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The Subcortical And Neurochemical Organization Of The Ventral And Dorsal Attention Networks, Pedro Nascimento Alves, Stephanie J Forkel, Maurizio Corbetta, Michel Thiebaut De Schotten Dec 2022

The Subcortical And Neurochemical Organization Of The Ventral And Dorsal Attention Networks, Pedro Nascimento Alves, Stephanie J Forkel, Maurizio Corbetta, Michel Thiebaut De Schotten

2020-Current year OA Pubs

Attention is a core cognitive function that filters and selects behaviourally relevant information in the environment. The cortical mapping of attentional systems identified two segregated networks that mediate stimulus-driven and goal-driven processes, the Ventral and the Dorsal Attention Networks (VAN, DAN). Deep brain electrophysiological recordings, behavioral data from phylogenetic distant species, and observations from human brain pathologies challenge purely corticocentric models. Here, we used advanced methods of functional alignment applied to resting-state functional connectivity analyses to map the subcortical architecture of the Ventral and Dorsal Attention Networks. Our investigations revealed the involvement of the pulvinar, the superior colliculi, the head …


Acetyl-Coa-Mediated Autoacetylation Of Fatty Acid Synthase As A Metabolic Switch Of De Novo Lipogenesis In Drosophila, Ting Miao, Jinoh Kim, Ping Kang, Hideji Fujiwara, Fong-Fu Hsu, Hua Bai Dec 2022

Acetyl-Coa-Mediated Autoacetylation Of Fatty Acid Synthase As A Metabolic Switch Of De Novo Lipogenesis In Drosophila, Ting Miao, Jinoh Kim, Ping Kang, Hideji Fujiwara, Fong-Fu Hsu, Hua Bai

2020-Current year OA Pubs

De novo lipogenesis is a highly regulated metabolic process, which is known to be activated through transcriptional regulation of lipogenic genes, including fatty acid synthase (FASN). Unexpectedly, we find that the expression of FASN protein remains unchanged during


Future Newborns With Opioid-Induced Neonatal Abstinence Syndrome (Nas) Could Be Assessed With The Genetic Addiction Risk Severity (Gars) Test And Potentially Treated Using Precision Amino-Acid Enkephalinase Inhibition Therapy (Kb220) As A Frontline Modality Instead Of Potent Opioids, Mauro Ceccanti, Mark S Gold, Et Al. Dec 2022

Future Newborns With Opioid-Induced Neonatal Abstinence Syndrome (Nas) Could Be Assessed With The Genetic Addiction Risk Severity (Gars) Test And Potentially Treated Using Precision Amino-Acid Enkephalinase Inhibition Therapy (Kb220) As A Frontline Modality Instead Of Potent Opioids, Mauro Ceccanti, Mark S Gold, Et Al.

2020-Current year OA Pubs

In this nonsystematic review and opinion, including articles primarily selected from PubMed, we examine the pharmacological and nonpharmacological treatments of neonatal abstinence syndrome (NAS) in order to craft a reasonable opinion to help forge a paradigm shift in the treatment and prevention of primarily opioid-induced NAS. Newborns of individuals who use illicit and licit substances during pregnancy are at risk for withdrawal, also known as NAS. In the US, the reported prevalence of NAS has increased from 4.0 per 1000 hospital births in 2010 to 7.3 per 1000 hospital births in 2017, which is an 82% increase. The management of …


Impact Of International Travel And Diarrhea On Gut Microbiome And Resistome Dynamics, Manish Boolchandani, Kevin S Blake, Drake H Tilley, Miguel M Cabada, Drew J Schwartz, Sanket Patel, Maria Luisa Morales, Rina Meza, Giselle Soto, Sandra D Isidean, Chad K Porter, Mark P Simons, Gautam Dantas Dec 2022

Impact Of International Travel And Diarrhea On Gut Microbiome And Resistome Dynamics, Manish Boolchandani, Kevin S Blake, Drake H Tilley, Miguel M Cabada, Drew J Schwartz, Sanket Patel, Maria Luisa Morales, Rina Meza, Giselle Soto, Sandra D Isidean, Chad K Porter, Mark P Simons, Gautam Dantas

2020-Current year OA Pubs

International travel contributes to the global spread of antimicrobial resistance. Travelers' diarrhea exacerbates the risk of acquiring multidrug-resistant organisms and can lead to persistent gastrointestinal disturbance post-travel. However, little is known about the impact of diarrhea on travelers' gut microbiomes, and the dynamics of these changes throughout travel. Here, we assembled a cohort of 159 international students visiting the Andean city of Cusco, Peru and applied next-generation sequencing techniques to 718 longitudinally-collected stool samples. We find that gut microbiome composition changed significantly throughout travel, but taxonomic diversity remained stable. However, diarrhea disrupted this stability and resulted in an increased abundance …


The Polyamine Spermine Potentiates The Propagation Of Negatively Charged Molecules Through The Astrocytic Syncytium, Jan Benedikt, Christian J Malpica-Nieves, Yomarie Rivera, Miguel Méndez-González, Colin G Nichols, Rüdiger W Veh, Misty J Eaton, Serguei N Skatchkov Dec 2022

The Polyamine Spermine Potentiates The Propagation Of Negatively Charged Molecules Through The Astrocytic Syncytium, Jan Benedikt, Christian J Malpica-Nieves, Yomarie Rivera, Miguel Méndez-González, Colin G Nichols, Rüdiger W Veh, Misty J Eaton, Serguei N Skatchkov

2020-Current year OA Pubs

The interest in astrocytes, the silent brain cells that accumulate polyamines (PAs), is growing. PAs exert anti-inflammatory, antioxidant, antidepressant, neuroprotective, and other beneficial effects, including increasing longevity in vivo. Unlike neurons, astrocytes are extensively coupled to others via connexin (Cx) gap junctions (GJs). Although there are striking modulatory effects of PAs on neuronal receptors and channels, PA regulation of the astrocytic GJs is not well understood. We studied GJ-propagation using molecules of different (i) electrical charge, (ii) structure, and (iii) molecular weight. Loading single astrocytes with patch pipettes containing membrane-impermeable dyes, we observed that (i) even small molecules do not …


Federated Learning Enables Big Data For Rare Cancer Boundary Detection, Sarthak Pati, Pamela Lamontagne, Daniel Marcus, Et Al. Dec 2022

Federated Learning Enables Big Data For Rare Cancer Boundary Detection, Sarthak Pati, Pamela Lamontagne, Daniel Marcus, Et Al.

2020-Current year OA Pubs

No abstract provided.


Genome-Edited Zebrafish Model Of Abcc8 Loss-Of-Function Disease, Jennifer M Ikle, Robert C Tryon, Soma S Singareddy, Nathaniel W York, Maria S Remedi, Colin G Nichols Dec 2022

Genome-Edited Zebrafish Model Of Abcc8 Loss-Of-Function Disease, Jennifer M Ikle, Robert C Tryon, Soma S Singareddy, Nathaniel W York, Maria S Remedi, Colin G Nichols

2020-Current year OA Pubs

ATP-sensitive potassium channel (K


Identification Of Novel Antifungal Skeleton Of Hydroxyethyl Naphthalimides With Synergistic Potential For Chemical And Dynamic Treatments, Pengli Zhang, Vijai Kumar Reddy Tangadanchu, Chenghe Zhou Dec 2022

Identification Of Novel Antifungal Skeleton Of Hydroxyethyl Naphthalimides With Synergistic Potential For Chemical And Dynamic Treatments, Pengli Zhang, Vijai Kumar Reddy Tangadanchu, Chenghe Zhou

2020-Current year OA Pubs

The invasion of pathogenic fungi poses nonnegligible threats to the human health and agricultural industry. This work exploited a family of hydroxyethyl naphthalimides as novel antifungal species with synergistic potential of chemical and dynamic treatment to combat the fungal resistance. These prepared naphthalimides showed better antifungal potency than fluconazole towards some tested fungi including


Distinct Tumor Necrosis Factor Alpha Receptors Dictate Stem Cell Fitness Versus Lineage Output In Dnmt3a-Mutant Clonal Hematopoiesis, Jennifer M Sanmiguel, Elizabeth Eudy, Matthew A Loberg, Kira A Young, Jayna J Mistry, Kristina D Mujica, Logan S Schwartz, Timothy M Stearns, Grant A Challen, Jennifer J Trowbridge Dec 2022

Distinct Tumor Necrosis Factor Alpha Receptors Dictate Stem Cell Fitness Versus Lineage Output In Dnmt3a-Mutant Clonal Hematopoiesis, Jennifer M Sanmiguel, Elizabeth Eudy, Matthew A Loberg, Kira A Young, Jayna J Mistry, Kristina D Mujica, Logan S Schwartz, Timothy M Stearns, Grant A Challen, Jennifer J Trowbridge

2020-Current year OA Pubs

UNLABELLED: Clonal hematopoiesis resulting from the enhanced fitness of mutant hematopoietic stem cells (HSC) associates with both favorable and unfavorable health outcomes related to the types of mature mutant blood cells produced, but how this lineage output is regulated is unclear. Using a mouse model of a clonal hematopoiesis-associated mutation, DNMT3AR882/+ (Dnmt3aR878H/+), we found that aging-induced TNFα signaling promoted the selective advantage of mutant HSCs and stimulated the production of mutant B lymphoid cells. The genetic loss of the TNFα receptor TNFR1 ablated the selective advantage of mutant HSCs without altering their lineage output, whereas the loss of TNFR2 resulted …


First-Generation And Continuing-Generation College Graduates' Application, Acceptance, And Matriculation To U.S. Medical Schools: A National Cohort Study, Hyacinth R C Mason, Ashar Ata, Mytien Nguyen, Sunny Nakae, Devasmita Chakraverty, Branden Eggan, Sarah Martinez, Donna B Jeffe Dec 2022

First-Generation And Continuing-Generation College Graduates' Application, Acceptance, And Matriculation To U.S. Medical Schools: A National Cohort Study, Hyacinth R C Mason, Ashar Ata, Mytien Nguyen, Sunny Nakae, Devasmita Chakraverty, Branden Eggan, Sarah Martinez, Donna B Jeffe

Open Access Publications

Many U.S. medical schools conduct holistic review of applicants to enhance the socioeconomic and experiential diversity of the physician workforce. The authors examined the role of first-generation college-graduate status on U.S. medical school application, acceptance, and matriculation, hypothesizing that first-generation (vs. continuing-generation) college graduates would be less likely to apply and gain acceptance to medical school.Secondary analysis of de-identified data from a retrospective national-cohort study was conducted for individuals who completed the 2001-2006 Association of American Medical Colleges (AAMC) Pre-Medical College Admission Test Questionnaire (PMQ) and the Medical College Admissions Test (MCAT). AAMC provided medical school application, acceptance, and matriculation …


Diptoindonesin G Is A Middle Domain Hsp90 Modulator For Cancer Treatment, Kristine Donahue, Haibo Xie, Miyang Li, Ang Gao, Min Ma, Yidan Wang, Rose Tipton, Nicole Semanik, Tina Primeau, Shunqiang Li, Lingjun Li, Weiping Tang, Wei Xu Dec 2022

Diptoindonesin G Is A Middle Domain Hsp90 Modulator For Cancer Treatment, Kristine Donahue, Haibo Xie, Miyang Li, Ang Gao, Min Ma, Yidan Wang, Rose Tipton, Nicole Semanik, Tina Primeau, Shunqiang Li, Lingjun Li, Weiping Tang, Wei Xu

2020-Current year OA Pubs

HSP90 inhibitors can target many oncoproteins simultaneously, but none have made it through clinical trials due to dose-limiting toxicity and induction of heat shock response, leading to clinical resistance. We identified diptoindonesin G (dip G) as an HSP90 modulator that can promote degradation of HSP90 clients by binding to the middle domain of HSP90 (K


Examining Shortened Versions Of The Social Responsiveness Scale For Use In Autism Spectrum Disorder Prediction And As A Quantitative Trait Measure: Results From A Validation Study Of 3-5 Year Old Children, Kristen Lyall, Juliette Rando, Bridget Toroni, Tobechukwu Ezeh, John N Constantino, Lisa A Croen, Brigid Garvin, Kate Piselli, James Connell, Aaron J Kaat, Craig J Newschaffer, Program Collaborators For Environmental Influences On Child Health Outcomes Dec 2022

Examining Shortened Versions Of The Social Responsiveness Scale For Use In Autism Spectrum Disorder Prediction And As A Quantitative Trait Measure: Results From A Validation Study Of 3-5 Year Old Children, Kristen Lyall, Juliette Rando, Bridget Toroni, Tobechukwu Ezeh, John N Constantino, Lisa A Croen, Brigid Garvin, Kate Piselli, James Connell, Aaron J Kaat, Craig J Newschaffer, Program Collaborators For Environmental Influences On Child Health Outcomes

2020-Current year OA Pubs

BACKGROUND: The Social Responsiveness Scale (SRS) is a 65-item measure yielding a continuous score capturing autism-related traits. Scores based on SRS item subsets have been analytically examined but administration of shortened versions has not been evaluated prospectively.

OBJECTIVE: The goal of this study was to compare psychometric properties of two shortened versions of the SRS to the full 65-item SRS, in young children from both a clinical and general population setting.

METHODS: Study participants (aged 3-5 years) were drawn from the AJ Drexel Autism Institute clinic (

RESULTS: Overall, distributional properties of the three administration methods were highly comparable, with …


Transferability Of Alzheimer Disease Polygenic Risk Score Across Populations And Its Association With Alzheimer Disease-Related Phenotypes, Sang-Hyuk Jung, Carlos Cruchaga, Et Al. Dec 2022

Transferability Of Alzheimer Disease Polygenic Risk Score Across Populations And Its Association With Alzheimer Disease-Related Phenotypes, Sang-Hyuk Jung, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

IMPORTANCE: Polygenic risk scores (PRSs), which aggregate the genetic effects of single-nucleotide variants identified in genome-wide association studies (GWASs), can help distinguish individuals at a high genetic risk for Alzheimer disease (AD). However, genetic studies have predominantly focused on populations of European ancestry.

OBJECTIVE: To evaluate the transferability of a PRS for AD in the Korean population using summary statistics from a prior GWAS of European populations.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study developed a PRS based on the summary statistics of a large-scale GWAS of a European population (the International Genomics of Alzheimer Project; 21 982 AD cases …


Basal Bodies Bend In Response To Ciliary Forces, Anthony D Junker, Louis G Woodhams, Adam W J Soh, Eileen T O'Toole, Philip V Bayly, Chad G Pearson Dec 2022

Basal Bodies Bend In Response To Ciliary Forces, Anthony D Junker, Louis G Woodhams, Adam W J Soh, Eileen T O'Toole, Philip V Bayly, Chad G Pearson

2020-Current year OA Pubs

Motile cilia beat with an asymmetric waveform consisting of a power stroke that generates a propulsive force and a recovery stroke that returns the cilium back to the start. Cilia are anchored to the cell cortex by basal bodies (BBs) that are directly coupled to the ciliary doublet microtubules (MTs). We find that, consistent with ciliary forces imposing on BBs, bending patterns in BB triplet MTs are responsive to ciliary beating. BB bending varies as environmental conditions change the ciliary waveform. Bending occurs where striated fibers (SFs) attach to BBs and mutants with short SFs that fail to connect to …


The Clinical Spectrum Of Sma-Pme And In Vitro Normalization Of Its Cellular Ceramide Profile, Michelle M Lee, Toni S Pearson, Et Al. Dec 2022

The Clinical Spectrum Of Sma-Pme And In Vitro Normalization Of Its Cellular Ceramide Profile, Michelle M Lee, Toni S Pearson, Et Al.

2020-Current year OA Pubs

OBJECTIVE: The objectives of this study were to define the clinical and biochemical spectrum of spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) and to determine if aberrant cellular ceramide accumulation could be normalized by enzyme replacement.

METHODS: Clinical features of 6 patients with SMA-PME were assessed by retrospective chart review, and a literature review of 24 previously published cases was performed. Leukocyte enzyme activity of acid ceramidase was assessed with a fluorescence-based assay. Skin fibroblast ceramide content and was assessed by high performance liquid chromatography, electrospray ionization tandem mass spectroscopy. Enzyme replacement was assessed using recombinant human acid ceramidase …


X-Linked Hypophosphatemia Caused By The Prevailing North American Phex Variant C.*231a>G; Exon 13–15 Duplication Is Often Misdiagnosed As Ankylosing Spondylitis And Manifests In Both Men And Women, Kathryn Mccrystal Dahir, Margo Black, Gary S Gottesman, Erik A Imel, Steven Mumm, Cindy M Nichols, Michael P Whyte Dec 2022

X-Linked Hypophosphatemia Caused By The Prevailing North American Phex Variant C.*231a>G; Exon 13–15 Duplication Is Often Misdiagnosed As Ankylosing Spondylitis And Manifests In Both Men And Women, Kathryn Mccrystal Dahir, Margo Black, Gary S Gottesman, Erik A Imel, Steven Mumm, Cindy M Nichols, Michael P Whyte

2020-Current year OA Pubs

Inactivating mutations of the gene coding for phosphate-regulating endopeptidase homolog X-linked (PHEX) cause X-linked hypophosphatemia (XLH). A novel


Vascular Endothelial-Cadherin As A Marker Of Endothelial Injury In Preclinical Alzheimer Disease, Rawan Tarawneh, Rachel S Kasper, Jessie Sanford, Chia-Ling Phuah, Jason Hassenstab, Carlos Cruchaga Dec 2022

Vascular Endothelial-Cadherin As A Marker Of Endothelial Injury In Preclinical Alzheimer Disease, Rawan Tarawneh, Rachel S Kasper, Jessie Sanford, Chia-Ling Phuah, Jason Hassenstab, Carlos Cruchaga

2020-Current year OA Pubs

OBJECTIVE: Endothelial dysfunction is an early and prevalent pathology in Alzheimer disease (AD). We here investigate the value of vascular endothelial-cadherin (VEC) as a cerebrospinal fluid (CSF) marker of endothelial injury in preclinical AD.

METHODS: Cognitively normal participants (Clinical Dementia Rating [CDR] 0) from the Knight Washington University-ADRC were included in this study (n = 700). Preclinical Alzheimer's Cognitive Composite (PACC) scores, CSF VEC, tau, p-tau181, Aβ42/Aβ40, neurofilament light-chain (NFL) levels, and magnetic resonance imaging (MRI) assessments of white matter injury (WMI) were obtained from all participants. A subset of participants underwent brain amyloid imaging using positron emission tomography (amyloid-PET) …


The Clinical Landscape Of Cell-Free Dna Alterations In 1671 Patients With Advanced Biliary Tract Cancer, J E Berchuck, B Tan, Et Al. Dec 2022

The Clinical Landscape Of Cell-Free Dna Alterations In 1671 Patients With Advanced Biliary Tract Cancer, J E Berchuck, B Tan, Et Al.

2020-Current year OA Pubs

BACKGROUND: Targeted therapies have transformed clinical management of advanced biliary tract cancer (BTC). Cell-free DNA (cfDNA) analysis is an attractive approach for cancer genomic profiling that overcomes many limitations of traditional tissue-based analysis. We examined cfDNA as a tool to inform clinical management of patients with advanced BTC and generate novel insights into BTC tumor biology.

PATIENTS AND METHODS: We analyzed next-generation sequencing data of 2068 cfDNA samples from 1671 patients with advanced BTC generated with Guardant360. We carried out clinical annotation on a multi-institutional subset (n = 225) to assess intra-patient cfDNA-tumor concordance and the association of cfDNA variant …


Listeria Motility Increases The Efficiency Of Epithelial Invasion During Intestinal Infection, Inge M. N. Wortel, Seonyoung Kim, Annie Y. Liu, Enid C. Ibarra, Mark J. Miller Dec 2022

Listeria Motility Increases The Efficiency Of Epithelial Invasion During Intestinal Infection, Inge M. N. Wortel, Seonyoung Kim, Annie Y. Liu, Enid C. Ibarra, Mark J. Miller

2020-Current year OA Pubs

Listeria monocytogenes (Lm) is a food-borne pathogen that causes severe bacterial gastroenteritis, with high rates of hospitalization and mortality. Lm is ubiquitous in soil, water and livestock, and can survive and proliferate at low temperatures. Following oral ingestion of contaminated food, Lm crosses the epithelium through intestinal goblet cells in a mechanism mediated by Lm InlA binding host E-cadherin. Importantly, human infections typically occur with Lm growing at or below room temperature, which is flagellated and motile. Even though many important human bacterial pathogens are flagellated, little is known regarding the effect of Lm motility on invasion and immune evasion. …


Mouse Tissue Harvest-Induced Hypoxia Rapidly Alters The In Vivo Metabolome, Between-Genotype Metabolite Level Differences, And 13c-Tracing Enrichments, Adam J Rauckhorst, Nicholas Borcherding, Daniel J Pape, Alora S Kraus, Diego A Scerbo, Eric B Taylor Dec 2022

Mouse Tissue Harvest-Induced Hypoxia Rapidly Alters The In Vivo Metabolome, Between-Genotype Metabolite Level Differences, And 13c-Tracing Enrichments, Adam J Rauckhorst, Nicholas Borcherding, Daniel J Pape, Alora S Kraus, Diego A Scerbo, Eric B Taylor

2020-Current year OA Pubs

OBJECTIVE: Metabolomics as an approach to solve biological problems is exponentially increasing in use. Thus, this a pivotal time for the adoption of best practices. It is well known that disrupted tissue oxygen supply rapidly alters cellular energy charge. However, the speed and extent to which delayed mouse tissue freezing after dissection alters the broad metabolome is not well described. Furthermore, how tissue genotype may modulate such metabolomic drift and the degree to which traced

METHODS: By combined liquid chromatography (LC)- and gas chromatography (GC)-mass spectrometry (MS), we measured how levels of 255 mouse liver metabolites changed following 30-second, 1-minute, …


G Protein Gamma Subunit, A Hidden Master Regulator Of Gpcr Signaling, Dinesh Kankanamge, Mithila Tennakoon, Ajith Karunarathne, N Gautam Dec 2022

G Protein Gamma Subunit, A Hidden Master Regulator Of Gpcr Signaling, Dinesh Kankanamge, Mithila Tennakoon, Ajith Karunarathne, N Gautam

2020-Current year OA Pubs

Heterotrimeric G proteins (αβγ subunits) that are activated by G protein-coupled receptors (GPCRs) mediate the biological responses of eukaryotic cells to extracellular signals. The α subunits and the tightly bound βγ subunit complex of G proteins have been extensively studied and shown to control the activity of effector molecules. In contrast, the potential roles of the large family of γ subunits have been less studied. In this review, we focus on present knowledge about these proteins. Induced loss of individual γ subunit types in animal and plant models result in strikingly distinct phenotypes indicating that γ subtypes play important and …


Identification Of Patients With Ovarian Cancer Experiencing The Highest Benefit From Bevacizumab In The First-Line Setting On The Basis Of Their Tumor-Intrinsic Chemosensitivity (Kelim): The Gog-0218 Validation Study, Benoit You, David Mutch, Et Al. Dec 2022

Identification Of Patients With Ovarian Cancer Experiencing The Highest Benefit From Bevacizumab In The First-Line Setting On The Basis Of Their Tumor-Intrinsic Chemosensitivity (Kelim): The Gog-0218 Validation Study, Benoit You, David Mutch, Et Al.

2020-Current year OA Pubs

PURPOSE: In patients with high-grade ovarian cancer, predictors of bevacizumab efficacy in first-line setting are needed. In the ICON-7 trial, a poor tumor intrinsic chemosensitivity (defined by unfavorable modeled cancer antigen-125 [CA-125] ELIMination rate constant K [KELIM] score) was a predictive biomarker. Only the patients with high-risk disease (suboptimally resected stage III, or stage IV) exhibiting unfavorable KELIM score < 1.0 had overall survival (OS) benefit from bevacizumab (median: 29.7

METHODS: In GOG-0218, 1,873 patients were treated with carboplatin-paclitaxel ± concurrent-maintenance bevacizumab/placebo. Patient KELIM values were calculated with CA-125 kinetics during the first 100 chemotherapy days by the Lyon University team. The association between KELIM score (favorable ≥ 1.0, or unfavorable …


Cognition And The Single Neuron: How Cell Types Construct The Dynamic Computations Of Frontal Cortex, Amelia J Christensen, Torben Ott, Adam Kepecs Dec 2022

Cognition And The Single Neuron: How Cell Types Construct The Dynamic Computations Of Frontal Cortex, Amelia J Christensen, Torben Ott, Adam Kepecs

2020-Current year OA Pubs

Frontal cortex is thought to underlie many advanced cognitive capacities, from self-control to long term planning. Reflecting these diverse demands, frontal neural activity is notoriously idiosyncratic, with tuning properties that are correlated with endless numbers of behavioral and task features. This menagerie of tuning has made it difficult to extract organizing principles that govern frontal neural activity. Here, we contrast two successful yet seemingly incompatible approaches that have begun to address this challenge. Inspired by the indecipherability of single-neuron tuning, the first approach casts frontal computations as dynamical trajectories traversed by arbitrary mixtures of neurons. The second approach, by contrast, …


A Novel, Likely Pathogenic Variant In Ubtf-Related Neurodegeneration With Brain Atrophy Is Associated With A Severe Divergent Neurodevelopmental Phenotype, Rory J Tinker, Tiffany Guess, David C Rinker, Jonathan H Sheehan, Daniel Lubarsky, Binu Porath, Mackenzie Mosera, Ping Mayo, Emily Solem, Laura A Lee, Asha Sharam, Jennifer Brault Dec 2022

A Novel, Likely Pathogenic Variant In Ubtf-Related Neurodegeneration With Brain Atrophy Is Associated With A Severe Divergent Neurodevelopmental Phenotype, Rory J Tinker, Tiffany Guess, David C Rinker, Jonathan H Sheehan, Daniel Lubarsky, Binu Porath, Mackenzie Mosera, Ping Mayo, Emily Solem, Laura A Lee, Asha Sharam, Jennifer Brault

2020-Current year OA Pubs

BACKGROUND: A de novo, pathogenic, missense variant in UBTF, c.628G>A p.Glu210Lys, has been described as the cause of an emerging neurodegenerative disorder, Childhood-Onset Neurodegeneration with Brain Atrophy (CONDBA). The p.Glu210Lys alteration yields a positively charged stretch of three lysine residues. Functional studies confirmed this change results in a stronger interaction with negatively charged DNA and gain-of-function activity when compared to the wild-type sequence. The CONDBA phenotype reported in association with p.Glu210Lys consists of normal early-neurodevelopment followed by progressive motor, cognitive, and behavioral regression in early-to-middle childhood.

METHODS AND RESULTS: The current proband presented at 9 months of age with …


Targeting The Autophagy-Lysosome Pathway In A Pathophysiologically Relevant Murine Model Of Reversible Heart Failure, Sarah Evans, Xiucui Ma, Xiqiang Wang, Yana Chen, Chen Zhao, Carla J Weinheimer, Attila Kovacs, Brian Finck, Abhinav Diwan, Douglas L Mann Dec 2022

Targeting The Autophagy-Lysosome Pathway In A Pathophysiologically Relevant Murine Model Of Reversible Heart Failure, Sarah Evans, Xiucui Ma, Xiqiang Wang, Yana Chen, Chen Zhao, Carla J Weinheimer, Attila Kovacs, Brian Finck, Abhinav Diwan, Douglas L Mann

2020-Current year OA Pubs

The key biological "drivers" that are responsible for reverse left ventricle (LV) remodeling are not well understood. To gain an understanding of the role of the autophagy-lysosome pathway in reverse LV remodeling, we used a pathophysiologically relevant murine model of reversible heart failure, wherein pressure overload by transaortic constriction superimposed on acute coronary artery (myocardial infarction) ligation leads to a heart failure phenotype that is reversible by hemodynamic unloading. Here we show transaortic constriction + myocardial infarction leads to decreased flux through the autophagy-lysosome pathway with the accumulation of damaged proteins and organelles in cardiac myocytes, whereas hemodynamic unloading is …


A Sarm1-Mitochondrial Feedback Loop Drives Neuropathogenesis In A Charcot-Marie-Tooth Disease Type 2a Rat Model, Yurie Sato-Yamada, Amy Strickland, Yo Sasaki, Joseph Bloom, Aaron Diantonio, Jeffrey Milbrandt Dec 2022

A Sarm1-Mitochondrial Feedback Loop Drives Neuropathogenesis In A Charcot-Marie-Tooth Disease Type 2a Rat Model, Yurie Sato-Yamada, Amy Strickland, Yo Sasaki, Joseph Bloom, Aaron Diantonio, Jeffrey Milbrandt

2020-Current year OA Pubs

Charcot-Marie-Tooth disease type 2A (CMT2A) is an axonal neuropathy caused by mutations in the mitofusin 2 (MFN2) gene. MFN2 mutations result in profound mitochondrial abnormalities, but the mechanism underlying the axonal pathology is unknown. Sterile α and Toll/IL-1 receptor motif-containing 1 (SARM1), the central executioner of axon degeneration, can induce neuropathy and is activated by dysfunctional mitochondria. We tested the role of SARM1 in a rat model carrying a dominant CMT2A mutation (Mfn2H361Y) that exhibits progressive dying-back axonal degeneration, neuromuscular junction (NMJ) abnormalities, muscle atrophy, and mitochondrial abnormalities - all hallmarks of the human disease. We generated Sarm1-KO (Sarm1-/-) and …


Macrophage Depletion Blocks Congenital Sarm1-Dependent Neuropathy, Caitlin B Dingwall, Amy Strickland, Sabrina W Yum, Aldrin Ky Yim, Jian Zhu, Peter L. Wang, Yurie Yamada, Robert E. Schmidt, Yo Sasaki, A. Joseph Bloom, Aaron Diantonio, Jeffrey Milbrandt Dec 2022

Macrophage Depletion Blocks Congenital Sarm1-Dependent Neuropathy, Caitlin B Dingwall, Amy Strickland, Sabrina W Yum, Aldrin Ky Yim, Jian Zhu, Peter L. Wang, Yurie Yamada, Robert E. Schmidt, Yo Sasaki, A. Joseph Bloom, Aaron Diantonio, Jeffrey Milbrandt

2020-Current year OA Pubs

Axon loss contributes to many common neurodegenerative disorders. In healthy axons, the axon survival factor NMNAT2 inhibits SARM1, the central executioner of programmed axon degeneration. We identified 2 rare NMNAT2 missense variants in 2 brothers afflicted with a progressive neuropathy syndrome. The polymorphisms resulted in amino acid substitutions V98M and R232Q, which reduced NMNAT2 NAD+-synthetase activity. We generated a mouse model to mirror the human syndrome and found that Nmnat2V98M/R232Q compound-heterozygous CRISPR mice survived to adulthood but developed progressive motor dysfunction, peripheral axon loss, and macrophage infiltration. These disease phenotypes were all SARM1-dependent. Remarkably, macrophage depletion therapy blocked and reversed …


Mild Hypoxic-Ischemic Encephalopathy (Hie): Timing And Pattern Of Mri Brain Injury, Yi Li, Jessica L Wisnowski, Lina Chalak, Amit M Mathur, Robert C Mckinstry, Genesis Licona, Dennis E Mayock, Taeun Chang, Krisa P Van Meurs, Tai-Wei Wu, Kaashif A Ahmad, Marie-Coralie Cornet, Rakesh Rao, Aaron Scheffler, Yvonne W Wu Dec 2022

Mild Hypoxic-Ischemic Encephalopathy (Hie): Timing And Pattern Of Mri Brain Injury, Yi Li, Jessica L Wisnowski, Lina Chalak, Amit M Mathur, Robert C Mckinstry, Genesis Licona, Dennis E Mayock, Taeun Chang, Krisa P Van Meurs, Tai-Wei Wu, Kaashif A Ahmad, Marie-Coralie Cornet, Rakesh Rao, Aaron Scheffler, Yvonne W Wu

2020-Current year OA Pubs

BACKGROUND: Mild hypoxic-ischemic encephalopathy (HIE) is increasingly recognized as a risk factor for neonatal brain injury. We examined the timing and pattern of brain injury in mild HIE.

METHODS: This retrospective cohort study includes infants with mild HIE treated at 9 hospitals. Neonatal brain MRIs were scored by 2 reviewers using a validated classification system, with discrepancies resolved by consensus. Severity and timing of MRI brain injury (i.e., acute, subacute, chronic) was scored on the subset of MRIs that were performed at or before 8 days of age.

RESULTS: Of 142 infants with mild HIE, 87 (61%) had injury on …


Comparing Antigenaemia- And Microfilaraemia As Criteria For Stopping Decisions In Lymphatic Filariasis Elimination Programmes In Africa, Wilma A. Stolk, Luc E. Coffeng, Fatorma K. Bolay, Obiora A. Eneanya, Peter U. Fischer, T. Déirdre Hollingsworth, Benjamin G. Koudou, Aboulaye Méité, Edwin Michael, Joaquin M. Prada, Rocio M. Caja Rivera, Swarnali Sharma, Panayiota Touloupou, Gary J. Weil, Sake J. De Vlas Dec 2022

Comparing Antigenaemia- And Microfilaraemia As Criteria For Stopping Decisions In Lymphatic Filariasis Elimination Programmes In Africa, Wilma A. Stolk, Luc E. Coffeng, Fatorma K. Bolay, Obiora A. Eneanya, Peter U. Fischer, T. Déirdre Hollingsworth, Benjamin G. Koudou, Aboulaye Méité, Edwin Michael, Joaquin M. Prada, Rocio M. Caja Rivera, Swarnali Sharma, Panayiota Touloupou, Gary J. Weil, Sake J. De Vlas

2020-Current year OA Pubs

BACKGROUND: Mass drug administration (MDA) is the main strategy towards lymphatic filariasis (LF) elimination. Progress is monitored by assessing microfilaraemia (Mf) or circulating filarial antigenaemia (CFA) prevalence, the latter being more practical for field surveys. The current criterion for stopping MDA requires <2% CFA prevalence in 6- to 7-year olds, but this criterion is not evidence-based. We used mathematical modelling to investigate the validity of different thresholds regarding testing method and age group for African MDA programmes using ivermectin plus albendazole.

METHODOLGY/PRINCIPAL FINDINGS: We verified that our model captures observed patterns in Mf and CFA prevalence during annual MDA, assuming that CFA tests are positive if at least one adult worm is present. We then assessed how well elimination can be predicted from CFA prevalence in 6-7-year-old children or from Mf or CFA prevalence in the 5+ or 15+ …


Racial And Ethnic Disparities In Access To Minimally Invasive Mitral Valve Surgery, Laurent G Glance, Karen E Joynt Maddox, Michael Mazzefi, Peter W Knight, Michael P Eaton, Changyong Feng, Miklos D Kertai, James Albernathy, Isaac Y Wu, Julie A Wyrobek, Marisa Cevasco, Nimesh Desai, Andrew W Dick Dec 2022

Racial And Ethnic Disparities In Access To Minimally Invasive Mitral Valve Surgery, Laurent G Glance, Karen E Joynt Maddox, Michael Mazzefi, Peter W Knight, Michael P Eaton, Changyong Feng, Miklos D Kertai, James Albernathy, Isaac Y Wu, Julie A Wyrobek, Marisa Cevasco, Nimesh Desai, Andrew W Dick

2020-Current year OA Pubs

IMPORTANCE: Whether people from racial and ethnic minority groups experience disparities in access to minimally invasive mitral valve surgery (MIMVS) is not known.

OBJECTIVE: To investigate racial and ethnic disparities in the utilization of MIMVS.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used data from the Society of Thoracic Surgeons Database for patients who underwent mitral valve surgery between 2014 and 2019. Statistical analysis was performed from January 24 to August 11, 2022.

EXPOSURES: Patients were categorized as non-Hispanic White, non-Hispanic Black, and Hispanic individuals.

MAIN OUTCOMES AND MEASURES: The association between MIMVS (vs full sternotomy) and race and ethnicity …