Digital Commons Network^™

Chronic Social Defeat Alters Brain Vascular-Associated Cell Gene Expression Patterns Leading To Vascular Dysfunction And Immune System Activation, Joshua D Samuels, Madison L Lotstein, Michael L Lehmann, Abdel G Elkahloun, Subhadra Banerjee, Miles Herkenham

Faculty, Staff and Student Publications

Brain vascular integrity is critical for brain health, and its disruption is implicated in many brain pathologies, including psychiatric disorders. Brain-vascular barriers are a complex cellular landscape composed of endothelial, glial, mural, and immune cells. Yet currently, little is known about these brain vascular-associated cells (BVACs) in health and disease. Previously, we demonstrated that 14 days of chronic social defeat (CSD), a mouse paradigm that produces anxiety and depressive-like behaviors, causes cerebrovascular damage in the form of scattered microbleeds. Here, we developed a technique to isolate barrier-related cells from the mouse brain and subjected the isolated cells to single-cell RNA …

Hdac1 Regulates The Chromatin Landscape To Control Transcriptional Dependencies In Chronic Lymphocytic Leukemia, Tzung-Huei Lai, Hatice Gulcin Ozer, Pierluigi Gasparini, Giovanni Nigita, Rosario Distefano, Lianbo Yu, Janani Ravikrishnan, Selen Yilmaz, Juan Gallegos, Sachet Shukla, Vinay Puduvalli, Jennifer Woyach, Rosa Lapalombella, James Blachly, John C Byrd, Deepa Sampath

Faculty, Staff and Student Publications

Chronic lymphocytic leukemia (CLL) is a quiescent B-cell malignancy that depends on transcriptional dysregulation for survival. The histone deacetylases are transcriptional regulators whose role within the regulatory chromatin and consequence on the CLL transcriptome is poorly characterized. Here, we profiled and integrated the genome-wide occupancy of HDAC1, BRD4, H3K27Ac, and H3K9Ac signals with chromatin accessibility, Pol2 occupancy, and target expression signatures in CLL cells. We identified that when HDAC1 was recruited within super-enhancers (SEs) marked by acetylated H3K27 and BRD4, it functioned as a transcriptional activator that drove the de novo expression of select genes to facilitate survival and progression …

Cortex-Wide Neural Dynamics Predict Behavioral States And Provide A Neural Basis For Resting-State Dynamic Functional Connectivity, Somayeh Shahsavarani, David N Thibodeaux, Weihao Xu, Sharon H Kim, Fatema Lodgher, Chinwendu Nwokeabia, Morgan Cambareri, Alexis J Yagielski, Hanzhi T Zhao, Daniel A Handwerker, Javier Gonzalez-Castillo, Peter A Bandettini, Elizabeth M C Hillman

Faculty, Staff and Student Publications

Although resting-state functional magnetic resonance imaging (fMRI) studies have observed dynamically changing brain-wide networks of correlated activity, fMRI's dependence on hemodynamic signals makes results challenging to interpret. Meanwhile, emerging techniques for real-time recording of large populations of neurons have revealed compelling fluctuations in neuronal activity across the brain that are obscured by traditional trial averaging. To reconcile these observations, we use wide-field optical mapping to simultaneously record pan-cortical neuronal and hemodynamic activity in awake, spontaneously behaving mice. Some components of observed neuronal activity clearly represent sensory and motor function. However, particularly during quiet rest, strongly fluctuating patterns of activity across …

Spatial Single-Cell Sequencing Of Meiosis I Arrested Oocytes Indicates Acquisition Of Maternal Transcripts From The Soma, Kenneth A Trimmer, Peisen Zhao, Jacob Seemann, Shin-Yu Chen, Sudip Mondal, Adela Ben-Yakar, Swathi Arur

Faculty, Staff and Student Publications

Maternal RNAs are stored from minutes to decades in oocytes throughout meiosis I arrest in a transcriptionally quiescent state. Recent reports, however, propose a role for nascent transcription in arrested oocytes. Whether arrested oocytes launch nascent transcription in response to environmental or hormonal signals while maintaining the meiosis I arrest remains undetermined. We test this by integrating single-cell RNA sequencing, RNA velocity, and RNA fluorescence in situ hybridization on C. elegans meiosis I arrested oocytes. We identify transcripts that increase as the arrested meiosis I oocyte ages, but rule out extracellular signaling through ERK MAPK and nascent transcription as a …

Effect Of Ishophloroglucin A Isolated From Ishige Okamurae On In Vitro Osteoclastogenesis And Osteoblastogenesis, Su-Hyeon Cho, Hyun-Soo Kim, Hye-Yeon Jung, Jae-Il Park, You-Jee Jang, Juhee Ahn, Kil-Nam Kim

Faculty, Staff and Student Publications

The balance between bone-resorbing osteoclasts and bone-forming osteoblasts is essential for the bone remodeling process. This study aimed to investigate the effect of Ishophloroglucin A (IPA) isolated from Ishige okamurae on the function of osteoclasts and osteoblasts in vitro. First, we demonstrated the effect of IPA on osteoclastogenesis in receptor activator of nuclear factor κB ligand (RANKL)-induced RAW 264.7 cells. IPA inhibited the tartrate-resistant acid phosphatase (TRAP) activity and osteoclast differentiation in RANKL-induced RAW 264.7 cells. Moreover, it inhibited the RANKL-induced osteoclast-related factors, such as TRAP, matrix metalloproteinase-9 (MMP-9), and calcitonin receptor (CTR), and transcription factors, such as nuclear factor …

Transcriptome- And Proteome-Wide Association Studies Nominate Determinants Of Kidney Function And Damage, Pascal Schlosser, Jingning Zhang, Hongbo Liu, Aditya L Surapaneni, Eugene P Rhee, Dan E Arking, Bing Yu, Eric Boerwinkle, Paul A Welling, Nilanjan Chatterjee, Katalin Susztak, Josef Coresh, Morgan E Grams

Faculty, Staff and Student Publications

BACKGROUND: The pathophysiological causes of kidney disease are not fully understood. Here we show that the integration of genome-wide genetic, transcriptomic, and proteomic association studies can nominate causal determinants of kidney function and damage.

RESULTS: Through transcriptome-wide association studies (TWAS) in kidney cortex, kidney tubule, liver, and whole blood and proteome-wide association studies (PWAS) in plasma, we assess for effects of 12,893 genes and 1342 proteins on kidney filtration (glomerular filtration rate (GFR) estimated by creatinine; GFR estimated by cystatin C; and blood urea nitrogen) and kidney damage (albuminuria). We find 1561 associations distributed among 260 genomic regions that are …

Integrative Genetic Approach Facilitates Precision Strategies For Acute Myocardial Infarction, Muzamil Khawaja, Rehma Siddiqui, Salim S Virani, Christopher I Amos, Dhrubajyoti Bandyopadhyay, Hafeez Ul Hassan Virk, Mahboob Alam, Hani Jneid, Chayakrit Krittanawong

Faculty, Staff and Students Publications

Acute myocardial infarction remains a significant cause of mortality worldwide and its burden continues to grow. Its pathophysiology is known to be complex and multifactorial, with several acquired and inherited risk factors. As advances in technology and medical therapy continue, there is now increasing recognition of the role that genetics play in the development and management of myocardial infarction. The genetic determinants of acute coronary syndrome are still vastly understudied, but the advent of whole-genome scanning and genome-wide association studies has significantly expanded the current understanding of genetics and simultaneously fostered hope that genetic profiling and gene-guided treatments could substantially …

Systemic Review Of Clot Retraction Modulators, Alaina Guilbeau, Rinku Majumder

School of Graduate Studies Faculty Publications

Through a process termed clot retraction, platelets cause thrombi to shrink and become more stable. After platelets are activated via inside-out signaling, glycoprotein αIIbβIII binds to fibrinogen and initiates a cascade of intracellular signaling that ends in actin remodeling, which causes the platelet to change its shape. Clot retraction is also important for wound healing. Although the detailed molecular biology of clot retraction is only partially understood, various substances and physiological conditions modulate clot retraction. In this review, we describe some of the current literature pertaining to clot retraction modulators. In addition, we discuss compounds from Cudrania trucuspidata, Arctium lappa, …

Quantitative Risk Assessment Of Oocyst Versus Bradyzoite Foodborne Transmission Of Toxoplasma Gondii In Brazil, Sophie Zhu, Elizabeth Vanwormer, Beatriz Martínez-López, Lílian Maria Garcia Bahia-Oliveira, Renato Augusto Damatta, Pedro Souto Rodrigues, Karen Shapiro

School of Veterinary and Biomedical Sciences: Faculty Publications

Toxoplasma gondii is a globally distributed zoonotic protozoan parasite. Infection with T. gondii can cause congenital toxoplasmosis in developing fetuses and acute outbreaks in the general population, and the disease burden is especially high in South America. Prior studies found that the environmental stage of T. gondii, oocysts, is an important source of infection in Brazil; however, no studies have quantified this risk relative to other parasite stages. We developed a Bayesian quantitative risk assessment (QRA) to estimate the relative attribution of the two primary parasite stages (bradyzoite and oocyst) that can be transmitted in foods to people in …

Mdm2/P53 Levels In Bone Marrow Mesenchymal Stromal Cells Are Essential For Maintaining The Hematopoietic Niche In Response To Dna Damage, Rasoul Pourebrahim, Rafael Heinz Montoya, Zoe Alaniz, Lauren Ostermann, Patrick P Lin, Bin Liu, Edward Ayoub, Jared K Burks, Michael Andreeff

Faculty, Staff and Student Publications

Mesenchymal stromal cells (MSCs) are a key component of the bone marrow (BM) niche, providing essential support required for the maintenance of hematopoietic stem cells. To advance our understanding of physiological functions of p53 and Mdm2 in BM-MSCs, we developed traceable conditional mouse models targeting Mdm2 and/or Trp53 in vivo. We demonstrate that Mdm2 is essential for the emergence, maintenance, and hematopoietic support of BM-MSCs. Mdm2 haploinsufficiency in BM-MSCs resulted in genotoxic stress-associated thrombocytopenia, suggesting a functional role for Mdm2 in hematopoiesis. In a syngeneic mouse model of acute myeloid leukemia (AML), Trp53 deletion in BM-MSCs improved survival, and protected …

Drugging Evolution Of Antibiotic Resistance At A Regulatory Network Hub, Yin Zhai, John P Pribis, Sean W Dooling, Libertad Garcia-Villada, P J Minnick, Jun Xia, Jingjing Liu, Qian Mei, Devon M Fitzgerald, Christophe Herman, P J Hastings, Mauro Costa-Mattioli, Susan M Rosenberg

Faculty, Staff and Students Publications

Evolution of antibiotic resistance is a world health crisis, fueled by new mutations. Drugs to slow mutagenesis could, as cotherapies, prolong the shelf-life of antibiotics, yet evolution-slowing drugs and drug targets have been underexplored and ineffective. Here, we used a network-based strategy to identify drugs that block hubs of fluoroquinolone antibiotic-induced mutagenesis. We identify a U.S. Food and Drug Administration- and European Medicines Agency-approved drug, dequalinium chloride (DEQ), that inhibits activation of the

Downregulation Of Fkbp5 Promotes Atrial Arrhythmogenesis, Xiaolei Wang, Jia Song, Yue Yuan, Luge Li, Issam Abu-Taha, Jordi Heijman, Liang Sun, Shokoufeh Dobrev, Markus Kamler, Liang Xie, Xander H T Wehrens, Frank T Horrigan, Dobromir Dobrev, Na Li

Faculty, Staff and Students Publications

BACKGROUND: Atrial fibrillation (AF), the most common arrhythmia, is associated with the downregulation of

METHODS: Right atrial samples from patients with AF were used to assess the protein levels of FKBP5. A cardiomyocyte-specific FKBP5 knockdown mouse model was established by crossbreeding

RESULTS: FKBP5 protein levels were lower in the atrial lysates of patients with paroxysmal AF or long-lasting persistent (chronic) AF. Cardiomyocyte-specific knockdown mice exhibited increased AF inducibility and duration compared with control mice. Enhanced AF susceptibility in cardiomyocyte-specific knockdown mice was associated with the development of action potential alternans and spontaneous Ca

CONCLUSIONS: This is the first study to …

Dual Functions Of Tet1 In Germ Layer Lineage Bifurcation Distinguished By Genomic Context And Dependence On 5-Methylcytosine Oxidation, Bernard K Van Der Veer, Lehua Chen, Colin Custers, Paraskevi Athanasouli, Mariana Schroiff, Riet Cornelis, Jonathan Sai-Hong Chui, Richard H Finnell, Frederic Lluis, Kian Peng Koh

Faculty, Staff and Students Publications

Gastrulation begins when the epiblast forms the primitive streak or becomes definitive ectoderm. During this lineage bifurcation, the DNA dioxygenase TET1 has bipartite functions in transcriptional activation and repression, but the mechanisms remain unclear. By converting mouse embryonic stem cells (ESCs) into neuroprogenitors, we defined how Tet1-/- cells switch from neuroectoderm fate to form mesoderm and endoderm. We identified the Wnt repressor Tcf7l1 as a TET1 target that suppresses Wnt/β-catenin and Nodal signalling. ESCs expressing catalytic dead TET1 retain neural potential but activate Nodal and subsequently Wnt/β-catenin pathways to generate also mesoderm and endoderm. At CpG-poor distal enhancers, TET1 maintains …

Secretogranin Iii Selectively Promotes Vascular Leakage In The Deep Vascular Plexus Of Diabetic Retinopathy, Liyang Ji, Prabuddha Waduge, Yan Wu, Chengchi Huang, Avinash Kaur, Paola Oliveira, Hong Tian, Jinsong Zhang, J Timothy Stout, Christina Y Weng, Keith A Webster, Wei Li

Faculty, Staff and Students Publications

Diabetic retinopathy (DR), a leading cause of vision loss in working-age adults, induces mosaic patterns of vasculopathy that may be associated with spatial heterogeneity of intraretinal endothelial cells. We recently reported that secretogranin III (Scg3), a neuron-derived angiogenic and vascular leakage factor, selectively binds retinal vessels of diabetic but not healthy mice. Here, we investigated endothelial heterogeneity of three retinal vascular plexuses in DR pathogenesis and the therapeutic implications. Our unique in vivo ligand binding assay detected a 22.7-fold increase in Scg3 binding to retinal vessels of diabetic mice relative to healthy mice. Functional immunohistochemistry revealed that Scg3 predominantly binds …

Gabaergic Synaptic Scaling Is Triggered By Changes In Spiking Activity Rather Than Transmitter Receptor Activation, Carlos Gonzalez-Islas, Zahraa Sabra, Ming-Fai Fong, Pernille Bülow, Nicholas Au Yong, Kathrin Engisch, Peter Wenner

Biological Sciences Faculty Publications

Homeostatic plasticity represents a set of mechanisms that are thought to recover some aspect of neural function. One such mechanism called AMPAergic scaling was thought to be a likely candidate to homeostatically control spiking activity. However, recent findings have forced us to reconsider this idea as several studies suggest AMPAergic scaling is not directly triggered by changes in spiking. Moreover, studies examining homeostatic perturbations in vivo have suggested that GABAergic synapses may be more critical in terms of spiking homeostasis. Here we show results that GABAergic scaling can act to homeostatically control spiking levels. We find that increased or decreased …

Normal Saline Remodels The Omentum And Stimulates Its Receptivity For Transcoelomic Metastasis, Hironari Akasaka, Wonjae Lee, Song Yi Ko, Ernst Lengyel, Honami Naora

Faculty, Staff and Student Publications

The omentum contains immune cell structures called milky spots that are niches for transcoelomic metastasis. It is difficult to remove the omentum completely, and there are no effective strategies to minimize the risk of colonization of preserved omental tissues by cancer cells that circulate in the peritoneal fluid. Normal saline is commonly administered into the peritoneal cavity for diagnostic and intraoperative lavage. Here we show that normal saline, when administered into the peritoneal cavity of mice, is prominently absorbed by the omentum, exfoliates its mesothelium, and induces expression of CX3CL1, the ligand for CX3CR1, within and surrounding the omental vasculature. …

Nanoparticle-Enhanced Proton Beam Immunoradiotherapy Drives Immune Activation And Durable Tumor Rejection, Yun Hu, Sébastien Paris, Narayan Sahoo, Genevieve Bertolet, Qi Wang, Qianxia Wang, Hampartsoum B Barsoumian, Jordan Da Silva, Ailing Huang, Denaha J Doss, David P Pollock, Ethan Hsu, Nanez Selene, Claudia S Kettlun Leyton, Tiffany A Voss, Fatemeh Masrorpour, Shonik Ganjoo, Carola Leuschner, Jordan T Pietz, Nahum Puebla-Osorio, Saumil Gandhi, Quynh-Nhu Nguyen, Jing Wang, Maria Angelica Cortez, James W Welsh

Faculty, Staff and Student Publications

The combination of radiation therapy (RT) and immunotherapy has emerged as a promising treatment option in oncology. Historically, x-ray radiation (XRT) has been the most commonly used form of RT. However, proton beam therapy (PBT) is gaining recognition as a viable alternative, as it has been shown to produce similar outcomes to XRT while minimizing off-target effects. The effects of PBT on the antitumor immune response have only just begun to be described, and to our knowledge no studies to date have examined the effect of PBT as part of a combinatorial immunoradiotherapeutic strategy. Here, using a 2-tumor model of …

Sodium-Glucose Cotransporter 2 Inhibitors To Decrease The Uric Acid Concentration-A Novel Mechanism Of Action, Anna Kochanowska, Przemysław Rusztyn, Karolina Szczerkowska, Stanisław Surma, Aleksandra Gąsecka, Miłosz J Jaguszewski, Łukasz Szarpak, Krzysztof J Filipiak

Faculty, Staff and Students Publications

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are glucose-lowering agents whose positive impact on cardiovascular risk has been described extensively. Not only do they influence lipid profile, blood pressure, atherosclerosis risk, hemoglobin level, and insulin resistance, but they also reduce cardiovascular events, all-cause mortality, and hospitalization rates. Some of these effects may be due to their impact on serum uric acid (SUA) concentration. Findings from nine meta-analyses showed that, indeed, SGLT2is significantly reduce SUA. The data on the drug- and dose-dependency of this effect were inconclusive. Several factors alternating the beneficial effects of SGLT2is on SUA, such as glycated hemoglobin concentration (HbA1c), …

Sirna Drug Delivery Across The Blood–Brain Barrier In Alzheimer's Disease, Muhammad Imran Sajid, Fahad Sultan Sheikh, Faiza Anis, Nourina Nasim, Rachita K. Sumbria, Surya M. Nauli, Rakesh K. Tiwari

Pharmacy Faculty Articles and Research

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a few FDA-approved drugs that provide modest symptomatic benefits and only two FDA-approved disease-modifying treatments for AD. The advancements in understanding the causative genes and non-coding sequences at the molecular level of the pathophysiology of AD have resulted in several exciting research papers that employed small interfering RNA (siRNA)-based therapy. Although siRNA is being sought by academia and biopharma industries, several challenges still need to be addressed. We comprehensively report the latest advances in AD pathophysiology, druggable targets, ongoing clinical trials, and the siRNA-based approaches across the blood–brain barrier for addressing …

Effects Of Age On Amplitude-Modulated Cvemp Temporal Modulation Transfer Function, Raghav H. Jha

Dissertations, 2020-current

With the aging population on the rise, the need for effective assessment tools to identify risk factors for falls among the elderly is paramount. One independent risk factor for falls is vestibular impairment, but the available vestibular diagnostic tests have limitations. A promising new methodology: amplitude-modulated tones to elicit a vestibular-evoked myogenic potential (AMcVEMP), offers a more detailed examination of vestibular (sacculo-collic reflex) functions. This method assesses non-linearities, synchrony, and magnitude, providing a more thorough evaluation compared to the conventional transient cVEMP. So far, AMcVEMP has only been utilized in young adults.

The current study aimed to investigate the impact …

Slc7a11 Expression Level Dictates Differential Responses To Oxidative Stress In Cancer Cells, Yuelong Yan, Hongqi Teng, Qinglei Hang, Lavanya Kondiparthi, Guang Lei, Amber Horbath, Xiaoguang Liu, Chao Mao, Shiqi Wu, Li Zhuang, M James You, Masha V Poyurovsky, Li Ma, Kellen Olszewski, Boyi Gan

Faculty, Staff and Student Publications

The cystine transporter solute carrier family 7 member 11 (SLC7A11; also called xCT) protects cancer cells from oxidative stress and is overexpressed in many cancers. Here we report a surprising finding that, whereas moderate overexpression of SLC7A11 is beneficial for cancer cells treated with H2O2, a common oxidative stress inducer, its high overexpression dramatically increases H2O2-induced cell death. Mechanistically, high cystine uptake in cancer cells with high overexpression of SLC7A11 in combination with H2O2 treatment results in toxic buildup of intracellular cystine and other disulfide molecules, NADPH depletion, redox system collapse, and rapid cell death (likely disulfidptosis). We further show …

An Improved Reporter Identifies Ruxolitinib As A Potent And Cardioprotective Camkii Inhibitor, Oscar E Reyes Gaido, Nikoleta Pavlaki, Jonathan M Granger, Olurotimi O Mesubi, Bian Liu, Brian L Lin, Alan Long, David Walker, Joshua Mayourian, Kate L Schole, Chantelle E Terrillion, Lubika J Nkashama, Mohit M Hulsurkar, Lauren E Dorn, Kimberly M Ferrero, Richard L Huganir, Frank U Müller, Xander H T Wehrens, Jun O Liu, Elizabeth D Luczak, Vassilios J Bezzerides, Mark E Anderson

Faculty, Staff and Students Publications

Ca2+/calmodulin-dependent protein kinase II (CaMKII) hyperactivity causes cardiac arrhythmias, a major source of morbidity and mortality worldwide. Despite proven benefits of CaMKII inhibition in numerous preclinical models of heart disease, translation of CaMKII antagonists into humans has been stymied by low potency, toxicity, and an enduring concern for adverse effects on cognition due to an established role of CaMKII in learning and memory. To address these challenges, we asked whether any clinically approved drugs, developed for other purposes, were potent CaMKII inhibitors. For this, we engineered an improved fluorescent reporter, CaMKAR (CaMKII activity reporter), which features superior sensitivity, kinetics, and …

Arginine Depletion Attenuates Renal Cystogenesis In Tuberous Sclerosis Complex Model, Athar Amleh, Hadass Pri Chen, Lana Watad, Ifat Abramovich, Bella Agranovich, Eyal Gottlieb, Iddo Z Ben-Dov, Morris Nechama, Oded Volovelsky

Faculty, Staff and Student Publications

Cystic kidney disease is a leading cause of morbidity in patients with tuberous sclerosis complex (TSC). We characterize the misregulated metabolic pathways using cell lines, a TSC mouse model, and human kidney sections. Our study reveals a substantial perturbation in the arginine biosynthesis pathway in TSC models with overexpression of argininosuccinate synthetase 1 (ASS1). The rise in ASS1 expression is dependent on the mechanistic target of rapamycin complex 1 (mTORC1) activity. Arginine depletion prevents mTORC1 hyperactivation and cell cycle progression and averts cystogenic signaling overexpression of c-Myc and P65. Accordingly, an arginine-depleted diet substantially reduces the TSC cystic load in …

Il-11 Induces Nlrp3 Inflammasome Activation In Monocytes And Inflammatory Cell Migration To The Central Nervous System, Maryamsadat Seyedsadr, Yan Wang, Manal Elzoheiry, Sowmya Shree Gopal, Soohwa Jang, Gayel Duran, Inna Chervoneva, Ezgi Kasimoglu, John A. Wrobel, Daniel Hwang, James Garifallou, Xin Zhang, Tabish H. Khan, Ulrike Lorenz, Maureen Su, Jenny P. Ting, Bieke Broux, A M Rostami, Dhanashri Miskin, Silva Markovic-Plese

Department of Neurology Faculty Papers

The objective of this study is to examine IL-11-induced mechanisms of inflammatory cell migration to the central nervous system (CNS). We report that IL-11 is produced at highest frequency by myeloid cells among the peripheral blood mononuclear cell (PBMC) subsets. Patients with relapsing-remitting multiple sclerosis (RRMS) have an increased frequency of IL-11+ monocytes, IL-11+ and IL-11R+ CD4+ lymphocytes, and IL-11R+ neutrophils in comparison to matched healthy controls. IL-11+ and granulocyte-macrophage colony-stimulating factor (GM-CSF)+ monocytes, CD4+ lymphocytes, and neutrophils accumulate in the cerebrospinal fluid (CSF). The effect of IL-11 in-vitro stimulation, examined using single-cell RNA sequencing, revealed the highest number of …

Pentoxifylline For Treatment Of Sepsis And Necrotising Enterocolitis In Neonates, Mohan Pammi, Khalid N Haque

Faculty, Staff and Students Publications

BACKGROUND: Mortality and morbidity due to neonatal sepsis and necrotising enterocolitis (NEC) remain high despite the use of potent antimicrobial agents. Agents that modulate inflammation may improve outcomes. Pentoxifylline (PTX), a phosphodiesterase inhibitor, is one such agent. This is an update of a review first published in 2003 and updated in 2011 and 2015.

OBJECTIVES: To assess the effectiveness and safety of intravenous PTX as an adjunct to antibiotic therapy on mortality and morbidity in neonates with suspected or confirmed sepsis and neonates with NEC.

SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, and trial registries in July 2022. We …

Anticancer Potential Of Natural Chalcones: In Vitro And In Vivo Evidence, Radka Michalkova, Ladislav Mirossay, Martin Kello, Gabriela Mojzisova, Janette Baloghova, Anna Podracka, Jan Mojzis

Faculty, Staff and Student Publications

There is no doubt that significant progress has been made in tumor therapy in the past decades. However, the discovery of new molecules with potential antitumor properties still remains one of the most significant challenges in the field of anticancer therapy. Nature, especially plants, is a rich source of phytochemicals with pleiotropic biological activities. Among a plethora of phytochemicals, chalcones, the bioprecursors of flavonoid and isoflavonoids synthesis in higher plants, have attracted attention due to the broad spectrum of biological activities with potential clinical applications. Regarding the antiproliferative and anticancer effects of chalcones, multiple mechanisms of action including cell cycle …

Sox7 Deficiency Causes Ventricular Septal Defects Through Its Effects On Endocardial-To-Mesenchymal Transition And The Expression Of Wnt4 And Bmp2, Andrés Hernández-García, Katherine E Pendleton, Sangbae Kim, Yumei Li, Bum J Kim, Hitisha P Zaveri, Valerie K Jordan, Aliska M Berry, M Cecilia Ljungberg, Rui Chen, Rainer B Lanz, Daryl A Scott

Faculty, Staff and Students Publications

SOX7 is a transcription factor-encoding gene located in a region on chromosome 8p23.1 that is recurrently deleted in individuals with ventricular septal defects (VSDs). We have previously shown that Sox7-/- embryos die of heart failure around E11.5. Here, we demonstrate that these embryos have hypocellular endocardial cushions with severely reduced numbers of mesenchymal cells. Ablation of Sox7 in the endocardium also resulted in hypocellular endocardial cushions, and we observed VSDs in rare E15.5 Sox7flox/-;Tie2-Cre and Sox7flox/flox;Tie2-Cre embryos that survived to E15.5. In atrioventricular explant studies, we showed that SOX7 deficiency leads to a severe reduction in endocardial-to-mesenchymal transition (EndMT). RNA-seq …

Evidence-Based Guide To Using Artificial Introns For Tissue-Specific Knockout In Mice, Elena Mcbeath, Keigi Fujiwara, Marie-Claude Hofmann

Faculty, Staff and Student Publications

Up until recently, methods for generating floxed mice either conventionally or by CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-Cas9 (CRISPR-associated protein 9) editing have been technically challenging, expensive and error-prone, or time-consuming. To circumvent these issues, several labs have started successfully using a small artificial intron to conditionally knockout (KO) a gene of interest in mice. However, many other labs are having difficulty getting the technique to work. The key problem appears to be either a failure in achieving correct splicing after the introduction of the artificial intron into the gene or, just as crucial, insufficient functional KO of the …

Novel Potential Targets For Function-Promoting Therapies: Orphan Nuclear Receptors, Anti-Inflammatory Drugs, Troponin Activators, Mas Receptor Agonists, And Urolithin A, Waly Dioh, Vihang Narkar, Anurag Singh, Fady Malik, Luigi Ferrucci, Cendrine Tourette, Jean Mariani, Rob Van Maanen, Roger A Fielding

Faculty, Staff and Student Publications

In recent years, several new classes of therapies have been investigated with their potential for restoring or improving physical functioning in older adults. These have included Mas receptor agonists, regulators of mitophagy, skeletal muscle troponin activators, anti-inflammatory compounds, and targets of orphan nuclear receptors. The present article summarizes recent developments of the function-promoting effects of these exciting new compounds and shares relevant preclinical and clinical data related to their safety and efficacy. The development of novel compounds in this area is expanding and likely will need the advent of a new treatment paradigm for age-associated mobility loss and disability.

Dietary Sources Of Linoleic Acid (La) Differ By Race/Ethnicity In Adults Participating In The National Health And Nutrition Examination Survey (Nhanes) Between 2017-2018, Shabnam R Momin, Mackenzie K Senn, Ani Manichaikul, Chaojie Yang, Rasika Mathias, Mimi Phan, Stephen S Rich, Susan Sergeant, Michael Seeds, Lindsay Reynolds, Floyd H Chilton, Alexis C Wood

Faculty, Staff and Students Publications

Linoleic acid (LA) is a primary n-6 polyunsaturated fatty acid (PUFA), which is of interest to nutritional professionals as it has been associated with health outcomes. However, as some LA-rich foods offer protection against chronic diseases such as CVD (e.g., fatty fish), while others increase risk (e.g., red meat), the individual foods contributing to LA intake may be an important factor to consider. Therefore, this analysis sought to examine whether there are racial/ethnic differences in the proportion of overall LA intake accounted for by individual food groups, via a cross-sectional analysis of 3815 adults participating in the National Health …