Digital Commons Network^™

Metabolomics Of Dietary Intake Of Total, Animal, And Plant Protein: Results From The Atherosclerosis Risk In Communities (Aric) Study, Lauren Bernard, Jingsha Chen, Hyunju Kim, Kari E Wong, Lyn M Steffen, Bing Yu, Eric Boerwinkle, Casey M Rebholz

Faculty, Staff and Student Publications

BACKGROUND: Dietary consumption has traditionally been studied through food intake questionnaires. Metabolomics can be used to identify blood markers of dietary protein that may complement existing dietary assessment tools.

OBJECTIVES: We aimed to identify associations between 3 dietary protein sources (total protein, animal protein, and plant protein) and serum metabolites using data from the Atherosclerosis Risk in Communities Study.

METHODS: Participants' dietary protein intake was derived from a food frequency questionnaire administered by an interviewer, and fasting serum samples were collected at study visit 1 (1987-1989). Untargeted metabolomic profiling was performed in 2 subgroups (subgroup 1:

RESULTS: In this study …

An Antibody-Drug Conjugate Targeting Gpr56 Demonstrates Efficacy In Preclinical Models Of Colorectal Cancer, Joan Jacob, Liezl E Francisco, Treena Chatterjee, Zhengdong Liang, Shraddha Subramanian, Qingyun J Liu, Julie H Rowe, Kendra S Carmon

Faculty, Staff and Student Publications

Background: Long-term prognosis remains poor for colorectal cancer (CRC) patients with advanced disease due to treatment resistance. The identification of novel targets is essential for the development of new therapeutic approaches. GPR56, an adhesion GPCR, is highly expressed in CRC tumours and correlates with poor survival. Here, we describe the generation and preclinical evaluation of a novel ADC consisting of an anti-GPR56 antibody (10C7) conjugated with the DNA-damaging payload duocarmycin.

Methods: RNA-seq dataset analysis was performed to determine GPR56 expression in CRC subtypes. The specificity of binding, epitope mapping, and internalisation of 10C7 was examined. 10C7 was conjugated to payload …

Aerosolized Immunotherapeutic Nanoparticle Inhalation Potentiates Pd-L1 Blockade For Locally Advanced Lung Cancer, Yang Liu, William N Crowe, Lulu Wang, W Jeffrey Petty, Amyn A Habib, Dawen Zhao

Faculty, Staff and Student Publications

Despite therapeutic advancements, the prognosis of locally advanced non-small cell lung cancer (LANSCLC), which has invaded multiple lobes or the other lung and intrapulmonary lymph nodes, remains poor. The emergence of immunotherapy with immune checkpoint blockade (ICB) is transforming cancer treatment. However, only a fraction of lung cancer patients benefit from ICB. Significant clinical evidence suggests that the proinflammatory tumor microenvironment (TME) and programmed death-ligand 1 (PD-L1) expression correlate positively with response to the PD-1/PD-L1 blockade. We report here a liposomal nanoparticle loaded with cyclic dinucleotide and aerosolized (AeroNP-CDN) for inhalation delivery to deep-seated lung tumors and target CDN to …

Sensing Fear: Fast And Precise Threat Evaluation In Human Sensory Cortex, Wen Li, Andreas Keil

Faculty, Staff and Student Publications

Animal models of threat processing have evolved beyond the amygdala to incorporate a distributed neural network. In human research, evidence has intensified in recent years to challenge the canonical threat circuitry centered on the amygdala, urging revision of threat conceptualization. A strong surge of research into threat processing in the sensory cortex in the past decade has generated particularly useful insights to inform the reconceptualization. Here, synthesizing findings from both animal and human research, we highlight sensitive, specific, and adaptable threat representations in the sensory cortex, arising from experience-based sculpting of sensory coding networks. We thus propose that the human …

Dietary Intake Of Total, Heme And Non-Heme Iron And The Risk Of Colorectal Cancer In A European Prospective Cohort Study, Elom K Aglago, Amanda J Cross, Elio Riboli, Veronika Fedirko, David J Hughes, Agnes Fournier, Paula Jakszyn, Heinz Freisling, Marc J Gunter, Christina C Dahm, Kim Overvad, Anne Tjønneland, Cecilie Kyrø, Marie-Christine Boutron-Ruault, Joseph A Rothwell, Gianluca Severi, Verena Katzke, Bernard Srour, Matthias B Schulze, Clemens Wittenbecher, Domenico Palli, Sabina Sieri, Fabrizio Pasanisi, Rosario Tumino, Fulvio Ricceri, Bas Bueno-De-Mesquita, Jeroen W G Derksen, Guri Skeie, Torill Enget Jensen, Marko Lukic, Maria-Jose Sánchez, Pilar Amiano, Sandra Colorado-Yohar, Aurelio Barricarte, Ulrika Ericson, Bethany Van Guelpen, Keren Papier, Anika Knuppel, Corinne Casagrande, Inge Huybrechts, Alicia K Heath, Konstantinos K Tsilidis, Mazda Jenab

Faculty, Staff and Student Publications

BACKGROUND: Iron is an essential micronutrient with differing intake patterns and metabolism between men and women. Epidemiologic evidence on the association of dietary iron and its heme and non-heme components with colorectal cancer (CRC) development is inconclusive.

METHODS: We examined baseline dietary questionnaire-assessed intakes of total, heme, and non-heme iron and CRC risk in the EPIC cohort. Sex-specific multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using Cox regression. We modelled substitution of a 1 mg/day of heme iron intake with non-heme iron using the leave one-out method.

RESULTS: Of 450,105 participants (318,680 women) followed for 14.2 …

Augmentation Of Bmp Signaling In Cranial Neural Crest Cells Leads To Premature Cranial Sutures Fusion Through Endochondral Ossification In Mice, Hiroki Ueharu, Haichun Pan, Xia Liu, Mamoru Ishii, Jessica Pongetti, Anshul K Kulkarni, Folasade E Adegbenro, Jaden Wurn, Robert E Maxson, Hongchen Sun, Yoshihiro Komatsu, Honghao Zhang, Jingwen Yang, Yuji Mishina

Faculty, Staff and Student Publications

Craniosynostosis is a congenital anomaly characterized by the premature fusion of cranial sutures. Sutures are a critical connective tissue that regulates bone growth; their aberrant fusion results in abnormal shapes of the head and face. The molecular and cellular mechanisms have been investigated for a long time, but knowledge gaps remain between genetic mutations and mechanisms of pathogenesis for craniosynostosis. We previously demonstrated that the augmentation of bone morphogenetic protein (BMP) signaling through constitutively active BMP type 1A receptor (caBmpr1a) in neural crest cells (NCCs) caused the development of premature fusion of the anterior frontal suture, leading to craniosynostosis in …

Botulinum Toxin A Use In The Gastrointestinal Tract: A Reappraisal After Three Decades, Wasay A Mohajir, Shruti Khurana, Khushboo Singh, Reubyn William Chong, Manoop S Bhutani

Faculty, Staff and Student Publications

The discovery of botulinum toxin A (BTX)'s therapeutic properties has led to studies evaluating its usefulness in multiple medical disorders. Its use in the gastrointestinal (GI) tract has been studied for 30 years. Multiple databases, including PubMed, AccessMedicine, ClinicalKey, Cochrane Library, Embase, and Medline, were used to review research from case series to randomized controlled trials on BTX use in the GI tract. This article reviews the current literature on the efficacy of BTX and the strength of recommendations for or against its use in various disorders, including cricopharyngeal dysphagia, achalasia, nonachalasia motility disorders, gastroparesis, obesity, sphincter of Oddi disorders, …

Seed Amplification Assay For The Detection Of Pathologic Alpha-Synuclein Aggregates In Cerebrospinal Fluid, Luis Concha-Marambio, Sandra Pritzkow, Mohammad Shahnawaz, Carly M Farris, Claudio Soto

Faculty, Staff and Student Publications

Misfolded alpha-synuclein (αSyn) aggregates are a hallmark event in Parkinson’s disease (PD) and other synucleinopathies. Recently, αSyn seed amplification assays (αSyn-SAAs) have shown promise as a test for biochemical diagnosis of synucleinopathies. αSyn-SAAs use the intrinsic self-replicative nature of misfolded αSyn aggregates (seeds) to multiply them in vitro. In these assays, αSyn seeds circulating in biological fluids are amplified by a cyclical process that includes aggregate fragmentation into smaller self-propagating seeds, followed by elongation at the expense of recombinant αSyn (rec-αSyn). Amplification of the seeds allows detection by fluorescent dyes specific for amyloids, such as thioflavin T. Several αSyn-SAA reports …

Functional Phenotyping Of Microglia Highlights The Dark Relationship Between Chronic Traumatic Brain Injury And Normal Age-Related Pathology, Rodney M Ritzel, Junfang Wu

Faculty, Staff and Student Publications

No abstract provided.

An Antibody-Drug Conjugate Targeting Gpr56 Demonstrates Efficacy In Preclinical Models Of Colorectal Cancer, Joan Jacob, Liezl E Francisco, Treena Chatterjee, Zhengdong Liang, Shraddha Subramanian, Qingyun J Liu, Julie H Rowe, Kendra S Carmon

Faculty, Staff and Student Publications

BACKGROUND: Long-term prognosis remains poor for colorectal cancer (CRC) patients with advanced disease due to treatment resistance. The identification of novel targets is essential for the development of new therapeutic approaches. GPR56, an adhesion GPCR, is highly expressed in CRC tumours and correlates with poor survival. Here, we describe the generation and preclinical evaluation of a novel ADC consisting of an anti-GPR56 antibody (10C7) conjugated with the DNA-damaging payload duocarmycin.

METHODS: RNA-seq dataset analysis was performed to determine GPR56 expression in CRC subtypes. The specificity of binding, epitope mapping, and internalisation of 10C7 was examined. 10C7 was conjugated to payload …

Effect Of The Physical Fibrillated Sweet Potato (Ipomoea Batatas) Stem On The Plant-Based Patty Analogues, Suyoon Lee, You Young Lee, Yang Kim, Seung Hwan Ham, Min Gyu Lee, Jungwoo Hahn, Young Jin Choi

Faculty, Staff and Student Publications

In this study, a dietary fiber extracted from sweet potato stems (Ipomoea batatas, PS) was evaluated for its ability to improve the quality of vegetable patty analogues. A patty analogues containing 0–50 wt% dietary fiber were prepared to analyze the utilized dietary fiber's performance. To evaluate the manufactured patty analogues, texture profile analysis, color analysis, emulsion stability, and microstructural analysis were conducted. As the PS increased, the hardness decreased, while the total expressible fluids tended to increase. The color analysis revealed that the a* value, which represents red, declined as the PS content increased, and heterogeneous colors showed …

Lipid Nanoparticle-Mediated Mrna Delivery In Lung Fibrosis, Matteo Massaro, Suhong Wu, Gherardo Baudo, Haoran Liu, Scott Collum, Hyunho Lee, Cinzia Stigliano, Victor Segura-Ibarra, Harry Karmouty-Quintana, Elvin Blanco

Faculty, Staff and Student Publications

mRNA delivery enables the specific synthesis of proteins with therapeutic potential, representing a powerful strategy in diseases lacking efficacious pharmacotherapies. Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by excessive extracellular matrix (ECM) deposition and subsequent alveolar remodeling. Alveolar epithelial type 2 cells (AEC2) and fibroblasts represent important targets in IPF given their role in initiating and driving aberrant wound healing responses that lead to excessive ECM deposition. Our objective was to examine a lipid nanoparticle (LNP)-based mRNA construct as a viable strategy to target alveolar epithelial cells and fibroblasts in IPF. mRNA-containing LNPs measuring ∼34 nm had …

The Circadian E3 Ligase Fbxl21 Regulates Myoblast Differentiation And Sarcomere Architecture Via Myoz1 Ubiquitination And Nfat Signaling, Bo Hu, Jian-Xing Ma, Adam S Duerfeldt

Faculty, Staff and Student Publications

Diabetic retinopathy and age-related macular degeneration are common retinal diseases with shared pathophysiology, including oxidative stress-induced inflammation. Cellular mechanisms responsible for converting oxidative stress into retinal damage are ill-defined but have begun to clarify. One common outcome of retinal oxidative stress is mitochondrial damage and subsequent release of mitochondrial DNA into the cytosol. This leads to activation of the cGAS-STING pathway, resulting in interferon release and disease-amplifying inflammation. This review summarizes the evolving link between aberrant cGAS-STING signaling and inflammation in common retinal diseases and provides prospective for targeting this system in diabetic retinopathy and age-related macular degeneration. Further defining …

Clinical Outcomes Of Immune Checkpoint Inhibitor Diabetes Mellitus At A Comprehensive Cancer Center, Rebecca Jeun, Priyanka C Iyer, Conor Best, Victor Lavis, Jeena M Varghese, Sireesha Yedururi, Veronica Brady, Isabella C Glitza Oliva, Ramona Dadu, Denai R Milton, Kristy Brock, Sonali Thosani

Faculty, Staff and Student Publications

Introduction: Immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) is a rare adverse event. In this study, we characterize clinical outcomes of patients with ICI-DM and evaluate survival impact of this complication on melanoma patients.

Research design & methods: We conducted a retrospective review of 76 patients diagnosed with ICI-DM from April 2014 to December 2020.

Results: 68% of patients presented in diabetic ketoacidosis, 16% had readmissions for hyperglycemia, and hypoglycemia occurred in 70% of patients after diagnosis. Development of ICI-DM did not impact overall survival or progression-free survival in melanoma patients.

Conclusion: Development of ICI-DM is associated with long-term insulin dependence …

Dnmt3a-Coordinated Splicing Governs The Stem State Switch Towards Differentiation In Embryonic And Haematopoietic Stem Cells, Raghav Ramabadran, Jarey H Wang, Jaime M Reyes, Anna G Guzman, Sinjini Gupta, Carina Rosas, Lorenzo Brunetti, Michael C Gundry, Ayala Tovy, Hali Long, Tianpeng Gu, Sean M Cullen, Siddhartha Tyagi, Danielle Rux, Jean J Kim, Steven M Kornblau, Michael Kyba, Fabio Stossi, Rachel E Rau, Koichi Takahashi, Thomas F Westbrook, Margaret A Goodell

Faculty, Staff and Student Publications

Upon stimulation by extrinsic stimuli, stem cells initiate a programme that enables differentiation or self-renewal. Disruption of the stem state exit has catastrophic consequences for embryogenesis and can lead to cancer. While some elements of this stem state switch are known, major regulatory mechanisms remain unclear. Here we show that this switch involves a global increase in splicing efficiency coordinated by DNA methyltransferase 3α (DNMT3A), an enzyme typically involved in DNA methylation. Proper activation of murine and human embryonic and haematopoietic stem cells depends on messenger RNA processing, influenced by DNMT3A in response to stimuli. DNMT3A coordinates splicing through recruitment …

Wwox P47t Partial Loss-Of-Function Mutation Induces Epilepsy, Progressive Neuroinflammation, And Cerebellar Degeneration In Mice Phenocopying Human Scar12, Tabish Hussain, Kevin Sanchez, Jennifer Crayton, Dhurjhoti Saha, Collene Jeter, Yue Lu, Martin Abba, Ryan Seo, Jeffrey L Noebels, Laura Fonken, C Marcelo Aldaz

Faculty, Staff and Student Publications

WWOX gene loss-of-function (LoF) has been associated with neuropathologies resulting in developmental, epileptic, and ataxic phenotypes of varying severity based on the level of WWOX dysfunction. WWOX gene biallelic germline variant p.Pro47Thr (P47T) has been causally associated with a new form of autosomal recessive cerebellar ataxia with epilepsy and intellectual disability (SCAR12, MIM:614322). This mutation affecting the WW1 protein binding domain of WWOX, impairs its interaction with canonical proline-proline-X-tyrosine motifs in partner proteins. We generated a mutant knock-in mouse model of Wwox P47T mutation that phenocopies human SCAR12. Wwox

Clonal Haematopoiesis And Risk Of Chronic Liver Disease, Waihay J Wong, Connor Emdin, Alexander G Bick, Seyedeh M Zekavat, Abhishek Niroula, James P Pirruccello, Laura Dichtel, Gabriel Griffin, Md Mesbah Uddin, Christopher J Gibson, Veronica Kovalcik, Amy E Lin, Marie E Mcconkey, Amelie Vromman, Rob S Sellar, Peter G Kim, Mridul Agrawal, Joshua Weinstock, Michelle T Long, Bing Yu, Rajarshi Banerjee, Rowan C Nicholls, Andrea Dennis, Matt Kelly, Po-Ru Loh, Steve Mccarroll, Eric Boerwinkle, Ramachandran S Vasan, Siddhartha Jaiswal, Andrew D Johnson, Raymond T Chung, Kathleen Corey, Daniel Levy, Christie Ballantyne, Benjamin L Ebert, Pradeep Natarajan

Faculty, Staff and Student Publications

Chronic liver disease is a major public health burden worldwide1. Although different aetiologies and mechanisms of liver injury exist, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis2. Here we examined the association between clonal haematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 214,563 individuals from 4 independent cohorts with whole-exome sequencing data (Framingham Heart Study, Atherosclerosis Risk in Communities Study, UK Biobank and Mass General Brigham Biobank). CHIP was associated with an increased risk of prevalent and incident chronic liver disease (odds ratio = 2.01, 95% confidence interval (95% CI) [1.46, …

Aberrant Activation Of Tcl1a Promotes Stem Cell Expansion In Clonal Haematopoiesis, Joshua S Weinstock, Jayakrishnan Gopakumar, Bala Bharathi Burugula, Md Mesbah Uddin, Nikolaus Jahn, Julia A Belk, Hind Bouzid, Bence Daniel, Zhuang Miao, Nghi Ly, Taralynn M Mack, Sofia E Luna, Katherine P Prothro, Shaneice R Mitchell, Cecelia A Laurie, Jai G Broome, Kent D Taylor, Xiuqing Guo, Moritz F Sinner, Aenne S Von Falkenhausen, Stefan Kääb, Alan R Shuldiner, Jeffrey R O'Connell, Joshua P Lewis, Eric Boerwinkle, Kathleen C Barnes, Nathalie Chami, Eimear E Kenny, Ruth J F Loos, Myriam Fornage, Lifang Hou, Donald M Lloyd-Jones, Susan Redline, Brian E Cade, Bruce M Psaty, Joshua C Bis, Jennifer A Brody, Edwin K Silverman, Jeong H Yun, Dandi Qiao, Nicholette D Palmer, Barry I Freedman, Donald W Bowden, Michael H Cho, Dawn L Demeo, Ramachandran S Vasan, Lisa R Yanek, Lewis C Becker, Sharon L R Kardia, Patricia A Peyser, Jiang He, Michiel Rienstra, Pim Van Der Harst, Robert Kaplan, Susan R Heckbert, Nicholas L Smith, Kerri L Wiggins, Donna K Arnett, Marguerite R Irvin, Hemant Tiwari, Michael J Cutler, Stacey Knight, J Brent Muhlestein, Adolfo Correa, Laura M Raffield, Yan Gao, Mariza De Andrade, Jerome I Rotter, Stephen S Rich, Russell P Tracy, Barbara A Konkle, Jill M Johnsen, Marsha M Wheeler, J Gustav Smith, Olle Melander, Peter M Nilsson, Brian S Custer, Ravindranath Duggirala, Joanne E Curran, John Blangero, Stephen Mcgarvey, L Keoki Williams, Shujie Xiao, Mao Yang, C Charles Gu, Yii-Der Ida Chen, Wen-Jane Lee, Gregory M Marcus, John P Kane, Clive R Pullinger, M Benjamin Shoemaker, Dawood Darbar, Dan M Roden, Christine Albert, Charles Kooperberg, Ying Zhou, Joann E Manson, Pinkal Desai, Andrew D Johnson, Rasika A Mathias, Thomas W Blackwell, Goncalo R Abecasis, Albert V Smith, Hyun M Kang, Ansuman T Satpathy, Pradeep Natarajan, Jacob O Kitzman, Eric A Whitsel, Alexander P Reiner, Alexander G Bick, Siddhartha Jaiswal

Faculty, Staff and Student Publications

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the …

Total Daily Energy Expenditure Has Declined Over The Past Three Decades Due To Declining Basal Expenditure, Not Reduced Activity Expenditure, John R Speakman, Jasper M A De Jong, Srishti Sinha, Klaas R Westerterp, Yosuke Yamada, Hiroyuki Sagayama, Philip N Ainslie, Liam J Anderson, Lenore Arab, Kweku Bedu-Addo, Stephane Blanc, Alberto G Bonomi, Pascal Bovet, Soren Brage, Maciej S Buchowski, Nancy F Butte, Stefan G J A Camps, Jamie A Cooper, Richard Cooper, Sai Krupa Das, Peter S W Davies, Lara R Dugas, Ulf Ekelund, Sonja Entringer, Terrence Forrester, Barry W Fudge, Melanie Gillingham, Santu Ghosh, Annelies H Goris, Michael Gurven, Lewis G Halsey, Catherine Hambly, Hinke H Haisma, Daniel Hoffman, Sumei Hu, Annemiek M Joosen, Jennifer L Kaplan, Peter Katzmarzyk, William E Kraus, Robert F Kushner, William R Leonard, Marie Löf, Corby K Martin, Eric Matsiko, Anine C Medin, Erwin P Meijer, Marian L Neuhouser, Theresa A Nicklas, Robert M Ojiambo, Kirsi H Pietiläinen, Jacob Plange-Rhule, Guy Plasqui, Ross L Prentice, Susan B Racette, David A Raichlen, Eric Ravussin, Leanne M Redman, Susan B Roberts, Michael C Rudolph, Luis B Sardinha, Albertine J Schuit, Analiza M Silva, Eric Stice, Samuel S Urlacher, Giulio Valenti, Ludo M Van Etten, Edgar A Van Mil, Brian M Wood, Jack A Yanovski, Tsukasa Yoshida, Xueying Zhang, Alexia J Murphy-Alford, Cornelia U Loechl, Anura Kurpad, Amy H Luke, Herman Pontzer, Matthew S Rodeheffer, Jennifer Rood, Dale A Schoeller, William W Wong

Faculty, Staff and Student Publications

Obesity is caused by prolonged positive energy balance1,2. Whether reduced energy expenditure stemming from reduced activity levels contributes, is debated3,4. Here we used the IAEA DLW database on energy expenditure of adults in the USA and Europe (n = 4799) to explore patterns in total (TEE: n=4799), basal (BEE: n = 1432) and physical activity energy expenditure (AEE: n = 1432) over time. In both sexes total energy expenditure (TEE) adjusted for body composition and age declined with time, while adjusted AEE increased over time. In males adjusted BEE decreased significantly, but …

Neurochemical Effects Of Sepsis On The Brain, Tatiana Barichello, Vijayasree V Giridharan, Carlos Henrique R Catalão, Cristiane Ritter, Felipe Dal-Pizzol

Faculty, Staff and Student Publications

Sepsis is a life-threatening organ dysfunction triggered by a dysregulated host immune response to eliminate an infection. After the host immune response is activated, a complex, dynamic, and time-dependent process is triggered. This process promotes the production of inflammatory mediators, including acute-phase proteins, complement system proteins, cytokines, chemokines, and antimicrobial peptides, which are required to initiate an inflammatory environment for eliminating the invading pathogen. The physiological response of this sepsis-induced systemic inflammation can affect blood-brain barrier (BBB) function; subsequently, endothelial cells produce inflammatory mediators, including cytokines, chemokines, and matrix metalloproteinases (MMPs) that degrade tight junction (TJ) proteins and decrease BBB …

Environmental Enrichment Devices Are Safe And Effective At Reducing Undesirable Behaviors In California Sea Lions And Northern Elephant Seals During Rehabilitation, Kirsten Donald, Amanda Benedetti, Vinícius Donisete Lima Rodrigues Goulart, Alissa Deming, Hendrik Nollens, Grey Stafford, Sabrina Brando

Faculty, Staff and Student Publications

Environmental enrichment devices (EEDs) have been proven to promote positive wellbeing in zoos and aquariums, and support animals' reintroduction success; however, their use in rehabilitation centers is still limited. This pilot study investigated the safety and efficacy of three EEDs, Artificial Kelp, Horse KONG™ and Wubba Kong™, and their ability to decrease and/or eliminate undesired stereotypic behaviors or looking at staff/staff areas in seven wild California sea lions (CSLs) and eight northern elephant seals (NESs) undergoing rehabilitation in Southern California. Observers conducted instantaneous sampling once a minute during a 30-min baseline, followed by a 30-min EED implementation on one focal …

The Emergence Of A Virus Variant: Dynamics Of A Competition Model With Cross-Immunity Time-Delay Validated By Wastewater Surveillance Data For Covid-19, Bruce Pell, Samantha Brozak, Tin Phan, Fuqing Wu, Yang Kuang

Faculty, Staff and Student Publications

We consider the dynamics of a virus spreading through a population that produces a mutant strain with the ability to infect individuals that were infected with the established strain. Temporary cross-immunity is included using a time delay, but is found to be a harmless delay. We provide some sufficient conditions that guarantee local and global asymptotic stability of the disease-free equilibrium and the two boundary equilibria when the two strains outcompete one another. It is shown that, due to the immune evasion of the emerging strain, the reproduction number of the emerging strain must be significantly lower than that of …

Rare Variant Enrichment Analysis Supports Greb1l As A Contributory Driver Gene In The Etiology Of Mayer-Rokitansky-Küster-Hauser Syndrome, Angad Jolly, Haowei Du, Christelle Borel, Na Chen, Sen Zhao, Christopher M Grochowski, Ruizhi Duan, Jawid M Fatih, Moez Dawood, Sejal Salvi, Shalini N Jhangiani, Donna M Muzny, André Koch, Konstantinos Rouskas, Stavros Glentis, Efthymios Deligeoroglou, Flora Bacopoulou, Carol A Wise, Jennifer E Dietrich, Ignatia B Van Den Veyver, Antigone S Dimas, Sara Brucker, V Reid Sutton, Richard A Gibbs, Stylianos E Antonarakis, Nan Wu, Zeynep H Coban-Akdemir, Lan Zhu, Jennifer E Posey, James R Lupski

Faculty, Staff and Student Publications

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by aplasia of the female reproductive tract; the syndrome can include renal anomalies, absence or dysgenesis, and skeletal anomalies. While functional models have elucidated several candidate genes, only WNT4 (MIM: 603490) variants have been definitively associated with a subtype of MRKH with hyperandrogenism (MIM: 158330). DNA from 148 clinically diagnosed MRKH probands across 144 unrelated families and available family members from North America, Europe, and South America were exome sequenced (ES) and by family-based genomics analyzed for rare likely deleterious variants. A replication cohort consisting of 442 Han Chinese individuals with MRKH was …

Hsc-Independent Definitive Hematopoiesis Persists Into Adult Life, Michihiro Kobayashi, Haichao Wei, Takashi Yamanashi, Nathalia Azevedo Portilho, Samuel Cornelius, Noemi Valiente, Chika Nishida, Haizi Cheng, Augusto Latorre, W Jim Zheng, Joonsoo Kang, Jun Seita, David J Shih, Jia Qian Wu, Momoko Yoshimoto

Faculty, Staff and Student Publications

It is widely believed that hematopoiesis after birth is established by hematopoietic stem cells (HSCs) in the bone marrow and that HSC-independent hematopoiesis is limited only to primitive erythro-myeloid cells and tissue-resident innate immune cells arising in the embryo. Here, surprisingly, we find that significant percentages of lymphocytes are not derived from HSCs, even in 1-year-old mice. Instead, multiple waves of hematopoiesis occur from embryonic day 7.5 (E7.5) to E11.5 endothelial cells, which simultaneously produce HSCs and lymphoid progenitors that constitute many layers of adaptive T and B lymphocytes in adult mice. Additionally, HSC lineage tracing reveals that the contribution …

School Parent Attitudes And Perceptions Relating To Animals, Animal-Assisted Interventions, And The Support Of Children's Mental Health, Rhoda A Leos, Paula M Cuccaro, John R Herbold, Belinda F Hernandez

Faculty, Staff and Student Publications

Growing awareness of the negative effects of trauma has led San Antonio, TX, school districts to expand efforts that can help mitigate these effects and support mental health. Given the literature around the psychological benefits of human-animal interactions, the concept of incorporating animals in treatments or interventions is not a new one. While schools have begun considering or utilizing animal-assisted interventions (AAIs), there have been limited efforts to understand existing perceptions relating to animals and AAIs among school parents in this Hispanic community. to address this gap, a cross-sectional study consisting of a 34-item survey was conducted to explore attitudes, …

Gingival Transcriptomic Patterns Of Macrophage Polarization During Initiation, Progression, And Resolution Of Periodontitis, Octavio A Gonzalez, Sreenatha S Kirakodu, Linh M Nguyen, Jeffrey L Ebersole

Faculty, Staff and Student Publications

Phenotypic and functional heterogeneity of macrophages is clearly a critical component of their effective functions in innate and adaptive immunity. This investigation hypothesized that altered profiles of gene expression in gingival tissues in health, disease, and resolution would reflect changes in macrophage phenotypes occurring in these tissues. The study used a nonhuman primate model to evaluate gene expression profiles as footprints of macrophage variation using a longitudinal experimental model of ligature-induced periodontitis in animals from 3 to 23 years of age to identify aging effects on the gingival environment. Significant differences were observed in distribution of expressed gene levels for …

Convergent Deployment Of Ancestral Functions During The Evolution Of Mammalian Flight Membranes, Charles Y Feigin, Jorge A Moreno, Raul Ramos, Sarah A Mereby, Ares Alivisatos, Wei Wang, Renée Van Amerongen, Jasmin Camacho, John J Rasweiler, Richard R Behringer, Bruce Ostrow, Maksim V Plikus, Ricardo Mallarino

Faculty, Staff and Student Publications

Lateral flight membranes, or patagia, have evolved repeatedly in diverse mammalian lineages. While little is known about patagium development, its recurrent evolution may suggest a shared molecular basis. By combining transcriptomics, developmental experiments, and mouse transgenics, we demonstrate that lateral Wnt5a expression in the marsupial sugar glider (Petaurus breviceps) promotes the differentiation of its patagium primordium. We further show that this function of Wnt5a reprises ancestral roles in skin morphogenesis predating mammalian flight and has been convergently used during patagium evolution in eutherian bats. Moreover, we find that many genes involved in limb development have been redeployed during …

Acupuncture Treatment For Post-Stroke Depression: Intestinal Microbiota And Its Role, Hailun Jiang, Shizhe Deng, Jieying Zhang, Junjie Chen, Boxuan Li, Weiming Zhu, Menglong Zhang, Chao Zhang, Zhihong Meng

Faculty, Staff and Student Publications

Stroke-induced depression is a common complication and an important risk factor for disability. Besides psychiatric symptoms, depressed patients may also exhibit a variety of gastrointestinal symptoms, and even take gastrointestinal symptoms as the primary reason for medical treatment. It is well documented that stress may disrupt the balance of the gut microbiome in patients suffering from post-stroke depression (PSD), and that disruption of the gut microbiome is closely related to the severity of the condition in depressed patients. Therefore, maintaining the balance of intestinal microbiota can be the focus of research on the mechanism of acupuncture in the treatment of …

A First-In-Human Phase I Study Of Milademetan, An Mdm2 Inhibitor, In Patients With Advanced Liposarcoma, Solid Tumors, Or Lymphomas, Mrinal M Gounder, Todd M Bauer, Gary K Schwartz, Amy M Weise, Patricia Lorusso, Prasanna Kumar, Ben Tao, Ying Hong, Parul Patel, Yasong Lu, Arnaud Lesegretain, Vijaya G Tirunagaru, Feng Xu, Robert C Doebele, David S Hong

Faculty, Staff and Student Publications

Purpose: This study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of milademetan, a small-molecule murine double minute-2 (MDM2) inhibitor, in patients with advanced cancers.

Patients and methods: In this first-in-human phase I study, patients with advanced solid tumors or lymphomas received milademetan orally once daily as extended/continuous (days 1-21 or 1-28 every 28 days) or intermittent (days 1-7, or days 1-3 and 15-17 every 28 days) schedules. The primary objective was to determine the recommended phase II dose and schedule. Secondary objectives included tumor response according to standard evaluation criteria. Predefined analyses by tumor type were performed. Safety and …

Ad-Syn-Net: Systematic Identification Of Alzheimer's Disease-Associated Mutation And Co-Mutation Vulnerabilities Via Deep Learning, Xingxin Pan, Zeynep H Coban Akdemir, Ruixuan Gao, Xiaoqian Jiang, Gloria M Sheynkman, Erxi Wu, Jason H Huang, Nidhi Sahni, S Stephen Yi

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is one of the most challenging neurodegenerative diseases because of its complicated and progressive mechanisms, and multiple risk factors. Increasing research evidence demonstrates that genetics may be a key factor responsible for the occurrence of the disease. Although previous reports identified quite a few AD-associated genes, they were mostly limited owing to patient sample size and selection bias. There is a lack of comprehensive research aimed to identify AD-associated risk mutations systematically. to address this challenge, we hereby construct a large-scale AD mutation and co-mutation framework ('AD-Syn-Net'), and propose deep learning models named Deep-SMCI and Deep-CMCI configured …