bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cranial Nerve Development, Distribution, and Function
Authors: Mosconi Tony 
Published: April 2020

Human evolution has produced a prodigious brain and fashioned an elaborate mechanism of convolution and gyrification to fit the neural tissue inside a rigid boney chamber. Critical systems, from olfaction and vision, to control of muscles for articulated speech, have been concentrated in the head, through a set of cranial nerves and their nuclei, located mainly in the brainstem. This presentation will trace the development, describe the distribution, and explore the functions of those cranial nerves.Early in development, dorsal and ventral columns emerge in the gray matter of the neural tube. Dorsally, the alar plate differentiates into sensory regions in both the spinal cord (dorsal horns) and the brainstem (sensory nuclei). The ventral portion of the neural tube, the basal plate, is the source of motor structures including the spinal cord ventral horn and brainstem motor nuclei. Bilaterally, a longitudinal furrow in the wall of the central canal, the sulcus limitans, divides the alar and basal plates and establishes the spatial segregation of motor and sensory neuronal systems. As the embryo elongates it differentiates into a five‐vesicle structure that is the progenitor of forebrain cerebral hemispheres and diencephalon, and brainstem midbrain, pons, and medulla.With the formation of the five‐vesicle embryo, the lumen of the central canal begins to elaborate rostrally to form the ventricular system. The lateral ventricles expand within the core of the cerebral hemispheres, and the third ventricle opens on the midline with the diencephalon forming its walls. The cerebral aqueduct is the ventricular correlate of the midbrain, connecting the third and fourth ventricles. The fourth ventricle is roughly pyramidal, tapering upward as it receives the cerebral aqueduct, being broadest at the pons‐medulla junction, and tapering again caudally to become continuous with the central canal of the spinal cord. The sulcus limitans persists in the walls of the fourth ventricle, separating alar plate derivative sensory nuclei dorsolaterally from the basal plate‐derived motor nuclei ventromedially. This effectively establishes the layout of brainstem cranial nerve nuclei. Functionally related nuclear columns are distributed throughout the rostro‐caudal length of the brainstem in consistent relative locations.Cranial nerves (CN) I (olfactory) and II (optic) are the only cranial nerves that have no brainstem nuclei, and their circuity is in the forebrain. Nuclei of CN III, the oculomotor nerve, and CN IV, the trochlear nerve occupy the midbrain. Cranial nerves V (trigeminal), VI (abducens) and the motor nucleus of CN VII (facial motor) are found in the pons, and CNn VIII (vestibulocochlear), IX (glossopharyngeal), X (vagus), XI (accessory), and XII (hypoglossal) develop in the medulla. Extensive cephalization of the brain and cranial nerves has shaped our facial morphology. The functions of the cranial nerves are well known, and predictable and diagnostic deficits appear after injuries.
The Paradox of Fragile but Dense Bones in Type 2 Diabetes
Authors: Donnelly Eve 
Published: April 2020

Epidemiologic evidence from the past decade has demonstrated that increased bone fracture risk is one of the myriad clinical complications of type 2 diabetes mellitus (T2DM). Counterintuitively, the increased fracture risk in T2DM occurs despite greater bone mineral density, and persists after accounting for potential confounders like body mass index, neuropathies, and falls. Therefore, T2DM may alter aspects of bone’s intrinsic resistance to fracture beyond bone mineral density, such as material properties or microarchitecture, thereby increasing bone fragility independently of bone mass. Although the mechanisms that underlie bone fragility in T2DM are not yet well established, a multiplicity of factors, including hyperglycemia, altered bone remodeling, and non‐enzymatic collagen crosslinking in the bone matrix are implicated. In this work we elucidate the factors that influence fragility in T2DM by characterizing the biochemical, material, microarchitectural, and mechanical properties of bone from a clinical population of men with and without T2DM. The cancellous bone from patients with T2DM had greater concentrations of the advanced glycation endproduct pentosidine and sugars bound to the collagen matrix, had greater mineral content, and trended toward a greater bone volume fraction than the non‐DM specimens. Surprisingly, the T2DM specimens had similar strength and toughness as those from non‐DM controls. Regression modeling of the mechanical outcomes revealed competing effects of T2DM on bone mechanical behavior. The trend toward greater bone volume fraction and greater mineral content of the T2DM specimens increased strength, while the greater concentrations of pentosidine in the T2DM group increased brittleness. These data suggest that high concentrations of AGEs can increase fragility by reducing the ability of bone to absorb energy prior to failure, especially for the subset of T2DM patients with low bone volume fraction. Further, our model shows that an increase in bone volume fraction offers a protective effect for T2DM patients, even with the inferior intrinsic quality of the T2DM bone, whereas loss of bone volume fraction substantially increases risk of bone fragility for T2DM patients. The primary clinical implications of these findings are that preservation of bone volume fraction is critical in patients with T2DM.Support or Funding InformationSupported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K01 AR064314)
Integrated analysis of bioelectric signaling in regulation of proportion.
Authors: Harris Matthew 
Published: April 2020

We are proportionate entities: the mechanical and physiological function of our bodies is dependent on allometric scaling between tissues and organs. How such scaling is genetically and developmentally regulated remains a long lasting question and requires knowledge at many levels and across disciplines. Using unbiased forward genetic screens in the zebrafish, we identify mutations in potassium channels that lead to increase in relative fin size. We assess how these mutations affect electrophysiological properties of the encoded potassium channels in Xenopus oocytes. Using the zebrafish fin as an experimental platform we detail key regulation of bioelectric signaling and its control of coordinated growth during development and regeneration. Complementing these experimental approaches, we extend our investigation through a broad scale phylogenomic analysis capitalizing on natural variation in fin length in evolution as well in clinical cases of coordinated overgrowth of extremities. The combination of approaches provides mechanistic insight into bioelectric regulation of coordinated growth during development and regeneration and the prevalence of bioelectric signaling in regulating form.Support or Funding InformationNIH R01HD084985
Link between miRNA‐19b and mTOR signaling pathway in cancer prognosis: from meta‐analysis to mechanism exploration
Authors: MAMAN SOURAKA TAPARA DRAMANI 
Published: April 2020

AIMSPrevious studies came to different conclusions regarding the relationship between miR‐19b and its prognostic value in cancers. Moreover, miR‐19b could affect tumor growth by different pathways mainly targeting PTEN‐PI3K‐AKT which activate mTOR pathway in the downstream. Therefore, we conducted this meta‐analysis to explore the possible correlation between miR‐19b and mTOR in cancers prognosis.Main methodsWe conducted online search and collected a total of 943 articles. According to different authors cross check and our study including/excluding criteria we at end retained 21 articles with 25 studies in this meta‐analysis. Then TCGA data containing miR‐19b level with cancer progression were obtained using OncomiR. Furthermore, Trial Sequential Analysis (TSA) was performed to determine whether the results of our meta‐analysis could be used in clinical applications. After that, articles regarding the mechanism of miR‐19b in various cancers were analyzed and KEGG pathway database was used to find the main regulatory function of miR‐19b in human cancers.Key FindingsOverall hazard ratio results displayed that higher expression of miR‐19b was correlated with shorter overall survival (HRs=1.54, 95%CIs=1.20–1.98) by promoting distant metastasis, but had no relation with disease‐free survival/progression‐free survival (HRs=0.61, 95%CIs=0.31–1.19). TCGA datasets also revealed the tumorigenesis role of miR‐19b. According to TSA results, more evidence are needed to support that miR‐19b had no correlation with DFS/PFS. Exploration of the mechanism revealed the possible link between miR‐19b and mTOR pathway.SignificanceMiR‐19b might play its pro‐cancer role through mTOR pathway and it is likely to be a therapeutic target for cancers.Support or Funding InformationThe study was supported by Zhongnan Hospital of Wuhan University Science and Technology, Innovation and Education Fund [Project cxpy2018067] and Zhongnan Hospital of Wuhan University Science and Technology, Innovation and Education Fund [Project ZNPY2017054].
Inflammation due to Chronic Alcohol Exposure Promotes Cardiac Atrophy and Dysfunction Resulting from Impaired Fibroblast‐Myocyte Crosstalk
Authors: El Hajj Elia C. , Mouton Alan J. , Ninh Van K. , Gardner Jason D. 
Published: April 2020

Alcoholic cardiomyopathy (ACM) is a cardiac disease caused by chronic heavy alcohol abuse. ACM is most notably a type of dilated cardiomyopathy (DCM), accounting for approximately 21–50% of all idiopathic non‐ischemic DCM cases in Western countries. ACM is typically characterized by left ventricular dilation and LV muscle wasting (atrophy), with diastolic and systolic dysfunction (ejection fraction < 40%) occurring in later stages. Previous studies in our lab have shown that chronic alcohol exposure prevents compensatory hypertrophy in both volume‐ and pressure‐overload models of heart failure. However, the mechanisms of alcohol‐induced cardiac atrophy and dysfunction are not clear. The purpose of this study was to investigate mechanisms of chronic alcohol‐induced cardiac remodeling and dysfunction. We also sought to determine the role of cardiac fibroblasts, which play a dynamic role in cardiac remodeling, in mediating these effects.Adult male Wistar rats were exposed to ethanol (EtOH) vapor inhalation for 16 weeks. Echocardiography was performed to assess terminal cardiac structure and function. Cardiac fibroblasts were isolated from the left ventricle (LV) for both ex vivo and in vitro analysis. Gene expression was determined by real‐time PCR and flow cytometry. Protein expression was determined via Western blot analysis. EtOH led to cardiac wall thinning and impaired systolic function, as evident by decreased LV wall thickness at diastole (LVPWd) and fractional shortening, respectively, Additionally, EtOH decreased mRNA levels of various contractile proteins including Acta1, Actc1, and Myh7. EtOH also increased mRNA and protein levels of LV inflammatory markers, TNF‐α and NF‐κB. Furthermore, EtOH induced increased activation of JNK and decreased mTOR activation, suggestive of decreased hypertrophic signaling and atrophy. EtOH led to myofibroblast activation as assessed by flow cytometry and led to ECM remodeling (increased collagen III content). EtOH increased Tnf and Il6 mRNA in cardiac fibroblasts ex vivo, and increased mRNA levels of several pro‐inflammatory cytokines and chemokines in vitro. Administration of conditioned media from EtOH‐treated fibroblasts decreased contractile protein mRNA levels and impaired Akt and mTOR signaling in differentiated H9C2 cardiomyocytes.Our results indicate that EtOH‐induced cardiac atrophy and dysfunction is associated with activation of inflammatory pathways. Furthermore, EtOH may induce a pro‐inflammatory cardiac fibroblast phenotype, leading to aberrant fibroblast‐myocyte cross‐talk.Support or Funding InformationFunding provided by the NIH/NIAAA 1R21AA022690 (JDG) and the Saving tiny Hearts Society (JDG).
Modification of the Endoplasmic Reticulum Translocon Impairs Protein Translocation
Authors: Richards Kyle A. , Runnebohm Avery , Dolan Molly , Vitali Halie , Rubenstein Eric 
Published: April 2020

The endoplasmic reticulum (ER) is the entry point for most proteins residing and functioning in the eukaryotic endomembrane system. The primary mechanism by which proteins enter the ER is via the translocon complex. Dysfunction in this complex can block access into the ER, which is detrimental to cellular health. The translocon is highly conserved and has been intensely studied in Saccharomyces cerevisiae. Analysis of translocon function in protein trafficking, localization, and interactions in yeast has been facilitated by the use of epitope tags. We have found that a tag on the translocon pore subunit previously suggested not to impair translocon function subtly affects translocation of proteins into the ER in yeast cells. Intriguingly, this tag also suppresses a phenotype associated with defective protein quality control pathways, consistent with a functional link between translocation and quality control. Ongoing work includes characterizing the effects of placing different epitope tags on different translocon subunits, with the goal of identifying tags that affect translocon function the least.Support or Funding InformationThis work was supported by Ball State University ASPiRE research awards to AR and MD, a Ball State University Faculty Advance research award to ER, an Indiana Academy of Science Senior Research Grant to ER, and an NIH grant to ER (GM111713).
A New Method for Converting Aptamers to Riboswitches Using the Theophylline Riboswitch
Authors: Schievelbein Mika Jeannette , Lucia Lauren , Dadlani Sonia , Zangrilli Toni , Tilton James , Ouellet Jonathan 
Published: April 2020

Fluorescence Activated Cell Sorting, or FACS, is a method that was used to convert the theophylline aptamer into a riboswitch. This method could theoretically be used to convert other discovered aptamers into riboswitches, however it is a costly method and is only available to those with access to these high‐tech, expensive machines. The theophylline riboswitch was previously discovered by implementing the theophylline aptamer, with random sequences linking it to the expression platform, into a specifically‐designed plasmid, and then using a FACS machine to sort the cells.We can structure a new system that would select only the correct sequence, containing the theophylline riboswitch out of a pool, without the use of a FACS machine. To do so, we place the pool of sequences containing the aptamer, linked to the Shine Dalgarno by eight randomized nucleotides, into a newly designed plasmid, placNEO, and transform the plasmid into bacteria cells. Then, the use of replica plating along with screening will select the cells that only contain the plasmid with the correct riboswitch sequence. By doing so, we confirm that this system is efficient in converting aptamers into riboswitches without the need for a FACS machine.After an aptamer has been successfully converted into its riboswitch, the system of ratiometric fluorescence will allow for testing of the riboswitch’s function. This is done by designing a plasmid, pTRFlac, that contains genes for red and green fluorescence proteins, mCherry and GFP respectively, on either side of the inserted riboswitch. A PCR product encoding for mCherry, the riboswitch, and GFP will be inserted downstream of the lactose operon in pUC18. Ratios of the fluorescence intensities of the two florescent proteins will provide the ability to measure the riboswitch’s function through fluorescence readings.Support or Funding InformationMonmouth University Summer Research Program ICFNJ
Investigating the Effects of 1700 FDA Approved Drugs on Proneural Protein Knockdown in Drosophila melanogaster
Authors: Mancini Isabella 
Published: April 2020

Basic Helix‐Loop‐Helix (bHLH) proneural proteins comprise a superfamily of transcription factors that are critical to early development. This superfamily includes the Daughterless (Da) gene in Drosophila melanogaster, the fruit fly, and the homologous TCF4 gene in mammals. These genes have many essential functions in sex determination, cell proliferation, muscle development, and neurogenesis. In addition to these roles in development, our laboratory has shown that both Da and TCF4 function in mature, differentiated neurons, where they restrict neurite branching and synapse number. Knockdown of Da thus results in decreased motor function, a readout of proper glutamatergic neurotransmission. These results are important because mutations in TCF4 have been associated with the neurodevelopmental diseases Pitt‐Hopkins syndrome and schizophrenia.The purpose of this research is to screen 1700 FDA approved drugs in our Da knockdown model with the hopes of using this information to better determine future therapy for individuals with Pitt‐Hopkins and schizophrenia.Support or Funding InformationThis research was supported by Drexel University Office of Undergraduate Research through the STAR Scholars program, under the mentorship of Dr. Daniel Marenda.
Emerging mechanistic insights into mTOR‐PASK signaling pathway that connects nutrient signaling to chromatin network in stem cells
Authors: Kikani Chintan , Xiao Michael , Wu Xiaoying 
Published: April 2020

Stem cell fate in the tissue niche is intimately connected with intracellular metabolic state and the extra‐cellular hormonal stimulations. We have shown that a sensory kinase, PAS domain Kinase (PASK) phosphorylates Wdr5, a member of COMPASS family of histone methyltransferases, to activate the stem cell differentiation program in multiple differentiation paradigms, in vivo and in vitro (eLife, 2016). PASK is expressed highly and exclusively in stem cells, yet the differentiation signaling cues are required to activate PASK and its downstream functions, suggesting PASK remains inaccessible to bind Wdr5 in proliferating stem cells. Here, we show that the mechanistic Target of Rapamycin (mTOR) phosphorylates PASK to promote Wdr5 recruitment and myogenesis in response to nutrient and hormonal signaling. How mTOR phosphorylation stimulates PASK‐Wdr5 interactions remains unknown but is a key mechanistic question that could help understand how nutrient and metabolic signaling can acutely control stem cell differentiation on demand. By using multi‐disciplinary approaches, we show that the PAS domain of PASK inhibits catalytic activity of the kinase domain. Interestingly, mTOR stimulated phosphorylation induces a conformational change resulting in the increased Wdr5 binding, and catalytic activity of PASK. Thus, our data show how information pertaining to nutrient availability is communicated to epigenetic complexes via sequential activation of the mTORC1‐PASK‐Wdr5 pathway.Support or Funding InformationNIH R01: Epigenetic Control of muscle stem cell function by PASK‐Wd5 signaling pathway.1R01AR073906‐01A1
A Selective AC1 Inhibitor as Non‐GPCR‐ or Ion Channel‐Dependent Approach for the Treatment of Pain
Authors: Giacoletti Gianna , Price Tatum , Msdi Abdulwhab Shremo , Cook Ryan , Hayes Michael , Vazquez-Falto Katerina , Gonzales Alexandra , Chapman Sumer , Santini Edwin , Nornoo Adwoa , Watts Val , Brust Tarsis 
Published: April 2020

Adenylyl cyclases (ACs) are enzymes that catalyze the synthesis of cAMP from ATP. The cAMP signaling cascade is involved in a number of physiological processes spanning from breathing to memory and cardiac function. Among the nine different membranous AC isoforms, a role for adenylyl cyclase 1 (AC1) has been suggested in learning, memory, pain, and opioid dependence. AC1 is one of the calcium/calmodulin‐stimulated ACs and previous studies suggest that inhibition AC1 could relieve inflammatory pain and reduce signs of opioid dependence. However, non‐selective inhibition of AC1 and closely related AC8 could lead to learning and memory impairments. We previously identified ST034307 as a selective inhibitor of AC1 and revealed anti‐allodynic activity in the mouse CFA inflammatory pain model. As part of our ongoing studies to identify selective AC inhibitors we developed a novel cellular model that used CRISPR/Cas 9 editing to remove 95% of the forskolin‐stimulated cAMP signal from wild type HEK293 cells (Soto‐Velasquez et al., 2018). We have now used this cellular model to re‐evaluate the AC isoform selectivity of ST034307. The results confirmed unprecedented selective inhibition of AC1 vs the closely related AC8. The development of AC1‐selective inhibitors like ST034307 now provides an opportunity to better study this protein and determine the physiological effects of inhibiting AC1 in additional animal models. The present work represents a comprehensive pre‐clinical study with the selective AC1 inhibitor ST034307. We have determined ST034307’s biodistribution to mouse blood and brain at different time points after injection. In addition, we have shown that the compound is effective and comparable to ketoprofen to relieve visceral and inflammatory pain in mice, and that it does not disrupt mouse innate behavior (nesting) at analgesic doses. In fear extinction experiments with rats ST034307 had no effects on extinction learning. However, the compound disrupted the consolidation of fear extinction compared to vehicle‐treated rats. These data support previous studies suggesting that AC1 inhibitors may be useful to treat pain and also indicates that normal innate behavior is not disrupted at analgesic doses. Moreover, the effect on consolidation of fear extinction may suggest a novel use for these compounds in anxiety disorders, such as post‐traumatic stress disorders (PTSD).Support or Funding InformationThis work was supported by the American Association of Colleges of Pharmacy (New Investigator Award), Palm Beach Atlantic University (Quality Initiative Grant), Lloyd L. Gregory School of Pharmacy (Integra Connect Grant), Purdue College of Pharmacy, and Richard and Anne Borch Award.