized. Labial surface arc segments for representative size class incisors were sequentially aligned in ascending order of age and incisor size. Over 120 morphometric points were documented along the total alignment and a custom R‐script used to fit spiral equations. This was used to describe the pattern of typical incisor growth throughout an individual's lifetime. Log‐likelihood fitting suggests an Archimedean spiral best describes those data. Next, circadian growth increments on the right upper incisor of 36 Kansas wild‐caught beavers of varying season and age class were measured and size‐specific growth rates were calculated. We found that average daily dentin growth rate decreases with age, while total number of increments increases with age. We then incorporated the average increment width (a proxy for developmental stage growth rates) for each tooth to estimate the placement of age classes on the spiral and infer the total amount of growth occurring in the lifetime of an individual (~1.8 meters for C. canadensis). Based on the data sets used in this study, we observed 4 to 5 size classes occupying approximately 3 ½ revolutions of the spiral throughout beaver ontogeny. The development of models such as this makes it possible to estimate size and age of individuals on the basis of their chronological position within the spiral. This provides a new tool for estimating age and growth rates in both living and fossil rodents using isolated incisors. Furthermore, the models facilitate our understanding of dental form, function, and scaling in rodents.Support or Funding InformationThis work was partially funded by NSF EAR 0959029 presented to GME.
A major paradigm shift in fish, tetrapod and limb evolution: characteristic tetrapod musculoskeletal limb phenotype emerged more than 400 MYA in basal lobe‐finned fishes
Authors: Diogo Rui , Molnar Julia , Esteve‐Altava Borja , Johnson Peter 
Published: November 2023

Previous accounts of the origin of tetrapod limbs have postulated a relatively sudden change, after the split between extant lobe‐finned fish and tetrapods, from a very simple fin phenotype with only two muscles to the highly complex tetrapod condition. The evolutionary changes that led to the muscular anatomy of tetrapod limbs has therefore remained relatively unexplored. We performed dissections, histological sections, and MRI scans of the closest living relatives of tetrapods: coelacanths and lungfish. Combined with previous comparative, developmental and paleontological information, our findings suggest that the characteristic tetrapod musculoskeletal limb phenotype was already present in the Silurian last common ancestor of extant sarcopterygians, with exception to the autopod (hand/foot) structures, which have no clear correspondence with fish structures. Remarkably, the two major steps in this long process – leading to the ancestral fin anatomy of extant sarcopterygians and limb anatomy of extant tetrapods, respectively – occurred at the same nodes as the two major similarity bottlenecks that led to the striking derived myological similarity between the pectoral and pelvic appendages within each taxon. Our identification of probable homologies between appendicular muscles of sarcopterygian fish and tetrapods will allow more detailed reconstructions of muscle anatomy in early tetrapods.Support or Funding InformationAm. Assoc. Anat. postdoctoral grant to JLM, and European Union's Horizon 2020 Marie Skłodowska‐Curie grant No 654155 to BE‐A.