Digital Commons Network^™

Python Tooth-Inspired Fixation Device For Enhanced Rotator Cuff Repair, Iden Kurtaliaj, Ethan D Hoppe, Yuxuan Huang, David Ju, Jacob A Sandler, Donghwan Yoon, Guy M Genin

2020-Current year OA Pubs

Rotator cuff repair surgeries fail frequently, with 20 to 94% of the 600,000 repairs performed annually in the United States resulting in retearing of the rotator cuff. The most common cause of failure is sutures tearing through tendons at grasping points. To address this issue, we drew inspiration from the specialized teeth of snakes of the Pythonoidea superfamily, which grasp soft tissues without tearing. To apply this nondamaging gripping approach to the surgical repair of tendon, we developed and optimized a python tooth-inspired device as an adjunct to current rotator cuff suture repair and found that it nearly doubled repair …

Detection Of Early-Stage Nash Using Non-Invasive Hyperpolarized 13c Metabolic Imaging, Cornelius Von Morze, Tyler Blazey, Ashley Shaw, William M Spees, Kooresh I Shoghi, Michael A Ohliger

2020-Current year OA Pubs

Non-alcoholic steatohepatitis (NASH) is characterized from its early stages by a profound remodeling of the liver microenvironment, encompassing changes in the composition and activities of multiple cell types and associated gene expression patterns. Hyperpolarized (HP)

Examining Associations Between Smartphone Use And Clinical Severity In Frontotemporal Dementia: Proof-Of-Concept Study, Emily W Paolillo, Nupur Ghoshal, Et Al.

2020-Current year OA Pubs

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD illustrate an urgent need to develop remote, accessible, and low-burden assessment techniques. Studies of unobtrusive monitoring of at-home computer use in older adults with mild cognitive impairment show that declining function is reflected in reduced computer use; however, associations with smartphone use are unknown.

OBJECTIVE: This study aims to characterize daily trajectories in smartphone battery use, a proxy for smartphone use, and examine relationships with clinical indicators of severity in FTLD.

METHODS: Participants were 231 adults (mean age 52.5, SD 14.9 years; n=94, 40.7% men; n=223, 96.5% non-Hispanic White) enrolled in the Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL study) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS study) Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Mobile App study, including 49 (21.2%) with mild neurobehavioral changes and no functional …

Role Of The Afferent Lymph As An Immunological Conduit To Analyze Tissue Antigenic And Inflammatory Load, Padma P Nanaware, Cheryl F Lichti, Xiaoxiao Wan, Emil R Unanue, Et Al.

2020-Current year OA Pubs

The lymphatic fluid is the conduit by which part of the tissue "omics" is transported to the draining lymph node for immunosurveillance. Following cannulation of the pre-nodal cervical and mesenteric afferent lymphatics, herein we investigate the lymph proteomic composition, uncovering that its composition varies according to the tissue of origin. Tissue specificity is also reflected in the dendritic cell-major histocompatibility complex class II-eluted immunopeptidome harvested from the cervical and mesenteric nodes. Following inflammatory disruption of the gut barrier, the lymph antigenic and inflammatory loads are analyzed in both mice and subjects with inflammatory bowel diseases. Gastrointestinal tissue damage reflects the …

Dorsal Raphe Neurons Integrate The Values Of Reward Amount, Delay, And Uncertainty In Multi-Attribute Decision-Making, Yang-Yang Feng, Ethan S Bromberg-Martin, Ilya E Monosov

2020-Current year OA Pubs

The dorsal raphe nucleus (DRN) is implicated in psychiatric disorders that feature impaired sensitivity to reward amount, impulsivity when facing reward delays, and risk-seeking when confronting reward uncertainty. However, it has been unclear whether and how DRN neurons signal reward amount, reward delay, and reward uncertainty during multi-attribute value-based decision-making, where subjects consider these attributes to make a choice. We recorded DRN neurons as monkeys chose between offers whose attributes, namely expected reward amount, reward delay, and reward uncertainty, varied independently. Many DRN neurons signaled offer attributes, and this population tended to integrate the attributes in a manner that reflected …

Airy-Beam Holographic Sonogenetics For Advancing Neuromodulation Precision And Flexibility, Zhongtao Hu, Yaoheng Yang, Leqi Yang, Yan Gong, Chinwendu Chukwu, Dezhuang Ye, Yimei Yue, Jinyun Yuan, Alexxai V Kravitz, Hong Chen

2020-Current year OA Pubs

Advancing our understanding of brain function and developing treatments for neurological diseases hinge on the ability to modulate neuronal groups in specific brain areas without invasive techniques. Here, we introduce Airy-beam holographic sonogenetics (AhSonogenetics) as an implant-free, cell type-specific, spatially precise, and flexible neuromodulation approach in freely moving mice. AhSonogenetics utilizes wearable ultrasound devices manufactured using 3D-printed Airy-beam holographic metasurfaces. These devices are designed to manipulate neurons genetically engineered to express ultrasound-sensitive ion channels, enabling precise modulation of specific neuronal populations. By dynamically steering the focus of Airy beams through ultrasound frequency tuning, AhSonogenetics is capable of modulating neuronal populations …

Injury-Induced Foxm1 Expression In The Mouse Kidney Drives Epithelial Proliferation By A Cyclin F-Dependent Mechanism, Megan L. Noonan, Yoshiharu Muto, Yasuhiro Yoshimura, Aidan Leckie-Harre, Haojia Wu, Vladimir V. Kalinichenko, Benjamin D. Humphreys, Monica Chang-Panesso

2020-Current year OA Pubs

Acute kidney injury (AKI) strongly upregulates the transcription factor Foxm1 in the proximal tubule in vivo, and Foxm1 drives epithelial proliferation in vitro. Here, we report that deletion of Foxm1 either with a nephron-specific Cre driver or by inducible global deletion reduced proximal tubule proliferation after ischemic injury in vivo. Foxm1 deletion led to increased AKI to chronic kidney disease transition, with enhanced fibrosis and ongoing tubule injury 6 weeks after injury. We report ERK mediated FOXM1 induction downstream of the EGFR in primary proximal tubule cells. We defined FOXM1 genomic binding sites by cleavage under targets and release using …

Noninvasive Assessment Of The Lung Inflammation-Fibrosis Axis By Targeted Imaging Of Cmklr1, Philip Z Mannes, Taylor S Adams, Samaneh Farsijani, Clayton E Barnes, Joseph D Latoche, Kathryn E Day, Jessie R Nedrow, Farida Ahangari, Naftali Kaminski, Janet S Lee, Sina Tavakoli

2020-Current year OA Pubs

Precision management of fibrotic lung diseases is challenging due to their diverse clinical trajectories and lack of reliable biomarkers for risk stratification and therapeutic monitoring. Here, we validated the accuracy of CMKLR1 as an imaging biomarker of the lung inflammation-fibrosis axis. By analyzing single-cell RNA sequencing datasets, we demonstrated

Harmonized Cross-Species Cell Atlases Of Trigeminal And Dorsal Root Ganglia, Shamsuddin A Bhuiyan, Lite Yang, Lisa A Mcilvried, Bryan A Copits, Zachariah Bertels, John S Del Rosario, Allie J Widman, Richard A Slivicki, Jiwon Yi, Robert W Gereau Iv, Et Al.

2020-Current year OA Pubs

Sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG) are specialized to detect and transduce diverse environmental stimuli to the central nervous system. Single-cell RNA sequencing has provided insights into the diversity of sensory ganglia cell types in rodents, nonhuman primates, and humans, but it remains difficult to compare cell types across studies and species. We thus constructed harmonized atlases of the DRG and TG that describe and facilitate comparison of 18 neuronal and 11 non-neuronal cell types across six species and 31 datasets. We then performed single-cell/nucleus RNA sequencing of DRG from both human and the …

Structural Basis For Hyperpolarization-Dependent Opening Of Human Hcn1 Channel, Verena Burtscher, Jonathan Mount, Jian Huang, John Cowgill, Yongchang Chang, Kathleen Bickel, Jianhan Chen, Peng Yuan, Baron Chanda

2020-Current year OA Pubs

Hyperpolarization and cyclic nucleotide (HCN) activated ion channels are critical for the automaticity of action potentials in pacemaking and rhythmic electrical circuits in the human body. Unlike most voltage-gated ion channels, the HCN and related plant ion channels activate upon membrane hyperpolarization. Although functional studies have identified residues in the interface between the voltage-sensing and pore domain as crucial for inverted electromechanical coupling, the structural mechanisms for this unusual voltage-dependence remain unclear. Here, we present cryo-electron microscopy structures of human HCN1 corresponding to Closed, Open, and a putative Intermediate state. Our structures reveal that the downward motion of the gating …

Protein Restriction Slows The Development And Progression Of Pathology In A Mouse Model Of Alzheimer's Disease, Reji Babygirija, Natalie M Niemi, Et Al.

2020-Current year OA Pubs

Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and dietary protein restriction extends the lifespan and healthspan of mice. In this study, we examined the effect of protein restriction (PR) on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD. Here, we show that PR promotes leanness and glycemic control in 3xTg mice, specifically rescuing the glucose intolerance of 3xTg females. PR induces sex-specific alterations in circulating and brain metabolites, downregulating sphingolipid subclasses in 3xTg females. PR also …

Structural Characterization Of Ligand Binding And Ph-Specific Enzymatic Activity Of Mouse Acidic Mammalian Chitinase, Roberto Efraín Díaz, Andrew K Ecker, Galen J Correy, Pooja Asthana, Iris D Young, Bryan Faust, Michael C Thompson, Ian B Seiple, Steven Van Dyken, Richard M Locksley, James S Fraser

2020-Current year OA Pubs

Chitin is an abundant biopolymer and pathogen-associated molecular pattern that stimulates a host innate immune response. Mammals express chitin-binding and chitin-degrading proteins to remove chitin from the body. One of these proteins, Acidic Mammalian Chitinase (AMCase), is an enzyme known for its ability to function under acidic conditions in the stomach but is also active in tissues with more neutral pHs, such as the lung. Here, we used a combination of biochemical, structural, and computational modeling approaches to examine how the mouse homolog (mAMCase) can act in both acidic and neutral environments. We measured kinetic properties of mAMCase activity across …

Cancer-Associated Histone H3 N-Terminal Arginine Mutations Disrupt Prc2 Activity And Impair Differentiation, Benjamin A Nacev, Benjamin A Garcia, Et Al.

2020-Current year OA Pubs

Dysregulated epigenetic states are a hallmark of cancer and often arise from genetic alterations in epigenetic regulators. This includes missense mutations in histones, which, together with associated DNA, form nucleosome core particles. However, the oncogenic mechanisms of most histone mutations are unknown. Here, we demonstrate that cancer-associated histone mutations at arginines in the histone H3 N-terminal tail disrupt repressive chromatin domains, alter gene regulation, and dysregulate differentiation. We find that histone H3R2C and R26C mutants reduce transcriptionally repressive H3K27me3. While H3K27me3 depletion in cells expressing these mutants is exclusively observed on the minor fraction of histone tails harboring the mutations, …

A Longitudinal Mri And Tspo Pet-Based Investigation Of Brain Region-Specific Neuroprotection By Diazepam Versus Midazolam Following Organophosphate-Induced Seizures, Brad A Hobson, Douglas J Rowland, Yimeng Dou, Naomi Saito, Zachary T Harmany, Donald A Bruun, Danielle J Harvey, Abhijit J Chaudhari, Joel R Garbow, Pamela J Lein

2020-Current year OA Pubs

Acute poisoning with organophosphorus cholinesterase inhibitors (OPs), such as OP nerve agents and pesticides, can cause life threatening cholinergic crisis and status epilepticus (SE). Survivors often experience significant morbidity, including brain injury, acquired epilepsy, and cognitive deficits. Current medical countermeasures for acute OP poisoning include a benzodiazepine to mitigate seizures. Diazepam was long the benzodiazepine included in autoinjectors used to treat OP-induced seizures, but it is now being replaced in many guidelines by midazolam, which terminates seizures more quickly, particularly when administered intramuscularly. While a direct correlation between seizure duration and the extent of brain injury has been widely reported, …

Prevalence Of Anti-Myelin Oligodendrocyte Glycoprotein Antibodies Across Neuroinflammatory And Neurodegenerative Diseases, Ritu R Trivedi, Angela S Archambault, Clarice Pavlak, Matteo Gastaldi, Claudia Cantoni, Laura Ghezzi, Anne H Cross, Timothy M Miller, Gregory F Wu

2020-Current year OA Pubs

Inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), are characterized by humoral immune abnormalities. Anti-MOG antibodies are not specific to MOGAD, with their presence described in MS. Autoantibodies may also be present and play a role in various neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease driven by motor neuron dysfunction. While immune involvement in ALS has been recognized, the presence of antibodies targeting CNS myelin antigens has not been established. We aimed to establish a live cell-based assay for quantification of serum anti-MOG IgG1 in …

Through The Cat-Map Gateway: A Brief History Of Cataract Genetics, Alan Shiels

2020-Current year OA Pubs

Clouding of the transparent eye lens, or cataract(s), is a leading cause of visual impairment that requires surgical replacement with a synthetic intraocular lens to effectively restore clear vision. Most frequently, cataract is acquired with aging as a multifactorial or complex trait. Cataract may also be inherited as a classic Mendelian trait-often with an early or pediatric onset-with or without other ocular and/or systemic features. Since the early 1990s, over 85 genes and loci have been genetically associated with inherited and/or age-related forms of cataract. While many of these underlying genes-including those for lens crystallins, connexins, and transcription factors-recapitulate signature …

Comorbid Neurotrauma Increases Neurodegenerative-Relevant Cognitive, Motor, And Autonomic Dysfunction In Patients With Rapid Eye Movement Sleep Behavior Disorder: A Substudy Of The North American Prodromal Synucleinopathy Consortium, Jonathan E Elliott, Jennifer Mcleland, Yo-El S Ju, Et Al.

2020-Current year OA Pubs

STUDY OBJECTIVES: Rapid eye movement sleep behavior disorder (RBD) is strongly associated with phenoconversion to an overt synucleinopathy, e.g. Parkinson's disease (PD), Lewy body dementia, and related disorders. Comorbid traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD)-henceforth "neurotrauma" (NT)-increase the odds of RBD by ~2.5-fold and are associated with an increased rate of service-connected PD in Veterans. Thus, RBD and NT are both independently associated with PD; however, it is unclear how NT influences neurological function in patients with RBD.

METHODS: Participants ≥18 years with overnight polysomnogram-confirmed RBD were enrolled between 8/2018 to 4/2021 through the North American Prodromal …

An Inducible Genetic Tool To Track And Manipulate Specific Microglial States Reveals Their Plasticity And Roles In Remyelination, Kia M Barclay, Nora Abduljawad, Min Woo Kim, Lu Zhou, Jin Yang, Justin Rustenhoven, Jose A Mazzitelli, Leon C D Smyth, Dvita Kapadia, Simone Brioschi, Wandy Beatty, Jinchao Hou, Naresha Saligrama, Marco Colonna, Jonathan Kipnis, Qingyun Li, Et Al.

2020-Current year OA Pubs

Recent single-cell RNA sequencing studies have revealed distinct microglial states in development and disease. These include proliferative-region-associated microglia (PAMs) in developing white matter and disease-associated microglia (DAMs) prevalent in various neurodegenerative conditions. PAMs and DAMs share a similar core gene signature. However, the extent of the dynamism and plasticity of these microglial states, as well as their functional significance, remains elusive, partly due to the lack of specific tools. Here, we generated an inducible Cre driver line, Clec7a-CreER

Limited Nerve Regeneration Across Acellular Nerve Allografts (Anas) Coincides With Changes In Blood Vessel Morphology And The Development Of A Pro-Inflammatory Microenvironment, Jesús A Acevedo Cintrón, Daniel A Hunter, Lauren Schellhardt, Deng Pan, Susan E Mackinnon, Matthew D Wood

2020-Current year OA Pubs

The use of acellular nerve allografts (ANAs) to reconstruct long nerve gaps (>3 cm) is associated with limited axon regeneration. To understand why ANA length might limit regeneration, we focused on identifying differences in the regenerative and vascular microenvironment that develop within ANAs based on their length. A rat sciatic nerve gap model was repaired with either short (2 cm) or long (4 cm) ANAs, and histomorphometry was used to measure myelinated axon regeneration and blood vessel morphology at various timepoints (2-, 4- and 8-weeks). Both groups demonstrated robust axonal regeneration within the proximal graft region, which continued across …

Tenovin-1, A Selective Sirt1/2 Inhibitor, Attenuates High-Fat Diet-Induced Hepatic Fibrosis Via Inhibition Of Hsc Activation In Zdf Rats, Swati Sharma, Sreevarsha Gali, Amit Kundu, Jae Hyeon Park, Jae-Sung Kim, Hyung Sik Kim

2020-Current year OA Pubs

Type 2 diabetes mellitus (T2DM) increases the risk of non-alcoholic fatty liver disease (NAFLD) progression to advanced stages, especially upon high-fat diet (HFD). HFD-induced hepatic fibrosis can be marked by oxidative stress, inflammation, and activation of hepatic stellate cells. Sirtuin 1/2 (SIRT1/2), NAD-dependent class III histone deacetylases, are involved in attenuation of fibrosis. In our conducted research, TGF-β1-activated LX-2 cells, free fatty acid (FFA)-treated simultaneous co-culture (SCC) cells, and HFD-induced hepatic fibrosis in Zucker diabetic fatty (ZDF) rats, a widely used animal model in the study of metabolic syndromes, were used to evaluate the protective effect of Tenovin-1, a SIRT1/2 …

Cis-Regulatory Evolution Of The Recently Expanded Ly49 Gene Family, Changxu Fan, Xiaoyun Xing, Samuel J H Murphy, Jennifer Poursine-Laurent, Heather Schmidt, Bijal A Parikh, Jeesang Yoon, Mayank N K Choudhary, Naresha Saligrama, Sytse J Piersma, Wayne M Yokoyama, Ting Wang

2020-Current year OA Pubs

Comparative genomics has revealed the rapid expansion of multiple gene families involved in immunity. Members within each gene family often evolved distinct roles in immunity. However, less is known about the evolution of their epigenome and cis-regulation. Here we systematically profile the epigenome of the recently expanded murine Ly49 gene family that mainly encode either inhibitory or activating surface receptors on natural killer cells. We identify a set of cis-regulatory elements (CREs) for activating Ly49 genes. In addition, we show that in mice, inhibitory and activating Ly49 genes are regulated by two separate sets of proximal CREs, likely resulting from …

Evaluation Of Copanlisib In Combination With Eribulin In Triple-Negative Breast Cancer Patient-Derived Xenograft Models, Zhanfang Guo, Jingqin Luo, R Jay Mashl, Jeremy Hoog, Piyush Maiti, Nikki Fettig, Sherri R Davies, Rebecca Aft, Jason M Held, Ramaswamy Govindan, Li Ding, Shunqiang Li, Cornelius Von Morze, Kooresh I Shoghi, Cynthia X Ma, Et Al.

2020-Current year OA Pubs

UNLABELLED: The PI3K pathway regulates essential cellular functions and promotes chemotherapy resistance. Activation of PI3K pathway signaling is commonly observed in triple-negative breast cancer (TNBC). However previous studies that combined PI3K pathway inhibitors with taxane regimens have yielded inconsistent results. We therefore set out to examine whether the combination of copanlisib, a clinical grade pan-PI3K inhibitor, and eribulin, an antimitotic chemotherapy approved for taxane-resistant metastatic breast cancer, improves the antitumor effect in TNBC. A panel of eight TNBC patient-derived xenograft (PDX) models was tested for tumor growth response to copanlisib and eribulin, alone or in combination. Treatment-induced signaling changes were …

Tl1a And Il-18 Synergy Promotes Gm-Csf-Dependent Thymic Granulopoiesis In Mice, Mario Ruiz Pérez, Kodi Ravichandran, Et Al.

2020-Current year OA Pubs

Acute systemic inflammation critically alters the function of the immune system, often promoting myelopoiesis at the expense of lymphopoiesis. In the thymus, systemic inflammation results in acute thymic atrophy and, consequently, impaired T-lymphopoiesis. The mechanism by which systemic inflammation impacts the thymus beyond suppressing T-cell development is still unclear. Here, we describe how the synergism between TL1A and IL-18 suppresses T-lymphopoiesis to promote thymic myelopoiesis. The protein levels of these two cytokines were elevated in the thymus during viral-induced thymus atrophy infection with murine cytomegalovirus (MCMV) or pneumonia virus of mice (PVM). In vivo administration of TL1A and IL-18 induced …

Generalized Genetic Liability To Substance Use Disorders, Alex P. Miller, Ryan Bogdan, Arpana Agrawal, Alexander S. Hatoum

2020-Current year OA Pubs

Lifetime and temporal co-occurrence of substance use disorders (SUDs) is common and compared with individual SUDs is characterized by greater severity, additional psychiatric comorbidities, and worse outcomes. Here, we review evidence for the role of generalized genetic liability to various SUDs. Coaggregation of SUDs has familial contributions, with twin studies suggesting a strong contribution of additive genetic influences undergirding use disorders for a variety of substances (including alcohol, nicotine, cannabis, and others). GWAS have documented similarly large genetic correlations between alcohol, cannabis, and opioid use disorders. Extending these findings, recent studies have identified multiple genomic loci that contribute to common …

Glutamatergic Supramammillary Nucleus Neurons Respond To Threatening Stressors And Promote Active Coping, Abraham Escobedo, Salli-Ann Holloway, Megan Votoupal, Aaron L Cone, Hannah Skelton, Alex A Legaria, Imeh Ndiokho, Tasheia Floyd, Alexxai V Kravitz, Michael R Bruchas, Aaron J Norris

2020-Current year OA Pubs

Threat-response neural circuits are conserved across species and play roles in normal behavior and psychiatric diseases. Maladaptive changes in these neural circuits contribute to stress, mood, and anxiety disorders. Active coping in response to stressors is a psychosocial factor associated with resilience against stress-induced mood and anxiety disorders. The neural circuitry underlying active coping is poorly understood, but the functioning of these circuits could be key for overcoming anxiety and related disorders. The supramammillary nucleus (SuM) has been suggested to be engaged by threat. SuM has many projections and a poorly understood diversity of neural populations. In studies using mice, …

Hexamerization: Explaining The Original Sin Of Igg-Mediated Complement Activation In Acute Lung Injury, Hrishikesh S. Kulkarni

2020-Current year OA Pubs

Although antibody-mediated lung damage is a major factor in transfusion-related acute lung injury (ALI), autoimmune lung disease (for example, coatomer subunit α [COPA] syndrome), and primary graft dysfunction following lung transplantation, the mechanism by which antigen-antibody complexes activate complement to induce lung damage remains unclear. In this issue of the JCI, Cleary and colleagues utilized several approaches to demonstrate that IgG forms hexamers with MHC class I alloantibodies. This hexamerization served as a key pathophysiological mechanism in alloimmune lung injury models and was mediated through the classical pathway of complement activation. Additionally, the authors provided avenues for exploring therapeutics for …

Neutrophils And Galectin-3 Defend Mice From Lethal Bacterial Infection And Humans From Acute Respiratory Failure, Sudipta Das, Janet S Lee, Et Al.

2020-Current year OA Pubs

Respiratory infection by Pseudomonas aeruginosa, common in hospitalized immunocompromised and immunocompetent ventilated patients, can be life-threatening because of antibiotic resistance. This raises the question of whether the host's immune system can be educated to combat this bacterium. Here we show that prior exposure to a single low dose of lipopolysaccharide (LPS) protects mice from a lethal infection by P. aeruginosa. LPS exposure trained the innate immune system by promoting expansion of neutrophil and interstitial macrophage populations distinguishable from other immune cells with enrichment of gene sets for phagocytosis- and cell-killing-associated genes. The cell-killing gene set in the neutrophil population uniquely …

Single-Cell Lineage Capture Across Genomic Modalities With Celltag-Multi Reveals Fate-Specific Gene Regulatory Changes, Kunal Jindal, Mohd Tayyab Adil, Naoto Yamaguchi, Xue Yang, Helen C Wang, Kenji Kamimoto, Guillermo C Rivera-Gonzalez, Samantha A Morris

2020-Current year OA Pubs

Complex gene regulatory mechanisms underlie differentiation and reprogramming. Contemporary single-cell lineage-tracing (scLT) methods use expressed, heritable DNA barcodes to combine cell lineage readout with single-cell transcriptomics. However, reliance on transcriptional profiling limits adaptation to other single-cell assays. With CellTag-multi, we present an approach that enables direct capture of heritable random barcodes expressed as polyadenylated transcripts, in both single-cell RNA sequencing and single-cell Assay for Transposase Accessible Chromatin using sequencing assays, allowing for independent clonal tracking of transcriptional and epigenomic cell states. We validate CellTag-multi to characterize progenitor cell lineage priming during mouse hematopoiesis. Additionally, in direct reprogramming of fibroblasts to …

Skeletal Abnormalities In Mice With Dnmt3a Missense Mutations, Austin Bell-Hensley, Diana C Beard, Kathryn Feeney, Hongjun Zheng, Yunhao Jiang, Xiyun Zhang, Jin Liu, Harrison Gabel, Audrey Mcalinden

2020-Current year OA Pubs

Overgrowth and intellectual disability disorders in humans are typified by length/height and/or head circumference ≥ 2 standard deviations above the mean as well as intellectual disability and behavioral comorbidities, including autism and anxiety. Tatton-Brown-Rahman Syndrome is one type of overgrowth and intellectual disability disorder caused by heterozygous missense mutations in the DNA methyltransferase 3A (DNMT3A) gene. Numerous DNMT3A mutations have been identified in Tatton-Brown-Rahman Syndrome patients and may be associated with varying phenotype severities of clinical presentation. Two such mutations are the R882H and P904L mutations which result in severe and mild phenotypes, respectively. Mice with paralogous mutations (Dnmt3a

Ethological Computational Psychiatry: Challenges And Opportunities, Ilya E Monosov, Jan Zimmermann, Michael J Frank, Mackenzie W Mathis, Justin T Baker

2020-Current year OA Pubs

Studying the intricacies of individual subjects' moods and cognitive processing over extended periods of time presents a formidable challenge in medicine. While much of systems neuroscience appropriately focuses on the link between neural circuit functions and well-constrained behaviors over short timescales (e.g., trials, hours), many mental health conditions involve complex interactions of mood and cognition that are non-stationary across behavioral contexts and evolve over extended timescales. Here, we discuss opportunities, challenges, and possible future directions in computational psychiatry to quantify non-stationary continuously monitored behaviors. We suggest that this exploratory effort may contribute to a more precision-based approach to treating mental …