Medical Sciences Commons^™

In-Silico Modeling And Characterization Of Kcc2 Protein Interaction With A Small Molecule Direct Agonist Identifies Potential Binding Sites For Modulating Behaviors Associated With Substances Of Abuse, William Hai Dang Ho, Alfred Amendolara, Kenyon Mitchell, Jaden Miner, Ruth Northcott, Braxton Bingham, Andrew J. Payne

Annual Research Symposium

Purpose

KCC2 is a potassium-chloride cotransporter that plays a critical role in neuronal function by regulating GABAergic signaling via chloride gradients. Maintaining this concentration gradient is crucial for balancing excitation and inhibition in the brain. While KCC2 dysregulation has been implicated in epilepsy and seizures, recent studies suggest that KCC2 inhibition results in phenotypes mirroring those seen in chronic opioid dependence. As such, increasing evidence support KCC2 being a potential therapeutic target for modulating behaviors associated with substances of abuse. Currently, only a few direct small molecule agonists against KCC2 have been reported, and no definitive active site on the …

Evaluation Of Seven Commercially Available Dna Extraction Kits For Ocular Tissues, Jakob Newton, Conrad K. Ashby, Michael Trapnell, Triston Crook, Mark Eisele, Porter Biggs, Prina Patel, Christina Nelson, John A. Kriak, Kyle B. Bills, David W. Sant

Annual Research Symposium

2025 Annual Roseman Research Symposium

Unraveling Physiologic Mechanisms In Passive And Active Mechanoreceptor Stimulation, Halah Khan, Braden Ashcraft

Annual Research Symposium

No abstract provided.

Poor Birth Outcomes Related To Cannabis Use In Pregnancy, Reese Weissenfluh, Madison Hall, Branden Kadlubowski, Makayla Eversole, Elizabeth Clary, Layla Dials, Brenna Hissong, Brianna Lu, Joshua Honaker, Manoranjan D'Souza

Pharmacy and Wellness Review

Pregnancy, a period of dynamic physiological changes, necessitates careful consideration of external influences on maternal and fetal health. Despite increasing legalization and prevalence, the impact of cannabis use during gestation remains a topic of significant concern and investigation.

Recent studies have shed light on the consequences of in utero cannabis exposure, encompassing both fetal and maternal outcomes. Notably, several studies have identified associations between cannabis exposure during pregnancy and adverse fetal outcomes, including small-for-gestational-age birth, altered neurodevelopment, preterm birth, and increased risk of neonatal morbidity. Evidence to date underscores the urgent need for education, intervention, and regulatory oversight regarding cannabis …

Contract To Kill: Gnas Mutation, Pratima Raut, Poompozhil Mathivanan, Surinder K. Batra, Moorthy P. Ponnusamy

Journal Articles: Biochemistry & Molecular Biology

The mutation in Gsα-coding GNAS exons, popular as gsp oncogene, is the most frequent mutation across all heterotrimeric G proteins involved in oncogenesis. GNAS R201, the most frequently mutated, followed by Q227, are found predominantly across various neoplasms and cancers such as IPMN, pituitary, thyroid, appendiceal, colorectal, etc. This review emphasizes the pivotal significance of the gsp oncogene and its ramifications underpinning the sustained addiction to GNAS mutation. Recent studies delineating the mechanistic intricacies that provide solid evidence of the profound impact of oncogenic GNAS on tumor formation, progression, and maintenance are highlighted. We have leveraged the discoveries of Gsα …

Targeting Cancer-Associated Fibroblast-Driven Lif/Lifr Axis Improves The Therapeutic Efficacy Of Gemcitabine And Nab-Paclitaxel In Pancreatic Cancer, Rakesh Bhatia, Imran Khan, Xiaoqi Li, Shailendra Gautam, Parthasarathy Seshacharyulu, Zahraa Wajih Alsafwani, Namita Bhyravbhatla, Moorthy P. Ponnusamy, Maneesh Jain, Mokenge Malafa, Santhamma Bindu, Ahmed Gulzar, Hareesh Nair, Surinder K. Batra, Sushil Kumar

Journal Articles: Biochemistry & Molecular Biology

Pancreatic ductal adenocarcinoma (PDAC) is inherently therapy resistant due to cancer cell-stroma crosstalk across several signaling pathways. Among these, the LIF/LIFR axis has been implicated in cancer cell and cancer-associated fibroblast (CAF) crosstalk. We evaluated the efficacy of EC359, a competitive inhibitor of LIFR, in combination with gemcitabine. EC359 reduced tumor burden by 90% compared to controls and by 55% compared to gemcitabine alone in cancer cell and CAFs co-implannation model. The RNA-seq analysis revealed a significant alteration in extracellular matrix components, stemness, microtubule assembly, and immune response, suggesting simultaneous targeting of cancer cell-intrinsic and stroma-mediated mechanisms by EC359. In …

Alpha-Synuclein Interaction With Gedunin, Tony Matundura Nyabayo

Graduate Theses/Dissertations

Parkinson’s disease (PD) and other Proteinopathies develop when α-synuclein misfolds and aggregates into toxic amyloids. While existing treatments for PD are primarily focused on managing its symptoms, a viable solution for slowing down the progress of Parkinson’s disease involves targeting the toxic α-synuclein amyloids. Gedunin, a natural inhibitor of heat shock protein 90, has been extensively used to treat malaria. Also, recent research investigations have shed light on its potential beyond malaria therapy, indicating that Gedunin may offer a possible solution for treating a variety of neurodegenerative diseases. Using plate-based assays, we examined how Gedunin influences α-synuclein fibrillation and its …

Niclosamide-Loaded Polyanhydride Nanoparticles To Combat Gemcitabine Resistance In Pancreatic Cancer, Brianna M. White, Venugopal Gunda, Susheel Kumar Nethi, Nagabhishek Sirpu Natesh, Adam S. Mullis, Mariaelena Roman Sotelo, Jeffrey North, Chris Destache, Balaji Narasimhan, Surinder K. Batra, Surya K. Mallapragada, Satyanarayan Rachagani

Journal Articles: Biochemistry & Molecular Biology

Purpose

Pancreatic cancer (PC) is a highly lethal malignancy and lacks effective treatments. Current chemotherapies, including gemcitabine (Gem) in combination treatment regimens, produce dose-limiting toxicity, drug resistance, and ultimately limited improvement in the overall survival of PC patients. Niclosamide (Nic), a clinically safe FDA-approved anthelmintic drug has been shown to have anti-cancer properties; however, its limited bioavailability makes Nic largely ineffective as a therapeutic agent. To address this challenge, we have developed a novel combination therapy of Gem with the repurposed drug, Nic, loaded in biodegradable polyanhydride nanoparticles (NicNp), as an effective treatment option for PC.

Methods

We synthesized and …

Proteomics Profiling Of Research Models For Studying Pancreatic Ductal Adenocarcinoma, Mathilde Resell, Hanne-Line Rabben, Animesh Sharma, Lars Hagen, Linh Hoang, Nan T. Skogaker, Anne Aarvik, Eirik Knudsen Bjåstad, Magnus K. Svensson, Manoj Amrutkar, Caroline S. Verbeke, Surinder K. Batra, Gunnar Qvigstad, Timothy C. Wang, Anil Rustgi, Duan Chen, Chun-Mei Zhao

Journal Articles: Biochemistry & Molecular Biology

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a five-year survival rate of 10-15% due to late-stage diagnosis and limited efficacy of existing treatments. This study utilized proteomics-based systems modelling to generate multimodal datasets from various research models, including PDAC cells, spheroids, organoids, and tissues derived from murine and human samples. Identical mass spectrometry-based proteomics was applied across the different models. The preparation and validation of the research models and the proteomics were described in detail. The assembly datasets we present here contribute to the data collection on PDAC, which will be useful for systems modelling, …

Metabolic And Proteomic Signatures Differentiate Inflammatory Phenotypes From Cancer And Predict Treatment Response In Patient Sera, Gabriel Cutshaw, Elena V. Demidova, Philip Czyzewicz, Elizabeth Quam, Nicole Lorang, Al Warith Al Siyabi, Surinder K. Batra, Sanjeevani Arora, Rizia Bardhan

Journal Articles: Biochemistry & Molecular Biology

Tumors shift their metabolic needs to enable uncontrolled proliferation. Therefore, metabolic assessment of cancer patient sera provides a significant opportunity to noninvasively monitor disease progression and enable mechanistic understanding of the pathways that lead to response. Here, we show Raman spectroscopy (RS), a highly sensitive and label-free analytical tool, is effective in metabolic profiling across diverse cancer types in patient sera from both pancreatic ductal adenocarcinoma (PDAC) and locally advanced rectal cancer (LARC). We also combine metabolic data with proteomic signatures to predict treatment response. Our data show RS peaks successfully differentiate PDAC patients from healthy controls. Peaks associated with …

Brightly Visualizing Pancreatic Cancer Margins In Orthotopic Mouse Models With An Anti-Ca19-9 Antibody Conjugated To A Near-Infrared Fluorophore, Kristin E. Cox, Javier Bravo, Sunidhi Jaiswal, Siamak Amirfakhri, Thinzar M. Lwin, Abhijit Aithal, Sumbal Talib, Lily J. Jih, Aylin Din Parast Saleh, Keita Kobayashi, Kavita Mallya, Maneesh Jain, Robert M. Hoffman, Aaron M. Mohs, Surinder K. Batra, Michael Bouvet

Journal Articles: Biochemistry & Molecular Biology

Background/Purpose: The only potentially curative procedure for pancreatic cancer is R0 resection, which is difficult to achieve due to poorly defined tumor margins. In the present study, we used an anti-CA19-9 antibody conjugated to a near-infrared fluorophore in orthotopic mouse models to target and visualize pancreatic cancer. Methods: Orthotopic models of the human pancreatic cancer cell lines SW1990 and BxPC3 were established by implanting tumor fragments into the pancreas of athymic nude mice. Anti-CA19-9 and control IgG were conjugated with IRDye800CW. Mice received 50 µg of CA19-9-IRDye800CW or IgG-IRDye800CW via tail-vein injection and were imaged after 72 h. MIA PaCa-2, …

Niclosamide Nanoparticles Enhance Pancreatic Cancer Sensitivity To Gemcitabine Via Hif-1Α Inhibition, Susheel Kumar Nethi, Venugopal Gunda, Nagabhishek Sirpu Natesh, Brianna M. White, Adam S. Mullis, Balaji Narasimhan, Surinder K. Batra, Surya K. Mallapragada, Satyanarayana Rachagani

Journal Articles: Biochemistry & Molecular Biology

Pancreatic cancer (PC) exhibits profound metabolic adaptations that support tumor progression, survival, and therapy resistance. Hypoxia-inducible factor-1α (HIF-1α) is a key regulator of these processes, promoting metabolic reprogramming and chemoresistance. Given that mitochondrial metabolites modulate HIF-1α stability, targeting mitochondrial metabolism offers a promising therapeutic strategy. Niclosamide (Nic), a clinically approved anthelmintic, disrupts mitochondrial function but is limited by poor bioavailability. To overcome this, we developed polyanhydride-based Nic nanoparticles (NicNps) to enhance bioavailability and efficacy. NicNps impaired mitochondrial function, suppressed metabolism, downregulated HIF-1α, and inhibited growth of PC cells and orthotopic gemcitabine (Gem)-resistant mouse tumor models. Notably, NicNps combined with Gem …

Automating The Amino Acid Identification In Elliptical Dichroism Spectrometer With Machine Learning, Ridhanya Sree Balamurugan, Yusuf Asad, Tommy Gao, Dharmakeerthi Nawarathna, Umamaheswara Rao Tida, Dali Sun

Electrical & Computer Engineering Faculty Publications

Amino acid identification is crucial across various scientific disciplines, including biochemistry, pharmaceutical research, and medical diagnostics. However, traditional methods such as mass spectrometry require extensive sample preparation and are time-consuming, complex and costly. Therefore, this study presents a pioneering Machine Learning (ML) approach for automatic amino acid identification by utilizing the unique absorption profiles from an Elliptical Dichroism (ED) spectrometer. Advanced data preprocessing techniques and ML algorithms to learn patterns from the absorption profiles that distinguish different amino acids were investigated to prove the feasibility of this approach. The results show that ML can potentially revolutionize the amino acid analysis …

Evaluation Of The Effect Of Vitamin D Deficiency On Liver And Kidney Functions Of Iraqi Type Ii Diabetic Patients, Alaa Matar, Sarah Al-Tamimi, Jamilah Borjac

BAU Journal - Science and Technology

Background: Vitamin D deficiency is widespread across different age groups globally, linking to conditions such as cardiovascular diseases, autoimmune disorders, and notably type 2 diabetes mellitus (T2DM). Investigating the impact of vitamin D on T2DM and associated kidney and liver functions has gained recent attention.

Objective: This study aimed to explore the effect of vitamin D deficiency on kidney and liver functions in T2DM Iraqi patients.

Methods: Fifty T2DM patients and 50 controls were enrolled in this study. Blood samples were analyzed for glucose, glycated hemoglobin (HbA1c), vitamin D, urea, creatinine, bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline …

Mnsod Gene Knockout Promotes Apoptosis In Triple-Negative Breast Cancer Bt-549 Cells Through Survivin Inhibition And Caspase-3 And Caspase-9 Modulation, Niken Rahmah Ghanny, Septelia Inawati Wanandi, Sekar Arumsari, Rafika Indah Paramita, Resda Akhra Syahrani, Putu Indah Paramita Adi Putri

Makara Journal of Science

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype characterized by the lack of estro-gen, progesterone, and human epidermal growth factor receptor 2 (HER2) receptors. TNBC cells are becoming more aggressive due to the high expression of manganese superoxide dismutase (MnSOD) antioxidants to suppress reactive oxygen species-induced apoptosis and promote oncogenic signaling. This study was aimed to evaluate the effects of MnSOD knockout (KO) on TNBC cell apoptosis by assessing the survivin, caspase-9, and caspase-3 expressions. BT-549 TNBC cells containing the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-edited MnSOD gene were used to evaluate the messenger RNA (mRNA) …

Targeting The Cholesterol Storage Enzyme Acat1/Soat1 In Brain Cells And Mouse Model: A Novel Approach To Address Aging And Apoe4-Related Neuroinflammation, Thao Nguyen Phuong Huynh Krumeich

Dartmouth College Ph.D Dissertations

Alzheimer’s Disease (AD) is a progressive neurodegenerative disease that significantly impacts nearly 7 million people in the United States. AD is characterized by the deposition of amyloid beta (Ab) plaque, tau neurofibrillary tangles (NFTs), lipids granules, and neuroinflammation. Age and apolipoprotein E4 (APOE4) are the two biggest risk factors for AD. Recent AD therapeutic development has mostly benefited the patient population with milder symptoms while causing serious side effects in APOE4 carriers, leaving the most impacted patients’ group - aged APOE4 carriers with no treatment option. With the increasing aging population, there is an urgent need for a …

Blood Biomarkers In Down Syndrome: Facilitating Alzheimer's Disease Detection And Monitoring, Melissa Petersen, Lisi Flores-Aguilar, Elizabeth Head, Laia Montoliu-Gaya, Andre Strydom, Sarah Pape, Juan Fortea, Nicholas Ashton, Chinedu Momoh, Sid O'Bryant

Brain and Mind Institute

Blood-based biomarkers continue to be explored for disease detection, monitoring of progression, and therapeutic outcomes as the diagnostic determination of Alzheimer's Disease in Down Syndrome (DS-AD) remains challenging in clinical settings. This perspective highlights the current status of this effort. Overall, amyloid (A), tau (T), and neurodegeneration (AT[N]) blood-based biomarkers have been shown to increase with disease pathology for individuals with DS. Phosphorylated tau biomarkers (p-tau217, p-tau181) have been consistently shown to track disease progression for DS-AD and are likely good candidates for use in clinical settings. Biomarkers of inflammation (glial fibrillary acidic protein) also show promise; however, additional work …

Space: An Open-Source, Single-Cell Analysis Of Cell Painting Data, Fabio Stossi, Pankaj K Singh, Michela Marini, Kazem Safari, Adam T Szafran, Alejandra Rivera Tostado, Christopher D Candler, Maureen G Mancini, Elina A Mosa, Michael J Bolt, Demetrio Labate, Michael A Mancini

Faculty, Staff and Students Publications

Phenotypic profiling by high throughput microscopy, including Cell Painting, has become a leading tool for screening large sets of perturbations in cellular models. To efficiently analyze this big data, available open-source software requires computational resources usually not available to most laboratories. In addition, the cell-to-cell variation of responses within a population, while collected and analyzed, is usually averaged and unused. We introduce SPACe (Swift Phenotypic Analysis of Cells), an open-source platform for analysis of single-cell image-based morphological profiles produced by Cell Painting. We highlight several advantages of SPACe, including processing speed, accuracy in mechanism of action recognition, reproducibility across biological …

Small Molecule Mcl-1 Inhibitor For Triple Negative Breast Cancer Therapy, Shengli Dong, Suresh K. Alahari

School of Medicine Faculty Publications

Apoptosis is an evolutionarily conserved cell death pathway that plays a crucial role in maintaining tissue homeostasis, orchestrating organismal development, and eliminating damaged cells. Dysregulation of apoptosis can contribute to the pathogenesis of malignant tumors and neurodegenerative diseases. Anticancer drugs typically possess the capacity to induce apoptosis in tumor cells. The Bcl-2 protein family, consisting of 27 members in humans, serves as the key regulator of mitochondrial function. This family can be divided into two functional groups: anti-apoptotic proteins (e.g., Bcl-2, Bcl-xl, Mcl-1) and pro-apoptotic proteins (e.g., Bad, Bax). Mcl-1 exerts its function by binding pro-apoptotic Bcl-2 proteins thereby preventing …

Curcumin Alleviates Inflammatory Effects Of Ketamine Anesthesia In Postnatal Rats, Soroush Afshar Ghahremani, Abbas Raisi, Sohrab Minaei Beirami, Houman Kahroba, Mahnaz Mardani, Omid Dezfoulian, Vahideh Tarhriz

School of Graduate Studies Faculty Publications

Curcumin has been employed in traditional medicine for over a millennium to treat various ailments, and its global use is now widespread. Chinese medicine relies heavily on curcumin as a primary element and uses it to cure infectious diseases, skin disorders, depression, and stress. It has cardioprotective, neuroprotective, and anti-diabetic properties, as well as pharmacological effects on disorders like type II diabetes, atherosclerosis, and human immunodeficiency virus replication. The anti-cancer activity of curcumin has been studied extensively with notable improvements in gastrointestinal, melanoma, urogenital, breast, and lung malignancies. We investigated the anti-inflammatory effects of curcumin on expression of tumor necrosis …

Characterizing The Monomer-Dimer Equilibrium Of Ubch8/Ube2l6: A Combined Saxs And Nmr Study, Kerem Kahraman, Scott A. Robson, Oktay Göcenler, Cansu M. Yenici, Cansu D. Tozkoparan Ceylan, Jennifer M. Klein, Volker Dötsch, Emine Sonay Elgin, Arthur L. Haas, Joshua J. Ziarek, Çağdaş Dağ

School of Medicine Faculty Publications

Interferon-stimulated gene-15 (ISG15) is an interferon-induced protein with two ubiquitin-like (Ubl) domains linked by a short peptide chain and is a conjugated protein of the ISGylation system. Similar to ubiquitin and other Ubls, ISG15 is ligated to its target proteins through a series of E1, E2, and E3 enzymes known as Uba7, Ube2L6/UbcH8, and HERC5, respectively. Ube2L6/UbcH8 plays a central role in ISGylation, underscoring it as an important drug target for boosting innate antiviral immunity. Depending on the type of conjugated protein and the ultimate target protein, E2 enzymes have been shown to function as monomers, dimers, or both. UbcH8 …

Microrna-532-3p Modulates Colorectal Cancer Cell Proliferation And Invasion Via Suppression Of Foxm1, Ketakee Mahajan, Ani V. Das, Suresh K. Alahari, Ramesh Pothuraju, S. Asha Nair

School of Graduate Studies Faculty Publications

Colorectal cancer (CRC) is a heterogeneous disease and classified into various subtypes, among which transcriptional alterations result in CRC progression, metastasis, and drug resistance. Forkhead-box M1 (FOXM1) is a proliferation-associated transcription factor which is overexpressed in CRC and the mechanisms of FOXM1 regulation have been under investigation. Previously, we showed that FOXM1 binds to promoters of certain microRNAs. Database mining led to several microRNAs that might interact with FOXM1 3’UTR. The interactions between shortlisted microRNAs and FOXM1 3’UTR were quantitated by a dual-luciferase reporter assay. MicroRNA-532-3p interacted with the 3’UTR of the FOXM1 mRNA transcript most efficiently. MicroRNA-532-3p was ectopically …

Combination Therapy Of Ido1 Inhibition And Anti-Pd1 Mediates Anti-Tumor Immunity By Promoting Memory Immunity Development And Cytotoxicity Of Γδ T And Nk Cells Via Il-2 Signaling And By Overcoming Pro-Tumor Effects Of Tgf-Β Signaling, Hyuk Jee

Dartmouth College Master’s Theses

Cutaneous melanoma is the most aggressive form of skin cancer even though it takes only about 1% of all skin cancers. Even among all cutaneous melanomas, NRAS-mutant melanoma is more aggressive than any other, and about 10-25% of all cutaneous melanoma cases have mutations in NRAS. NRAS is a member of the RAS family of proto-oncogenic GTPase proteins, and it plays a key role in signal transduction pathways responsible for cellular survival, proliferation, and metabolism. Immunotherapy is the first line of defense against NRAS-mutant melanoma because, despite tremendous efforts made for decades, it has not been successful to develop small …

Znf397 Deficiency Triggers Tet2-Driven Lineage Plasticity And Ar-Targeted Therapy Resistance In Prostate Cancer, Yaru Xu, Yuqiu Yang, Zhaoning Wang, Martin Sjöström, Yuyin Jiang, Yitao Tang, Siyuan Cheng, Su Deng, Choushi Wang, Julisa Gonzalez, Nickolas A Johnson, Xiang Li, Xiaoling Li, Lauren A Metang, Atreyi Mukherji, Quanhui Xu, Carla R Tirado, Garrett Wainwright, Xinzhe Yu, Spencer Barnes, Mia Hofstad, Yu Chen, Hong Zhu, Ariella B Hanker, Ganesh V Raj, Guanghui Zhu, Housheng H He, Zhao Wang, Carlos L Arteaga, Han Liang, Felix Y Feng, Yunguan Wang, Tao Wang, Ping Mu

Faculty, Staff and Students Publications

Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming that allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified zinc finger protein 397 (ZNF397) as a bona fide coactivator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a ten-eleven translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our …

Addendum: A Small Molecule Produced By Lactobacillus Species Blocks Candida Albicans Filamentation By Inhibiting A Dyrk1-Family Kinase, Jessie Macalpine, Martin Daniel-Ivad, Zhongle Liu, Junko Yano, Nicole M. Revie, Robert T. Todd, Peter J. Stogios, Hiram Sanchez, Teresa R. O'Meara, Thomas A. Tompkins, Alexei Savchenko, Anna Selmecki, Amanda O. Veri, David R. Andes, Paul L. Fidel, Nicole Robbins, Justin Nodwell, Luke Whitesell, Leah E. Cowen

School of Dentistry Faculty Publications

No abstract provided.

A Biallelic Variant Of The Rna Exosome Gene, Exosc4, Associated With Neurodevelopmental Defects Impairs Rna Exosome Function And Translation, Milo B Fasken, Sara W Leung, Lauryn A Cureton, Maha Al-Awadi, Adila Al-Kindy, Ambro Van Hoof, Sohail Khoshnevis, Homa Ghalei, Almundher Al-Maawali, Anita H Corbett

Faculty, Staff and Student Publications

The RNA exosome is an evolutionarily conserved complex required for both precise RNA processing and decay. Pathogenic variants in EXOSC genes, which encode structural subunits of this complex, are linked to several autosomal recessive disorders. Here, we describe a missense allele of the EXOSC4 gene that causes a collection of clinical features in two affected siblings. This missense variant (NM_019037.3: exon3:c.560T>C) changes a leucine residue within a conserved region of EXOSC4 to proline (p.Leu187Pro). The two affected individuals show prenatal growth restriction, failure to thrive, global developmental delay, intracerebral and basal ganglia calcifications, and kidney failure. Homozygosity for the …

Adaptative Survival Of Aspergillus Fumigatus To Echinocandins Arises From Cell Wall Remodeling Beyond Β−1,3-Glucan Synthesis Inhibition, Malitha C. Dickwella Widanage, Isha Gautam, Daipayan Sarkar, Frederic Mentink-Vigier, Josh V. Vermaas, Shi You Ding, Andrew S. Lipton, Thierry Fontaine, Jean Paul Latgé, Ping Wang, Tuo Wang

School of Graduate Studies Faculty Publications

Antifungal echinocandins inhibit the biosynthesis of β−1,3-glucan, a major and essential polysaccharide component of the fungal cell wall. However, the efficacy of echinocandins against the pathogen Aspergillus fumigatus is limited. Here, we use solid-state nuclear magnetic resonance (ssNMR) and other techniques to show that echinocandins induce dynamic changes in the assembly of mobile and rigid polymers within the A. fumigatus cell wall. The reduction of β−1,3-glucan induced by echinocandins is accompanied by a concurrent increase in levels of chitin, chitosan, and highly polymorphic α−1,3-glucans, whose physical association with chitin maintains cell wall integrity and modulates water permeability. The rearrangement of …

Challenges Of Spatially Resolved Metabolism In Cancer Research, Andrew N. Lane, Richard M. Higashi, Teresa W-M Fan

Markey Cancer Center Faculty Publications

Stable isotope-resolved metabolomics comprises a critical set of technologies that can be applied to a wide variety of systems, from isolated cells to whole organisms, to define metabolic pathway usage and responses to perturbations such as drugs or mutations, as well as providing the basis for flux analysis. As the diversity of stable isotope-enriched compounds is very high, and with newer approaches to multiplexing, the coverage of metabolism is now very extensive. However, as the complexity of the model increases, including more kinds of interacting cell types and interorgan communication, the analytical complexity also increases. Further, as studies move further …

Genetic Diversity Of 1,845 Rhesus Macaques Improves Genetic Variation Interpretation And Identifies Disease Models, Jun Wang, Meng Wang, Ala Moshiri, R Alan Harris, Muthuswamy Raveendran, Tracy Nguyen, Soohyun Kim, Laura Young, Keqing Wang, Roger Wiseman, David H O'Connor, Zach Johnson, Melween Martinez, Michael J Montague, Ken Sayers, Martha Lyke, Eric Vallender, Tim Stout, Yumei Li, Sara M Thomasy, Jeffrey Rogers, Rui Chen

Faculty, Staff and Students Publications

Understanding and treating human diseases require valid animal models. Leveraging the genetic diversity in rhesus macaque populations across eight primate centers in the United States, we conduct targeted-sequencing on 1845 individuals for 374 genes linked to inherited human retinal and neurodevelopmental diseases. We identify over 47,000 single nucleotide variants, a substantial proportion of which are shared with human populations. By combining rhesus and human allele frequencies with established variant prediction methods, we develop a machine learning-based score that outperforms established methods in predicting missense variant pathogenicity. Remarkably, we find a marked number of loss-of-function variants and putative deleterious variants, which …

Successful Management Of Chromoblastomycosis Utilizing Conventional Antifungal Agents And Imiquimod Therapy, Jinjin Zheng, Shougang Liu, Zhenmou Xie, Yangxia Chen, Liyan Xi, Hongfang Liu, Yinghui Liu

Faculty, Staff and Student Publications

Chromoblastomycosis (CBM), a chronic fungal infection affecting the skin and subcutaneous tissues, is predominantly caused by dematiaceous fungi in tropical and subtropical areas. Characteristically, CBM presents as plaques and nodules, often leading to scarring post-healing. Besides traditional diagnostic methods such as fungal microscopy, culture, and histopathology, dermatoscopy and reflectance confocal microscopy can aid in diagnosis. The treatment of CBM is an extended and protracted process. Imiquimod, acting as an immune response modifier, boosts the host's immune response against CBM, and controls scar hyperplasia, thereby reducing the treatment duration. We present a case of CBM in Guangdong with characteristic reflectance confocal …