Medicine and Health Sciences Commons^™

Exploration, Expansion, And Optimization Of Bacteriophage Virus-Like Particle Vaccines, Andzoa N. Jamus

Biomedical Sciences ETDs

Bacteriophage virus-like particles are highly immunogenic, self-assembling platforms used for various vaccines. This work shows efforts to explore new vaccine candidates against Chlamydia trachomatis, targeting proteins that play critical roles in attachment and entry into the host cell, as well as in pathogenesis and bacteria proliferation. This work also shows the optimization of previously identified candidates, by investigating how altering routes of immunization can change the antibody profiles elicited, both systemically and locally. Finally, this work shows the establishment of various Chlamydia infection models in an effort to expand the ways in which vaccine efficacy can be investigated, particularly …

Immune Regulation In Fungal Airway Inflammation And Host Defense, Ruoning Wang

Biomedical Sciences ETDs

Asthma is a chronic inflammatory disease of the lungs characterized by complex pathophysiological mechanisms and diverse endotypes, primarily categorized as T helper type 2 cell (Th2)-high and Th2-low asthma. Despite significant advances in understanding asthma pathogenesis, the mechanisms governing the pulmonary immune system’s response to external challenges have not been fully understood. To address these gaps, this comprehensive project was designed to investigate the interplay between fungal infections and specific CD4⁺ T cell populations in asthma. Our findings suggest that fungal infections can contribute to neutrophilic asthma by promoting the migration of platelet-myeloid aggregates into the lungs. We also …

Localization Of Alpha Power Deficits In First Episode Psychosis, Crystal A. Garcia, Juan Bustillo

Biomedical Sciences ETDs

The purpose of this study was to determine where in the brain there may be a difference in brain activity in patients during their first episode of psychosis (FEP) compared to healthy controls (HCs) while performing an auditory oddball task. Time-frequency analysis allows for spectral decomposition where the signal measured by magnetoencephalography (MEG) is used to characterize changes in neural oscillations and their synchronization over time and region. Previous EEG studies report reduced alpha (8-12Hz, 70-160ms) power but most studies focused on patients with chronic schizophrenia and with limited source localization.

Elizabethkingia Infections - An Important Emerging Cause Of Sepsis And Meningitis In Neonates And Infants: Case Series From North Batinah Region, Oman, And Literature Review, Mohammed Said Al Reesi, Latifa Abdullah Al Muttawa, Mariam Abdullah Albolushi, Naima Salim Al Risi

Sultan Qaboos University Medical Journal

Elizabethkingia species, particularly E. anophelis and E. meningoseptica, are gram negative bacilli known to be associated with neonatal infections. Although these bacteria are rare, they are highly concerning pathogens associated with severe sepsis, bacteraemia and meningitis in neonates and immunocompromised individuals. Managing Elizabethkingia infections presents significant challenges because of their multidrug resistance, including resistance to most β-lactam agents. They have been implicated in both nosocomial and community outbreaks worldwide, often with high mortality rates. In Oman, Elizabethkingia infections are underreported, with only 1 publication documenting 2 cases of E. meningoseptica bacteraemia and meningitis, both of which were successfully …

A Mutational Analysis Of Thatisin: How Single Point Mutations Impact The Biosynthetic Process Of A Group 16 Graspetide, John F. Boynton Jr

Chemistry and Chemical Biology ETDs

Abstract:

Graspetides are a family of Ribosomally synthesized and Post-translationally modified Peptide (RiPP) natural products named for their ATP Grasp Macrocyclases. We identified several Graspetide Biosynthetic Gene Clusters containing common double glycine cleavage motifs and attempted characterization of the mature Graspetides. One of the resulting peptides, Thatisin, has a topology with two interlocking macrolactones installed by a single ATP Grasp Ligase named ThtC. Here we use single and double point mutations to observe the impact or variation on the installation of these macrocycles. Alanine scan mutagenesis is used to assess leader peptide residues in the precursor peptide ThtA to determine …

Gallic, Aconitic, And Crocetin Acids As Potential Tnf Modulators: An Integrated Study Combining Molecular Docking, Dynamics Simulations, Admet Profiling, And Gene Expression Analysis, Adolat Manakbayeva, Ahdrey P. Bogoyavlenskiy, Timur Kerimov, Igor Yershov, Pavel Alexyuk, Madina Alexyuk, Vladimir Berezin, Vyacheslav Dushenkov

Publications and Research

Organic acids, as natural metabolites, play crucial roles in human metabolism and health. Tumor Necrosis Factor (TNF), a pivotal mediator in immune regulation and inflammation, is a key therapeutic target. We evaluated ten organic acids as TNF modulators using in silico molecular docking, followed by detailed ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiling and molecular dynamics (MD) simulations for three lead candidates: gallic, aconitic, and crocetin acids. Their effects on TNF gene expression were then assessed in vivo using a mouse leukocyte model. The in silico results indicated that crocetin had the highest TNF binding affinity (−5.6 to −4.6 …

Single-Nuclei Multiomics Analysis Identifies Abnormal Cardiomyocytes In A Murine Model Of Cardiac Development., Riley Leonard, Yi Zhao, Steven Eliason, Kathy Zimmerman, Ariana Batz, Cathy J. Hatcher, Robert M Weiss, Mason Sweat, Xiao Li, Brad A Amendt

PCOM Scholarly Works

Transcription factors such as Tbx5, Gata4, Mef2c and Pitx2 are required during cardiac development, and in adult cardiac homeostasis. We demonstrate that the gene dosage and modulation of these factors are mediated in vivo by the miR-200 family. Inhibition of a single miR-200 family member within the cluster results in defects of the left ventricle and cardiomyocyte maturation during development. Inhibition of the entire miR-200 family results in a ventricular septal defect and embryonic lethality by embryonic day (E)16.5. Inhibition of each miR-200 family has distinct heart phenotypes in cell specific differentiation and maturation. snRNA-sequencing reveals an immature cardiomyocyte cell …

Assessing The Effects Of Antibiotic Selectivity And Temperature On The Antimicrobial Activity Of Isolates Derived From The Deep-Sea Sponge Pheronema Capenteri, Lex L. Hilario

The Plymouth Student Scientist

The rapid increase of antibiotic resistance necessitates the discovery of novel antibiotic compounds capable to tackle these resistant bacteria. Deep-sea sponges accommodate a diverse and dense microbiome filled with an array of bacterial communities that have the potential to produce novel antimicrobials. Some discovered novel strains have already shown their capability in producing secondary metabolites that are effective against clinically relevant strains. This study aims to evaluate the impacts of different culture conditions; antibiotic selectivity and temperature, on the antimicrobial activity of isolates recovered from three different Pheronema carpenteri deep-sea sponges. Using culture-dependant methods, a total of 59 bacterial isolates …

Comparing P62 And Lc3 As Autophagy Biomarkers: Insights Into Cellular Homeostasis, Riya Roychan

The Plymouth Student Scientist

Autophagy is a fundamental cellular process that maintains homeostasis by the degradation of damaged organelles and proteins. It plays crucial roles in cellular remodelling, development, and disease progression. These roles apply to the study of neurodegenerative diseases which is heavily linked to the toxicity produced by unwarranted accumulation of cellular material. A key player in autophagy is LC3, which translocate to autophagosomal membranes during the process. Detecting fluorescently labelled LC3-II through immunofluorescence provides a valuable method for assessing autophagy levels in samples. In a similar premise p62, also known as sequestosome-1 (SQSTM-1), is an adaptor between LC3 and ubiquitinated substrates, …

Clinician And Caregiver Perspectives On A Community-Based Dynamic Temporal And Tactile Cueing Treatment Trial For Childhood Apraxia Of Speech: Exploring Perceptions Of Research And Routine Clinical Practice, Donna C. Thomas, Geraldine Bricker-Katz, Elizabeth Murray, Shelley L. Velleman, Jenya Iuzzini-Seigel

Speech Pathology and Audiology Faculty Research and Publications

Purpose:

Dynamic Temporal and Tactile Cueing (DTTC) is an evidence-based treatment for children with childhood apraxia of speech. In clinical practice, speech-language pathologists (SLPs) frequently use an eclectic approach incorporating aspects of DTTC, for reasons that are not well understood. This research note describes a qualitative investigation of the experiences of SLPs and caregivers who participated in protocolized research DTTC for a 24-session treatment efficacy study. Specifically, we sought to understand the perspectives of these SLPs and caregivers regarding (a) DTTC treatment, as provided during the study, and (b) participating in a treatment research study.

Method:

Four SLPs and three …

Elevated Nr2f1 Underlies The Persistence Of Invasive Disease After Treatment Of Braf-Mutant Melanoma, Manoela Tiago, Timothy J. Purwin, Casey D. Stefanski, Renaira Oliveira Da Silva, Mitchell E. Fane, Yash Chhabra, Jelan I. Haj, Jessica L. F. Teh, Rama Kadamb, Weijia Cai, Sheera Rosenbaum, Vivian Chua, Nir Hacohen, Michael A. Davies, Jessie Villanueva, Inna Chervoneva, Ashani T. Weeraratna, Dan A. Erkes, Claudia Capparelli, Julio A. Aguirre-Ghiso, Andrew E. Aplin

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Despite the success of targeted inhibitors in cutaneous melanoma, therapeutic responses are limited by the aged tumor microenvironment and drug-tolerant residual cells. Given the similarities between drug tolerance and cellular dormancy, we studied the dormancy marker, nuclear receptor subfamily 2 group F member 1 (NR2F1), in response to BRAF-V600E inhibitors (BRAFi) plus MEK inhibitors (MEKi) in BRAF-mutant melanoma models. Transcriptomic analysis of melanoma patient samples treated with BRAFi + MEKi showed increased NR2F1. NR2F1 was highly expressed in the drug-tolerant invasive cell state of minimal residual disease in patient-derived and mouse-derived xenografts on BRAFi + MEKi. NR2F1 over-expression was sufficient …

Epigenomic Diagnosis And Prognosis Of Acute Myeloid Leukemia., Francisco Marchi, Vivek M. Shastri, Richard J. Marrero, Nam H K Nguyen, Antonella Öttl, Ann-Kathrin Schade, Marieke Landwehr, Olga Krali, Jessica Nordlund, Matin Ghavami, Fernando Sckaff, Vikash K. Mansinghka, Xueyuan Cao, William Slayton, Petr Starostik, Christopher R. Cogle, Raul C. Ribeiro, Jeffrey E. Rubnitz, Jeffery Klco, Abdelrahman Elsayed, Alan S. Gamis, Timothy J. Triche, Rhonda Ries, E Anders Kolb, Richard Aplenc, Todd Alonzo, Stanley Pounds, Soheil Meshinchi, Jatinder K. Lamba

Manuscripts, Articles, Book Chapters and Other Papers

Despite the critical role of DNA methylation, clinical implementations harnessing its promise have not been described in acute myeloid leukemia. Utilizing DNA methylation from 3314 leukemia patient samples across 11 harmonized cohorts, we describe the Acute Leukemia Methylome Atlas, which includes robust models capable of accurately predicting AML subtypes. A genome-wide prognostic model as well as a targeted panel of 38 CpGs significantly predict five-year survival in our pediatric and adult test cohorts. To accelerate rapid clinical utility, we develop a specimen-to-result protocol that uses long-read nanopore sequencing and machine learning to characterize patients' whole genomes and epigenomes. Clinical validation …

Nursing Turnover Based On Age, Race, And Gender In Community Hospitals In Michigan, Laura Lawhorn

Walden Dissertations and Doctoral Studies

Hospitals struggle to maintain nursing staff to meet patient needs for a population that requires continuous care and experiences multiple illnesses. The purpose of this quantitative study was to investigate the variations in reasons for leaving the nursing profession (dependent variable) based on age, race, and gender (independent variables) within community hospitals in Michigan. The theoretical framework for this study was the Nursing Neuman Systems Model, which posits that nursing comprises four key components: environment, individual, nursing practice, and health. A correlational research design was utilized to address the research question and analyze the relationships between the variables. The secondary …

Implementation Of A Diabetic Complication Educational Intervention For Staff At A Community-Based Clinic, Virginia K. Dennis

Walden Dissertations and Doctoral Studies

Even though there are many modalities put in place to manage diabetes and its complications, there have been many barriers to reducing the complications associated with diabetes in health care institutions. In this educational intervention to reduce diabetes and its complications, a staff education program was implemented to enhance staff knowledge about diabetes and the complications associated with it. The staff education program was implemented at a community-based clinic for a DNP-prepared nurse, three RNs, and five medical assistants (MAs) working at the clinic. A pretest and a posttest were administered to assess the impact of the educational session. The …

Understanding Black American Pastors' Leadership Role And Interaction With Public Health During Covid-19, Stacy L. Tolbert

Walden Dissertations and Doctoral Studies

The COVID-19 pandemic tested the leadership, response, and resilience of Black American pastors and their communities. These pastors played a crucial role in supporting their communities to lessen the impact the virus had on underlying health conditions and socioeconomic hardships that were exacerbated by the pandemic. Despite their efforts, Black American pastors frequently encountered challenges helping their community. The current research sought to understand the lived experiences of Black American pastors during the pandemic and their interactions with public health institutions to secure resources for their communities through Interpretative Phenomenological Analysis (IPA). The study was guided by the research question, …

Glucose Metabolism And Its Direct Action In Cancer And Immune Regulation: Opportunities And Challenges For Metabolic Targeting, Bo-Syong Pan, Che-Chia Hsu, Hsin-En Wu, Yuan-Ru Chen, Xiaobo Zhou, Shu-Chi Wang, Chia-Yang Li, Hui-Kuan Lin

Faculty, Staff and Student Publications

Glucose metabolism is a pivotal hub for cellular energy production and the generation of building blocks that support cell growth, survival, and differentiation. Cancer cells undergo metabolic reprogramming to sustain rapid proliferation, survive in harsh microenvironments, and resist therapies. Beyond producing energy and building blocks to meet cancer cell demands, glucose metabolism generates numerous metabolites that serve as signaling molecules, orchestrating signaling pathways and epigenetic modifications that regulate cancer cell phenotypes and immunity. In this review, we discuss how glucose, through its metabolism and direct actions, influences diverse biological processes driving cancer progression and therapeutic resistance, while also exploring metabolic …

A Data Assimilation Framework For Predicting The Spatiotemporal Response Of High-Grade Gliomas To Chemoradiation, Hugo J M Miniere, David A Hormuth, Ernesto A B F Lima, Maguy Farhat, Bikash Panthi, Holly Langshaw, Mihir D Shanker, Wasif Talpur, Sara Thrower, Jodi Goldman, Sophia Ty, Caroline Chung, Thomas E Yankeelov

Faculty, Staff and Student Publications

Background: High-grade gliomas are highly invasive and respond variably to chemoradiation. Accurate, patient-specific predictions of tumor response could enhance treatment planning. We present a novel computational platform that assimilates MRI data to continually predict spatiotemporal tumor changes during chemoradiotherapy.

Methods: Tumor growth and response to chemoradiation was described using a two-species reaction-diffusion model of enhancing and non-enhancing regions of the tumor. Two evaluation scenarios were used to test the predictive accuracy of this model. In scenario 1, the model was calibrated on a patient-specific basis (n = 21) to weekly MRI data during the course of chemoradiotherapy. A data assimilation …

Non-Mutated Human Tau Stimulates Alzheimer’S Disease-Relevant Neurodegeneration In A Microglia-Dependent Manner, Ethan R Roy, Qiang Wang, Kexin Huang, Sanming Li, Yuanyuan Fan, Estrella Escobar, Constance L Atkins, Shuning Huang, Juan J Herrera, Wenbo Li, Clare Pridans, Xiaobo Zhou, Cynthia Ju, Wei Cao

Faculty, Staff and Student Publications

The accumulation of abnormal, non-mutated tau protein is a key pathological hallmark of Alzheimer's disease (AD). Despite its strong association with disease progression, the mechanisms by which tau drives neurodegeneration in the brain remain poorly understood. Here, we selectively expressed non-mutated or mutated human microtubule-associated protein tau (hMAPT) in neurons across the mouse brain and observed neurodegeneration in the hippocampus, especially associated with non-mutated human tau. Single-nuclei RNA sequencing confirmed a selective loss of hippocampal excitatory neurons by the wild-type tau and revealed the upregulation of neurodegeneration-related pathways in the affected populations. The accumulation of phosphorylated tau was accompanied by …

Treatment With Allogenic Mesenchymal Stromal Cells For Moderate To Severe Acute Respiratory Distress Syndrome: A Double-Blind, Placebo-Controlled, Multi-Center, Phase 2b Clinical Trial (Stat), Michael A Matthay, Hanjing Zhou, Aartik Sarma, Narges Alipanah-Lechner, Carolyn Hendrickson, Lucy Z Kornblith, Martin Schreiber, David Zonies, Akram Khan, Bryce Robinson, Nicholas J Johnson, Lorraine B Ware, Oscar Guillamondegui, Jonathan Casey, Laura Moore, Bela Patel, Lillian Kao, Charles E Wade, Erin Fox, Charles Cox, Farrakh Khawanja, Robier Aguillon Prada, Sami Hossri, Rachael Callcut, Timothy Albertson, Kevin L Delucchi, Melanie Mcmillan, Charles R Langelier, Shibani Pati, David H Mckenna, Carolyn Leroux, Carolyn S Calfee, Kathleen D Liu

Faculty, Staff and Student Publications

Background: Prior clinical trials established the safety, but not the efficacy of bone marrow-derived mesenchymal stromal cells (MSCs) in the acute respiratory distress syndrome (ARDS).

Methods: We conducted a prospective, double-blind, multi-center randomized phase 2b clinical trial of one dose of intravenous MSCs (10 x 106/kg predicted body weight) versus placebo in 120 ventilated patients with ARDS (PaO2/FiO2 < 250 mmHg). The primary endpoint was change in oxygenation index (OI) over 36 hours from baseline.

Findings: Enrollment began in January 2020. Due to the Coronavirus 2019 (COVID-19) pandemic, the majority of subjects (101/120, 84%) developed ARDS from COVID-19. There were no significant baseline differences in severity of illness between patients treated with MSCs and those who received …

Cd45 And Cd148 Are Critically Involved In Neutrophil Recruitment And Function During Inflammatory Arthritis In Mice, Jan-Niklas Heming, Andreas Margraf, Karolina Najder, Giulia Germena, Mathis Richter, Anika Cappenberg, Katharina Henke, Bernadette Bardel, Lena Schemmelmann, Marina Oguama, Pia Lindental, Wida Amini, Jacqueline Sobocik, Georg Schett, Gerhard Krönke, Helena Block, Jan Rossaint, Oliver Soehnlein, Alexander Zarbock

Faculty, Staff and Student Publications

Neutrophils play a key role in autoimmune diseases like rheumatoid arthritis, contributing to tissue damage through rapid recruitment and activation. In this study, we investigated the regulatory properties of two receptor-like tyrosine phosphatases (RPTPs), CD45 and CD148, in inflammatory arthritis. Using an in vivo mouse model of K/BxN serum transfer-induced arthritis, we found that CD45 and CD148 feature distinct regulatory properties during inflammatory arthritis. CD45 is required for neutrophil infiltration, cytokine release, and reactive oxygen species production, whereas CD148 deficiency leads to a delayed onset of arthritis but unaltered overall neutrophil infiltration and reduced ROS production. Furthermore, we could demonstrate …

Effects Of The Gut Microbiota On Placental Angiogenesis And Intrauterine Growth In Gnotobiotic Mice, Reyan Coskun, Zenan L Chang, Athziri Marcial Rodríguez, Haoxin Liu, Jiye Cheng, Yael Alippe, Michael S Diamond, Jeffrey I Gordon

2020-Current year OA Pubs

Environmental causes of intrauterine growth restriction (IUGR) remain poorly characterized. Here, we compare germ-free (GF) and conventionally raised (CONV-R) mice to assess the effects of the gut microbiota on placental/fetal development at embryonic day (E)11.5 (end of placentation) and E17.5 (near term). Pregnancy- and microbiota-associated changes in gene expression occur along the gut, including those related to angiogenesis, while bacterial composition and fermentation activity remain stable. Placental weights at E11.5 and fetal weights at E17.5 are significantly reduced in GF animals. Compared to CONV-R dams, the GF maternal decidua exhibits similar vascular histomorphometric features at E11.5 and E17.5, and numbers …

Cd206+Il-4rα+ Macrophages Are Drivers Of Adverse Cardiac Remodeling In Ischemic Cardiomyopathy, Qiongxin Wang, Mohamed Ameen Ismahil, Yujie Zhu, Gregg Rokosh, Tariq Hamid, Guihua Zhou, Steven M. Pogwizd, Sumanth D. Prabhu

2020-Current year OA Pubs

BACKGROUND: The role of cardiac CD (cluster of differentiation) 206

METHODS: Adult C57BL/6 mice underwent nonreperfused myocardial infarction to induce HF. Macrophages in murine and human hearts were profiled using flow cytometry and immunostaining. In vivo myeloid-specific IL-4Rα deletion and intramyocardial macrophage adoptive transfer defined the functional effects of macrophages polarized by IL-4 (M[IL-4]). Antisense oligonucleotides were used for in vivo IL-4Rα gene silencing in mice.

RESULTS: CD206

CONCLUSIONS: Cardiac CD206

A Phase I Trial Of Evorpacept, Lenalidomide And Rituximab For Patients With B-Cell Non-Hodgkin Lymphoma, Paolo Strati, Lei Feng, Andrey Tyshevich, Darya Shavronskaya, Julia Alesse, Noel English, Elizabeth Sheehan, Nikita Syzrantsev, Alexander Nesmelov, Tony Z Zhuang, Dai Chihara, Jason R Westin, Sairah Ahmed, Luis E Fayad, Jared Henderson, Kylie Dent, Elizabeth Mcchesney, Sattva S Neelapu, Christopher R Flowers

Faculty, Staff and Student Publications

Introduction: SIRPα+ macrophages can mediate resistance to lenalidomide and rituximab (R2) in patients with B-cell non-Hodgkin lymphoma (B-NHL). Evorpacept (ALX148) is a novel CD47 blocker that abrogates interactions between lymphoma cells and SIRPα+ macrophages.

Methods: Adult patients with B-NHL who had received at least 2 prior lines of systemic therapy were included in this single arm phase I study (NCT05025800). Evorpacept was administered intravenously (IV), in a 28-day cycle, until progression, at two dose levels (DL): 30 mg/Kg on day (D) 1 and D15 (DL1), or 60 mg/Kg on day 1 (DL2); rituximab 375 mg/m2 IV was given …

Transforming Cancer Care: A Narrative Review On Leveraging Artificial Intelligence To Advance Immunotherapy In Underserved Communities, Victor M. Vasquez Jr., Molly Mccabe, Jack C. Mckee, Sharon Siby, Usman Hussain, Farah Faizuddin, Aadil Sheikh, Subramanian Dhandayuthapani, Shrikanth Gadad, Jessica Chacon

School of Medicine Publications

Purpose: Cancer immunotherapy has transformed oncology, but underserved populations face persistent disparities in access and outcomes. This review explores how artificial intelligence (AI) can help mitigate these barriers. Methods: We conducted a narrative review based on peer-reviewed literature selected for relevance to artificial intelligence, cancer immunotherapy, and healthcare challenges, without restrictions on publication date. We searched three major electronic databases: PubMed, IEEE Xplore, and arXiv, covering both biomedical and computational literature. The search included publications from January 2015 through April 2024 to capture contemporary developments in AI and cancer immunotherapy. Results: AI tools such as machine learning, …

Potential Of Legume Seeds From The Leguminosae Family As Material Source Of Food And Medicine : A Literature Review, Ni Made Ayu Gangga Dewi, Nina Dewi Oktaviyanti, Aurapa Sakulpanich, Kartini Kartini

Pharmaceutical Sciences and Research

Leguminosae, also known as Fabaceae, is the third largest plant family after Orchidaceae and Asteraceae. This review aimed to explore the potential of several legume species indigenous to Indonesia, from the Leguminosae family, as sources of food and medicine. The data used for the analysis were collected from various online databases such as PubMed, ScienceDirect, and Google Scholar. The results showed that there were 13 species of Leguminosae family plants found easily in Indonesia including Cajanus cajan, Canavalia ensiformis, Mucuna pruriens, Arachis hypogaea, Vigna subterranea, Glycine max, Phaseolus vulgaris, Phaseolus lunatus, Vigna radiata, Vigna unguiculata subsp. unguiculata, Vigna angularis, Vigna …

Lessons In Longevity From Blood Stem Cells Under Protein Stress, André Catic

Center on Aging Staff Publications

Blood stem cells are among the body's longest-living cells despite being highly vulnerable to proteotoxic damage, which accelerates their aging. To maintain protein homeostasis (proteostasis), hematopoietic stem cells (HSCs) employ mechanisms such as reduced translation rates, high chaperone activity, autophagy, and selective protein degradation. These strategies mitigate protein misfolding, maintain quiescence, and preserve regenerative potential. Disruptions in proteostasis can lead to the elimination of impaired HSCs through differentiation or apoptosis, ensuring the integrity of the stem cell pool. Due to the systemic impact of the blood on aging and its experimental and clinical accessibility, investigating HSC proteostasis provides insights into …

Sleep Drive, Not Total Sleep Amount, Increases Seizure Risk, Vishnu Anand Cuddapah, Cynthia T Hsu, Fernanda Valle Sirias, Yongjun Li, Hrishit M Shah, Christopher Saul, Samantha Killiany, Camilo Guevara, Joy Shon, Zhifeng Yue, Gabrielle L Gionet, Mary E Putt, Amita Sehgal

Duncan NRI Faculty and Staff Publications

Sleep loss has been associated with increased seizure risk since antiquity. Using automated video detection of spontaneous seizures in Drosophila epilepsy models, we show that seizures worsen only when sleep restriction raises homeostatic "sleep drive," not simply when total sleep amount falls. This is supported by the paradoxical finding that acute activation of sleep-promoting circuits worsens seizures, because it increases sleep drive without changing sleep amount. Sleep-promoting circuits become hyperactive after sleep loss and are associated with increased whole-brain activity. During sleep restriction, optogenetic inhibition of sleep-promoting circuits to reduce sleep drive protects against seizures. Downregulation of the 5HT1A serotonin …

Structural Variants: Mechanisms, Mapping, And Interpretation In Human Genetics, Shruti Pande, Moez Dawood, Christopher M Grochowski

Faculty, Staff and Students Publications

Structural variations (SVs) represent genomic variations that involve breakage and rejoining of DNA segments. SVs can alter normal gene dosage, lead to rearrangements of genes and regulatory elements within a topologically associated domain, and potentially contribute to physical traits, genomic disorders, or complex traits. Recent advances in sequencing technologies and bioinformatics have greatly improved SV detection and interpretation at unprecedented resolution and scale. Despite these advances, the functional impact of SVs, the underlying SV mechanism(s) contributing to complex traits, and the technical challenges associated with SV detection and annotation remain active areas of research. This review aims to provide an …

Xpert Mtb/Rif Ultra Assay For Pulmonary Tuberculosis And Rifampicin Resistance In Adults And Adolescents, David J Horne, Jerry S Zifodya, Adrienne E Shapiro, Elizabeth Chandler Church, Jonah S Kreniske, Alexander W Kay, Katie Scandrett, Karen R Steingart, Yemisi Takwoingi

Faculty, Staff and Students Publications

Background: Xpert MTB/RIF Ultra (Xpert Ultra) is a molecular World Health Organization (WHO)-recommended rapid diagnostic test that simultaneously detects tuberculosis and rifampicin resistance. This review updates a comparative accuracy Cochrane review of Xpert MTB/RIF and Xpert Ultra as Xpert Ultra has replaced Xpert MTB/RIF.

Objectives: To determine the diagnostic accuracy of Xpert MTB/RIF Ultra (Xpert Ultra) for detecting pulmonary tuberculosis and rifampicin resistance in adults and adolescents with presumptive tuberculosis based on signs or symptoms or with an abnormal chest x-ray suggestive of tuberculosis.

Search methods: We searched seven databases including CENTRAL, MEDLINE, and Embase, plus two trial registers (ClinicalTrials.gov …

Cell Type-Specific Purifying Selection Of Synonymous Mitochondrial Dna Variation, Caleb A Lareau, Patrick Maschmeyer, Yajie Yin, Jacob C Gutierrez, Ryan S Dhindsa, Anne-Sophie Gribling-Burrer, Sebastian Zielinski, Yu-Hsin Hsieh, Lena Nitsch, Veronika Dimitrova, Benan Nalbant, Frank A Buquicchio, Tsion Abay, Robert R Stickels, Jacob C Ulirsch, Patrick Yan, Fangyi Wang, Zhuang Miao, Katalin Sandor, Bence Daniel, Vincent Liu, Paul L Mendez, Petra Knaus, Manpreet Meyer, William J Greenleaf, Anshul Kundaje, Redmond P Smyth, Mathias Munschauer, Leif S Ludwig, Ansuman T Satpathy

Duncan NRI Faculty and Staff Publications

While somatic variants are well-characterized drivers of tumor evolution, their influence on cellular fitness in nonmalignant contexts remains understudied. We identified a mosaic synonymous variant (m.7076A > G) in the mitochondrial DNA (mtDNA)-encoded cytochrome c-oxidase subunit 1 (MT-CO1, p.Gly391=), present at homoplasmy in 47% of immune cells from a healthy donor. Single-cell multiomics revealed strong, lineage-specific selection against the m.7076G allele in CD8+ effector memory T cells, but not other T cell subsets, mirroring patterns of purifying selection of pathogenic mtDNA alleles. The limited anticodon diversity of mitochondrial tRNAs forces m.7076G translation to rely on wobble pairing, unlike the Watson-Crick-Franklin pairing …