Chemicals and Drugs Commons^™

Sk609, A Novel Dopamine D3 Receptor Agonist And Norepinephrine Transporter Blocker With Putative Pro-Cognitive Actions, Does Not Induce Psychostimulant-Like Increases In Risky Choice During Probabilistic Discounting, Christopher P. Knapp, Brooke Fallon, Sandhya Kortagere, Barry D. Waterhouse, Stan B Floresco, Rachel L Navarra

Rowan-Virtua School of Osteopathic Medicine Departmental Research

RATIONALE: Psychostimulants, such as amphetamine (AMPH) and methylphenidate (MPH), non-selectively elevate extracellular concentrations of the catecholamine neurotransmitters, dopamine (DA) and norepinephrine (NE), and are common pharmacological strategies used to improve prefrontal cortex (PFC)-dependent cognitive dysfunction. However, this approach can be problematic given AMPH has been shown to increase preference for risky choices in a rodent assay of risk/reward decision making. SK609 is a novel NE reuptake blocker that selectively activates DA D3 receptors without affinity for the DA transporter. SK609 has been shown to improve cognitive performance without increasing psychostimulant-like spontaneous locomotor activity, suggesting SK609 may benefit neurocognitive function without …

Nuclear Expression Of Dynamin 2 Is Associated With Tumor Aggressiveness In Bladder Cancer Patients: A Bioinformatics And Experimental Approach, Mahdieh Razmi, Leili Saeednejad Zanjani, Mandana Rahimi, Roya Sajed, Sadegh Safaei, Zahra Madjd, Roya Ghods

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Dynamin 2 (DNM2) is aberrantly expressed in different malignancies and exerts a function in tumor progression.

AIMS: This study, for the first time, aimed to evaluate the clinical and prognostic value of DNM2 in the pathophysiology of bladder cancer using bioinformatics analysis and experimental evaluation.

METHODS AND RESULTS: We analyzed gene expression of DNM2 in bladder tumor by GEPIA2 and GENT2 platforms. Cluster subnetworks were recognized from the protein-protein interaction (PPI) network using the MCODE plugin to screen the key genes. Subsequently, the pathway enrichment analysis was evaluated. Then, the immunohistochemical examination was conducted on 209 paraffin-embedded bladder cancer …

Opa1 And Disease-Causing Mutants Perturb Mitochondrial Nucleoid Distribution, J. Macuada, I. Molina-Riquelme, G. Vidal, N. Pérez-Bravo, C. Vásquez-Trincado, G. Aedo, D. Lagos, P. Yu-Wai-Man, R. Horvath, T. J. Rudge, B. Cartes-Saavedra, V. Eisner

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Optic atrophy protein 1 (OPA1) mediates inner mitochondrial membrane (IMM) fusion and cristae organization. Mutations in OPA1 cause autosomal dominant optic atrophy (ADOA), a leading cause of blindness. Cells from ADOA patients show impaired mitochondrial fusion, cristae structure, bioenergetic function, and mitochondrial DNA (mtDNA) integrity. The mtDNA encodes electron transport chain subunits and is packaged into nucleoids spread within the mitochondrial population. Nucleoids interact with the IMM, and their distribution is tightly linked to mitochondrial fusion and cristae shaping. Yet, little is known about the physio-pathological relevance of nucleoid distribution. We studied the effect of OPA1 and ADOA-associated mutants on …

Low Concentrations Of Hexavalent Chromium In Drinking Water Induce Alzheimer’S Disease Neuropathology: Using A Toxic Aging Coin Approach To Assess Hexavalent Chromium Neurotoxicity, Liam Buchanan, Samuel Vielee, Spencer Roof, Haiyan Lu, Jamie L Young, Idoia Meaza Isusi, Aggie Williams, Joseph Kouokam, Sandra Wise, Luping Guo, Jun Cai, John Wise, John P. Wise Jr.

The Cardinal Edge

Introduction: We are currently facing an aging crisis, as 20% of the U.S. population will be geriatric (65+) by 2030. This growing geriatric population will result in increasing prevalence of age-related diseases, coinciding with increasingly prevalent environmental pollution. Environmental pollution is a ubiquitous health threat that affects people at all ages and contributes to aging pathology. However, geriatric individuals are likely more susceptible to the negative health effects from environmental pollution. The distinct effects of environmental pollutants across age groups are currently understudied. We use a Toxic Aging Coin approach to investigate: 1) how age impacts toxicity (heads), …

Identification Of New Leads Against Ubiquitin Specific Protease-7 (Usp7): A Step Towards The Potential Treatment Of Cancers, Sumaira Javaid, Seema Zadi, Muhammad Awais, Atai-Tul Wahab, Humaira Zafar, Innokentiy Maslennikov, M. Iqbal Choudhary

Pharmacy Faculty Articles and Research

Ubiquitin-specific protease-7 (USP7) is an important drug target as it regulates multiple proteins and genes (such as MDM2 and p53) with roles in cancer progression. Its inhibition can hinder the function of oncogenes, increase tumor suppression, and enhance immune response. The current study was designed to express USP7 in a prokaryotic system, followed by screening of small molecules against it using biophysical methods, primarily STD-NMR technique. Among them, 12 compounds showed interaction with USP7 as inferred from NMR-based screening. These compounds further caused destabilization of USP7 by reducing its melting temperature (T_m) up to 6 °C in …

Post-Transcriptional Methylation Of Mitochondrial-Trna Differentially Contributes To Mitochondrial Pathology, Sunita Maharjan, Howard Gamper, Yuka Yamaki, Thomas W. Christian, Robert Y. Henley, Nan-Sheng Li, Takeo Suzuki, Tsutomu Suzuki, Joseph A. Piccirilli, Meni Wanunu, Erin L. Seifert, Douglas C. Wallace, Ya-Ming Hou

Department of Biochemistry and Molecular Biology Faculty Papers

Human mitochondrial tRNAs (mt-tRNAs), critical for mitochondrial biogenesis, are frequently associated with pathogenic mutations. These mt-tRNAs have unusual sequence motifs and require post-transcriptional modifications to stabilize their fragile structures. However, whether a modification that stabilizes a wild-type (WT) mt-tRNA would also stabilize its pathogenic variants is unknown. Here we show that the N¹-methylation of guanosine at position 9 (m¹G9) of mt-Leu(UAA), while stabilizing the WT tRNA, has a destabilizing effect on variants associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). This differential effect is further demonstrated, as removal of the m¹G9 …

Extraction Method Effects On Structural Properties And Functional Characteristics Of Dietary Fiber Extracted From Ginseng Residue, Xiaoyu Feng, Kashif Ameer, Karna Ramachandraiah, Guihun Jiang

School of Medicine Faculty Publications

In this research, the dietary fibers (DFs) from ginseng residue were extracted by employing three different extraction methods (alkaline: AL, acidic: AC, enzymatic: EN). The extracted DFs were characterized in terms of their structural and functional properties. The results clearly showed that, regardless of the extraction methods, all DF samples exhibited representative infrared spectral features. The DF extracted by AC (citric acid) had more porous structures with a looser configuration, in conjunction with high apparent viscosity, whereas the DF extracted by EN (α-amylase and protease) exhibited higher thermal stability. Moreover, the monosaccharide composition of the DF samples was significantly influenced …

Cryo-Em Analysis Of Pseudomonas Phage Pa193 Structural Components, Stephano M. Iglesias, Chun-Feng Hou, Johnny Reid, Evan Schauer, Renae Geier, Angela Soriaga, Lucy Sim, Lucy Gao, Julian Whitelegge, Pierre Kyme, Deborah Birx, Sebastien Lemire, Gino Cingolani

Department of Biochemistry and Molecular Biology Faculty Papers

The World Health Organization has designated Pseudomonas aeruginosa as a critical pathogen for the development of new antimicrobials. Bacterial viruses, or bacteriophages, have been used in various clinical settings, commonly called phage therapy, to address this growing public health crisis. Here, we describe a high-resolution structural atlas of a therapeutic, contractile-tailed Pseudomonas phage, Pa193. We used bioinformatics, proteomics, and cryogenic electron microscopy single particle analysis to identify, annotate, and build atomic models for 21 distinct structural polypeptide chains forming the icosahedral capsid, neck, contractile tail, and baseplate. We identified a putative scaffolding protein stabilizing the interior of the capsid 5-fold …

The Effects Of Cannabinoids On Migration-Related Protein Expression In Ewing’S Sarcoma, Allison Lashall

Theses

Ewing’s sarcoma is an aggressive pediatric bone cancer that has low five-year survival rates, primarily due to metastatic disease and resistance of recurring tumors to traditional treatment options; therefore, novel treatment options are needed. The compound cannabidiol (CBD) has been shown to reduce cell viability, migration, and invasion in several tumor types, though the cellular mechanism of action is not well understood. Our lab has demonstrated the ability of CBD to reduce viability, migration, and invasion of Ewing’s sarcoma cells in vitro and is investigating differential protein and cytokine expression of known mediators of migration, such as intercellular adhesion molecule …

Authentication Of Shallots From Brebes Using Gas Chromatography Fingerprinting Technique Combined With Chemometrics, Yana Setyani Pradina, Adelia Puteri, Gina Fauzia Rachma, Nazwa Balqis, Gerli Puspita Anggraini, Hendri Wasito

Makara Journal of Science

Shallots from Brebes, also called Bima Brebes, have a more pungent aroma compared to other varieties. Its high demand results in increased prices in the market, leading to frequent cases of fraud wherein Bima Brebes shallots are replaced with other types of shallots. This study aimed to develop an analytical method using gas chromatography–flame ionization detector (GC-FID) fingerprinting combined with chemometrics to authenticate Bima Brebes shallots. Essential oils were extracted through ultrasonic hydrodistillation, followed by organoleptic, refractive index, GC-FID fingerprinting and chemometric analysis. The yield value of the five studied shallot varieties ranged from 0.02% to 0.08% w/w. Meanwhile, the …

Predicting Mutation-Induced Allosteric Changes In Structures And Conformational Ensembles Of The Abl Kinase Using Alphafold2 Adaptations With Alanine Sequence Scanning, Nishank Raisinghani, Mohammed Alshahrani, Grace Gupta, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Despite the success of AlphaFold2 approaches in predicting single protein structures, these methods showed intrinsic limitations in predicting multiple functional conformations of allosteric proteins and have been challenged to accurately capture the effects of single point mutations that induced significant structural changes. We examined several implementations of AlphaFold2 methods to predict conformational ensembles for state-switching mutants of the ABL kinase. The results revealed that a combination of randomized alanine sequence masking with shallow multiple sequence alignment subsampling can significantly expand the conformational diversity of the predicted structural ensembles and capture shifts in populations of the active and inactive ABL states. …

Investigation Of The Endogenous Opioid Neural Circuitry In Pain, Erin Nicole Bobeck

Funded Research Records

No abstract provided.

Engineered Nls-Chimera Downregulates Expression Of Aggregation-Prone Endogenous Fus, Miyuki Hayashi, Amandeep Girdhar, Ying-Hui Ko, Kevin Kim, Jacquelyn Depierro, Joseph R. Buchler, Nikhita Arunprakash, Aditya Bajaj, Gino Cingolani, Lin Guo

Department of Biochemistry and Molecular Biology Faculty Papers

Importin β-superfamily nuclear import receptors (NIRs) mitigate mislocalization and aggregation of RNA-binding proteins (RBPs), like FUS and TDP-43, which are implicated in neurodegenerative diseases. NIRs potently disaggregate RBPs by recognizing their nuclear localization signal (NLS). However, disease-causing mutations in NLS compromise NIR binding and activity. Here, we define features that characterize the anti-aggregation activity of NIR and NLS. We find that high binding affinity between NIR and NLS, and optimal NLS location relative to the aggregating domain plays a role in determining NIR disaggregation activity. A designed FUS chimera (FUS_IBB), carrying the importin β binding (IBB) domain, is …

Aars Online: A Collaborative Database On The Structure, Function, And Evolution Of The Aminoacyl-Trna Synthetases, Jordan Douglas, Haissi Cui, John J. Perona, Oscar Vargas-Rodriguez, Henna Tyynismaa, Claudia Alvarez Carreño, Jiqiang Ling, Lluís Ribas De Pouplana, Xiang-Lei Yang, Michael Ibba, Hubert Becker, Frédéric Fischer, Marie Sissler, Charles W. Carter Jr., Peter Wills

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The aminoacyl-tRNA synthetases (aaRS) are a large group of enzymes that implement the genetic code in all known biological systems. They attach amino acids to their cognate tRNAs, moonlight in various translational and non-translational activities beyond aminoacylation, and are linked to many genetic disorders. The aaRS have a subtle ontology characterized by structural and functional idiosyncrasies that vary from organism to organism, and protein to protein. Across the tree of life, the 22 coded amino acids are handled by 16 evolutionary families of Class I aaRS and 21 families of Class II aaRS. We introduce AARS Online, an interactive Wikipedia-like …

Perilous Consequences Of Chemotherapy Induced Alopecia In Afflicted Cancer Survivors: A Comprehensive State Of The Art Review, Salma A. Fereig, Mona Gamal Arafa, Ghada Mamdouh Elzaafarany, Mona Mohamed Ahmed Abdelmottaleb, John Youshia

Pharmacy

Due to researchers’ great efforts during previous and current centuries to cure cancer, a remarkable increase in the number of cancer survivors has been observed. However, side effects of chemotherapeutic agents greatly affect the quality of life of cancer cases, usually referred to as cancer stigma, the most psychologically traumatizing of which is chemotherapy-induced alopecia (anagen effluvium). Unfortunately, there is no preventive protocol for chemotherapy-induced alopecia to date. The only suggested technique is vasoconstriction by scalp cooling during and after chemotherapy sessions to minimize the absorption of cytotoxic agents within the hair follicle area; a technique that is not very …

Keratin 17 Is A Prognostic And Predictive Biomarker In Pancreatic Ductal Adenocarcinoma, Lyanne Delgado-Coka, Lucia Roa-Peña, Sruthi Babu, Michael Horowitz, Emanuel Petricoin, Lynn Matrisian, Edik Blais, Natalia Marchenko, Felicia Allard, Ali Akalin, Wei Jiang, Md, Phd, Brent Larson, Andrew Hendifar, Vincent Picozzi, Minsig Choi, Kenneth Shroyer, Luisa Escobar-Hoyos

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

OBJECTIVES: To determine the role of keratin 17 (K17) as a predictive biomarker for response to chemotherapy by defining thresholds of K17 expression based on immunohistochemical tests that could be used to optimize therapeutic intervention for patients with pancreatic ductal adenocarcinoma (PDAC).

METHODS: We profiled K17 expression, a hallmark of the basal molecular subtype of PDAC, by immunohistochemistry in 2 cohorts of formalin-fixed, paraffin-embedded PDACs (n = 305). We determined a K17 threshold of expression to optimize prognostic stratification according to the lowest Akaike information criterion and explored the potential relationship between K17 and chemoresistance by multivariate predictive analyses.

RESULTS: …

Exploiting The Heavy Chain Glycans For The Improvement Of Radioimmunoconjugates, Cindy Rodriguez

Dissertations, Theses, and Capstone Projects

Radiolabeled antibodies have become indispensable tools in nuclear medicine. However, the natural roles of antibodies within the immune system mean that they have several intrinsic limitations as a platform for radiopharmaceuticals. A handful of recent preclinical studies suggest that binding by FcR and particularly FcyRI can affect the pharmacokinetic profiles of 89Zr-labeled radioimmunoconjugates. Fc receptors (FcR) are responsible for many of the interactions between immunoglobulins (IgG) and immune cells. In biomedicine, this interplay is critical to the activity of several types of immunotherapeutics; however, relatively little is known about how FcRs affect the in vivo performance of radiolabeled antibodies. Antibodies …

Incorporating Solvation Thermodynamic Mapping In Computer-Aided Drug Design, Yeonji Ji

Dissertations, Theses, and Capstone Projects

Advancements in computational techniques have revolutionized structure-based drug design, substantially improving the efficiency and effectiveness of the drug discovery process by reducing time, costs, and labor requirements. These advancements include various methods, such as investigating small molecule ligands binding to proteins, exploring alternative protein conformations, and solvation mapping on the protein surfaces. Among these methods, understanding the correlation between protein-ligand binding and the role of solvation is important.

A fundamental concept in protein-ligand binding is shape and electrostatic complementarity, which is complicated by the inherent flexibility of proteins. In the absence of small molecule ligands, proteins are complementary to surface …

In Silico Modelling And Docking Simulation Of Egfr-Targeted Diphtheria Toxin Chimera With Various Targeting Moieties, Muhammad Afif Naufal Bmed, Benedictus Ansell Susanto Bmed, Talitha Dinda Gunawan Bmed, Azhar Ridha Lukman Bmed, Alifa Rahma Rizqina Bmed, Muhammad Misbahul Fuad Bmed

Indonesian Journal of Medical Chemistry and Bioinformatics

Introduction: Cancer is a major etiology of death worldwide due to high mortality and suboptimal medicine. However, an emerging field, targeted therapy enabled a more selective and effective therapeutic action. This article aims to analyze in-silico the hypothetical targeted therapy agent that is combinations of conjugate consisting of EGFR targeting moieties and diphtheria toxin (DT-390).

Method: Our novel peptide is a conjugate of a novel EGFR targeting peptide and DT-390, forming a chimera. The tertiary structure was predicted using AlphaFold 2.0. The best IDDT scoring and stereochemistry profiles were utilized. The HADDOCK2.4 webserver modelled the docking between our …

Bp1003 Decreases Stat3 Expression And Its Pro-Tumorigenic Functions In Solid Tumors And The Tumor Microenvironment, Maria Gagliardi, Rhonda Kean, Bingbing Dai, Jithesh Augustine, Michael Roberts, Jason Fleming, D. Craig Hooper, Ana Ashizawa

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Overexpression and aberrant activation of signal transducer and activator of transcription 3 (STAT3) contribute to tumorigenesis, drug resistance, and tumor-immune evasion, making it a potential cancer therapeutic target. BP1003 is a neutral liposome incorporated with a nuclease-resistant P-ethoxy antisense oligodeoxynucleotide (ASO) targeting the STAT3 mRNA. Its unique design enhances BP1003 stability, cellular uptake, and target affinity. BP1003 efficiently reduces STAT3 expression and enhances the sensitivity of breast cancer cells (HER2⁺, triple negative) and ovarian cancer cells (late stage, invasive ovarian cancer) to paclitaxel and 5-fluorouracil (5-FU) in both 2D and 3D cell cultures. Similarly, ex vivo and in …

Design, Synthesis, And Evaluation Of Oleyl-Wrh Peptides For Sirna Delivery, Mrigank Shekhar Rai, Muhammad Imran Sajid, Jonathan Moreno, Keykavous Parang, Rakesh Kumar Tiwari

Pharmacy Faculty Articles and Research

Delivering nucleic acid therapeutics across cell membranes is a significant challenge. Cell-penetrating peptides (CPPs) containing arginine (R), tryptophan (W), and histidine (H) show promise for siRNA delivery. To improve siRNA delivery and silence a model STAT3 gene, we hypothesized that oleyl acylation to CPPs, specifically (WRH)n, would enhance STAT3 silencing efficiency in breast and ovarian cancer cells. Using Fmoc/tBu solid-phase peptide chemistry, we synthesized, purified, and characterized the oleyl-conjugated (WRH)n (n = 1–4) peptides. The peptide/siRNA complexes were non-cytotoxic at N/P 40 (~20 μM) against MDA-MB-231, MCF-7, SK-OV-3, and HEK-293 cells after 72 h incubation. All peptide/siRNA complexes showed serum …

Preventive Effects Of Quercetin On The Leaky Gut By Suppression Of Il-1beta-Induced Transcription Factors Involved In An Inflammatory Pathway In Colonic Epithelial Cells, Wannaporn Chayalak, Sumpun Thammacharoen, Chatsri Deachapunya, Sutthasinee Poonyachoti

The Thai Journal of Veterinary Medicine

Flavonol quercetin (Q), found in vegetables and fruits, demonstrates the most potent anti-inflammatory effect. The preventive effect and cellular mechanisms of Q (Q1, Q10, and Q100 µM) on IL-1β induced leaky gut via the signaling molecules of inflammatory pathway, NF-κB p65-iκB/or p38/ERK1/2/MLCK/phospho(p)-MLC were investigated in Caco-2 cells. The cytotoxic effect of Q was initially determined by MTT assay. Transepithelial electrical resistance (TER) and apical-to-basolateral fluorescein isothiocyanate-labeled dextran (FD-4) flux were used to determine paracellular permeability. The protein expression of signaling molecules was examined by Western blot analysis, and their target MLCK mRNA expression was determined using real-time PCR. All Q …

Novel Mechanisms For The Neural Control Of Breathing In Acute Lung Injury, Kajal Kamra

Theses & Dissertations

Acute lung injury (ALI) triggers inflammation that disrupts the normal alveolar-capillary endothelial barrier, impairing gas exchange and causing hypoxemia, which reflexively increases respiration. An elevated respiratory rate (fR) usually develops within hours to days following ALI. This acute respiratory failure disorder affects approximately 200,000 new cases annually in the US and accounts for 10% of ICU admissions, with high morbidity and mortality. The neural mechanisms underlying respiratory dysfunction post-ALI are not fully understood. My doctoral dissertation aimed to investigate the mediators of abnormal ventilation during ALI. Systemic hypoxia stimulates the carotid body (CB) chemoreflex, a crucial protective reflex that maintains …

Inactivated Rabies-Based Lassa Fever Virus Vaccine Candidate Lassarab Protects Nonhuman Primates From Lethal Disease, Gabrielle Scher, Catherine Yankowski, Drishya Kurup, Nicole Josleyn, Eric Wilkinson, Jay Wells, Jesse Steffens, Ginger Lynn, Sean Vantongeren, Xiankun Zeng, Nancy Twenhafel, Kathleen Cashman, Matthias Schnell

Department of Microbiology and Immunology Faculty Papers

Lassa fever virus (LASV), a member of the Arenavirus family, is the etiological agent of Lassa fever, a severe hemorrhagic disease that causes considerable morbidity and mortality in the endemic areas of West Africa. LASV is a rodent-borne CDC Tier One biological threat agent and is on the World Health Organization's (WHO) Priority Pathogen list. Currently, no FDA-licensed vaccines or specific therapeutics are available. Here, we describe the efficacy of a deactivated rabies virus (RABV)-based vaccine encoding the glycoprotein precursor (GPC) of LASV (LASSARAB). Nonhuman primates (NHPs) were administered a two-dose regimen of LASSARAB or an irrelevant RABV-based vaccine to …

Enpp1 Enzyme Replacement Therapy Improves Ectopic Calcification But Does Not Rescue Skeletal Phenotype In A Mouse Model For Craniometaphyseal Dysplasia, Ernst Reichenberger, Kevin O'Brien, Ayano Hatori, Thomas Carpenter, Koen Van De Wetering, Lisa Flaman, Jennifer Howe, Daniel Ortiz, Yves Sabbagh, I-Ping Chen

Jefferson Institute of Molecular Medicine Papers and Presentations

Craniometaphyseal dysplasia (CMD) is a rare genetic bone disorder, characterized by progressive thickening of craniofacial bones and flared metaphyses of long bones. Craniofacial hyperostosis leads to the obstruction of neural foramina and neurological symptoms such as facial palsy, blindness, deafness, or severe headache. Mutations in ANKH (mouse ortholog ANK), a transporter of small molecules such as citrate and ATP, are responsible for autosomal dominant CMD. Knock-in (KI) mice carrying an ANK_F377del mutation (Ank^KI/KI) replicate many features of human CMD. Pyrophosphate (PPi) levels in plasma are significantly reduced in Ank^KI/KI mice. PPi is a potent inhibitor of …

Integration Of Machine Learning And Quantum Mechanical Calculations For De Novo Drug Design, Ayesh Madushanka Mahamada Kalapuwage

Chemistry Theses and Dissertations

The drug designing process is an intricate and resource-intensive endeavor, spanning approximately 12 years to transform a lead compound into a functional drug. Computer-aided drug design (CADD) plays a fundamental role in this process, mitigating the risk of failures in the later stage and saving valuable time and money. In the last decade, Artificial intelligence (AI) has provided remarkable alternatives for practical challenges, including drug design. Simultaneously, advanced QM calculations have achieved near-experimental accuracy in simulating drug-target interactions. However, introducing QM and AI-based techniques into drug discovery presents considerable challenges. AI techniques require high- quality data and often struggle with …

Stress Granule Formation Helps To Mitigate Neurodegeneration, M. Rebecca Glineburg, Evrim Yildirim, Nicolas Gomez, Genesis Rodriguez, Jaclyn Pak, Xingli Li, Christopher Altheim, Jacob Waksmacki, Gerald M. Mcinerney, Sami J. Barmada, Peter K. Todd

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Cellular stress pathways that inhibit translation initiation lead to transient formation of cytoplasmic RNA/protein complexes known as stress granules. Many of the proteins found within stress granules and the dynamics of stress granule formation and dissolution are implicated in neurodegenerative disease. Whether stress granule formation is protective or harmful in neurodegenerative conditions is not known. To address this, we took advantage of the alphavirus protein nsP3, which selectively binds dimers of the central stress granule nucleator protein G3BP and markedly reduces stress granule formation without directly impacting the protein translational inhibitory pathways that trigger stress granule formation. In Drosophila and …

Stanniocalcin 2 Governs Cancer Cell Adaptation To Nutrient Insufficiency Through Alleviation Of Oxidative Stress, Shuo Qie, Haijuan Xiong, Yaqi Liu, Chenhui Yan, Yalei Wang, Lifeng Tian, Chenguang Wang, Nianli Sang

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Solid tumours often endure nutrient insufficiency during progression. How tumour cells adapt to temporal and spatial nutrient insufficiency remains unclear. We previously identified STC2 as one of the most upregulated genes in cells exposed to nutrient insufficiency by transcriptome screening, indicating the potential of STC2 in cellular adaptation to nutrient insufficiency. However, the molecular mechanisms underlying STC2 induction by nutrient insufficiency and subsequent adaptation remain elusive. Here, we report that STC2 protein is dramatically increased and secreted into the culture media by Gln-/Glc- deprivation. STC2 promoter contains cis-elements that are activated by ATF4 and p65/RelA, two transcription factors activated by …

Advancement In In-Silico Drug Discovery From Virtual Screening Molecular Dockings To De-Novo Drug Design Transformer-Based Generative Ai And Reinforcement Learning, Dony Ang

Computational and Data Sciences (PhD) Dissertations

The field of drug discovery has seen remarkable advancements over the past few decades, transitioning from traditional experimental methods to highly sophisticated computational approaches. One of the pivotal techniques in this evolution is virtual screening, which utilizes molecular docking to predict the interaction between small molecules and target proteins. This method has significantly accelerated the initial stages of drug discovery by enabling the high-throughput screening of large chemical libraries. By simulating the binding affinity and stability of potential drug candidates, virtual screening has become a cornerstone in identifying promising compounds for further development.

A notable application of virtual screening was …

Molecular Mechanisms Of Exercise-Stimulated Resolution Of Inflammation And Its Dietary Dependence., Ernesto H. Pena Calderin

Electronic Theses and Dissertations

Diet-induced obesity and adipose tissue (AT) inflammation that ensues sets the stage for systemic metabolic inflammation, disrupted insulin signaling, and eventual type 2 diabetes (T2D) development. At the center of this pathology lies a disruption in endogenous inflammation resolution pathways characterized by an imbalance in lipid mediator production (greater abundance of pro-inflammatory to pro-resolving lipids). Additionally, obese states are characterized by adrenergic deficiency, especially in response to physical activity. Inflammatory processes have been experimentally mitigated by either the pharmacological inhibition of pro-inflammatory signals (i.e., Leukotriene B₄ (LTB₄) and its receptor BLT1, which establishes a potent chemotactic stimulus …