Digital Commons Network^™

Intragraft B Cell Differentiation During The Development Of Tolerance To Kidney Allografts Is Associated With A Regulatory B Cell Signature Revealed By Single Cell Transcriptomics, Michael Tyler Guinn, Edward S Szuter, Takahiro Yokose, Jifu Ge, Ivy A Rosales, Kashish Chetal, Ruslan I Sadreyev, Alex G Cuenca, Daniel Kreisel, Peter T Sage, Paul S Russell, Joren C Madsen, Robert B Colvin, Alessandro Alessandrini

2020-Current year OA Pubs

Mouse kidney allografts are spontaneously accepted in select, fully mismatched donor-recipient strain combinations, like DBA/2J to C57BL/6 (B6), by natural tolerance. We previously showed accepted renal grafts form aggregates containing various immune cells within 2 weeks posttransplant, referred to as regulatory T cell-rich organized lymphoid structures, which are a novel regulatory tertiary lymphoid organ. To characterize the cells within T cell-rich organized lymphoid structures, we performed single-cell RNA sequencing on CD45

Ube4a Maintains Metabolic Homeostasis And Facilitates Insulin Signaling In Vivo, Sandip Mukherjee, Andrew J Lutkewitte, Brian N Finck, Et Al.

2020-Current year OA Pubs

OBJECTIVE: Defining the regulators of cell metabolism and signaling is essential to design new therapeutic strategies in obesity and NAFLD/NASH. E3 ubiquitin ligases control diverse cellular functions by ubiquitination-mediated regulation of protein targets, and thus their functional aberration is associated with many diseases. The E3 ligase Ube4A has been implicated in human obesity, inflammation, and cancer. However, its in vivo function is unknown, and no animal models are available to study this novel protein.

METHODS: A whole-body Ube4A knockout (UKO) mouse model was generated, and various metabolic parameters were compared in chow- and high fat diet (HFD)-fed WT and UKO …

Host Interactions Of Novel Crassvirales Species Belonging To Multiple Families Infecting Bacterial Host, Bacteroides Cellulosilyticus Wh2host Interactions Of Novel Crassvirales Species Belonging To Multiple Families Infecting Bacterial Host, Bacteroides Cellulosilyticus Wh2, Bhavya Papudeshi, Lindsay Droit, Scott A Handley, David Wang, Et Al.

2020-Current year OA Pubs

Bacteroides, the prominent bacteria in the human gut, play a crucial role in degrading complex polysaccharides. Their abundance is influenced by phages belonging to the

Implementing An Interdisciplinary Procedure Curriculum, Bryce Montane, Abey Abraham, Sergio Bustamante, Tushar Vachharajani, Sabry Ayad, Jagan Devarajan, Dustin Thompson, Ran Lee, Penelope Rampersad, Brian Gage, Emily Reznicek, Chongliang Luo, Richard Wardrop

2020-Current year OA Pubs

INTRODUCTION: This curriculum was designed to improve access to procedures for our internal medicine residents.

METHODS: We created an interdisciplinary procedure course (IDPC) composed of two simulation sessions and a one-week procedural rotation supervised by multiple specialties including nephrology, cardiology, cardiothoracic anesthesiology, general anesthesiology, and interventional radiology. After the course, residents completed two surveys documenting the number of procedures and their level of confidence on a Likert scale (1 = very unconfident to 5 = very confident) prior to and after completing the curriculum.

RESULTS: Sixteen residents participated in the course from September 2021 to June 2022. The collective number …

Safety And Tolerability Of Moxidectin And Ivermectin Combination Treatments For Lymphatic Filariasis In Côte D'Ivoire: A Randomized Controlled Superiority Study, Catherine M. Bjerum, Benjamin G. Koudou, Allassane F. Ouattara, Daphne Lew, Charles W. Goss, Pascal T. Gabo, Christopher L. King, Peter U. Fischer, Gary J. Weil, Philip J. Budge

2020-Current year OA Pubs

BACKGROUND: Moxidectin is a macrocyclic lactone registered for the treatment of human onchocerciasis. The drug has a good safety profile, large volume of distribution and a long elimination half-life. This paper reports tolerability data from the first use of moxidectin in persons with Wuchereria bancrofti infection.

METHODS: In this randomized, open-label, masked-observer superiority trial, adults with Wuchereria bancrofti microfilaremia in Côte d'Ivoire were randomized to 1 of 4 treatment arms: ivermectin + albendazole (IA), moxidectin + albendazole (MoxA), ivermectin + diethylcarbamazine (DEC) + albendazole (IDA), or moxidectin + DEC + albendazole (MoxDA). As part of a larger efficacy trial, all …

The Emerging Importance Of Lymphatics In Health And Disease: An Nih Workshop Report, Babak J. Mehrara, Andrea J. Radtke, Gwendalyn J. Randolph, Brianna T. Wachter, Patricia Greenwel, Ilsa I. Rovira, Zorina S. Galis, Selen C. Muratoglu

2020-Current year OA Pubs

The lymphatic system (LS) is composed of lymphoid organs and a network of vessels that transport interstitial fluid, antigens, lipids, cholesterol, immune cells, and other materials in the body. Abnormal development or malfunction of the LS has been shown to play a key role in the pathophysiology of many disease states. Thus, improved understanding of the anatomical and molecular characteristics of the LS may provide approaches for disease prevention or treatment. Recent advances harnessing single-cell technologies, clinical imaging, discovery of biomarkers, and computational tools have led to the development of strategies to study the LS. This Review summarizes the outcomes …

Safety And Efficacy Of Riluzole In Acute Spinal Cord Injury Study (Riscis): A Multi-Center, Randomized, Placebo-Controlled, Double-Blinded Trial, Michael G Fehlings, Wilson Z Ray, Et Al.

2020-Current year OA Pubs

Riluzole is a sodium-glutamate antagonist that attenuates neurodegeneration in amyotrophic lateral sclerosis (ALS). It has shown favorable results in promoting recovery in pre-clinical models of traumatic spinal cord injury (tSCI) and in early phase clinical trials. This study aimed to evaluate the efficacy and safety of riluzole in acute cervical tSCI. An international, multi-center, prospective, randomized, double-blinded, placebo-controlled, adaptive, Phase III trial (NCT01597518) was undertaken. Patients with American Spinal Injury Association Impairment Scale (AIS) A-C, cervical (C4-C8) tSCI, and <12 h from injury were randomized to receive either riluzole, at an oral dose of 100 mg twice per day (BID) for the first 24 h followed by 50 mg BID for the following 13 days, or placebo. The primary efficacy end-point was change in Upper Extremity Motor (UEM) scores at 180 days. The primary efficacy analyses were conducted on an intention to treat (ITT) and completed cases (CC) basis. The study was powered at a planned enrolment of 351 patients. The trial began in October 2013 and was halted by the sponsor on May 2020 (and terminated in April 2021) in the face of the global COVID-19 pandemic. One hundred ninety-three patients (54.9% of the pre-planned enrolment) were randomized with a follow-up rate of 82.7% at 180 days. At 180 days, in the CC population the riluzole-treated patients compared with placebo had a mean gain of 1.76 UEM scores (95% confidence interval: -2.54-6.06) and 2.86 total motor scores (CI: -6.79-12.52). No drug-related serious adverse events were associated with the use of riluzole. Additional pre-planned sensitivity analyses revealed that in the AIS C population, riluzole was associated with significant improvement in total motor scores (estimate: standard error [SE] 8.0; CI 1.5-14.4) and upper extremity motor scores (SE 13.8; CI 3.1-24.5) at 6 months. AIS B patients had higher reported independence, measured by the Spinal Cord Independence Measure score (45.3 vs. 27.3; d: 18.0 CI: -1.7-38.0) and change in mental health scores, measured by the Short Form 36 mental health domain (2.01 vs. -11.58; d: 13.2 CI: 1.2-24.8) at 180 days. AIS A patients who received riluzole had a higher average gain in neurological levels at 6 months compared with placebo (mean 0.50 levels gained vs. 0.12 in placebo; d: 0.38, CI: -0.2-0.9). The primary analysis did not achieve the predetermined end-point of efficacy for riluzole, likely related to insufficient power. However, on pre-planned secondary analyses, all subgroups of cervical SCI subjects (AIS grades A, B and C) treated with riluzole showed significant gains in functional recovery. The results of this trial may warrant further investigation to extend these findings. Moreover, guideline development groups may wish to assess the possible clinical relevance of the secondary outcome analyses, in light of the fact that SCI is an uncommon orphan disorder without an accepted neuroprotective treatment.

Geospatial Modelling Of Lymphatic Filariasis And Malaria Co-Endemicity In Nigeria, Obiora A Eneanya, Lisa J Reimer, Peter U Fischer, Gary J Weil

2020-Current year OA Pubs

BACKGROUND: Lymphatic filariasis (LF) and malaria are important vector-borne diseases that are co-endemic throughout Nigeria. These infections are transmitted by the same mosquito vector species in Nigeria and their transmission is similarly influenced by climate and sociodemographic factors. The goal of this study was to assess the relationship between the geospatial distribution of both infections in Nigeria to better coordinate interventions.

METHODS: We used national survey data for malaria from the Demographic and Health Survey dataset and site-level LF mapping data from the Nigeria Lymphatic Filariasis Control Programme together with a suite of predictive climate and sociodemographic factors to build …

The Effect Of Fibre Cell Remodelling On The Power And Optical Quality Of The Lens, J Rodriguez, Q Tan, H Šikić, L A. Taber, S Bassnett

2020-Current year OA Pubs

Vertebrate eye lenses are uniquely adapted to form a refractive index gradient (GRIN) for improved acuity, and to grow slowly in size despite constant cell proliferation. The mechanisms behind these adaptations remain poorly understood. We hypothesize that cell compaction contributes to both. To test this notion, we examined the relationship between lens size and shape, refractive characteristics and the cross-sectional areas of constituent fibre cells in mice of different ages. We developed a block-face imaging method to visualize cellular cross sections and found that the cross-sectional areas of fibre cells rose and then decreased over time, with the most significant …

Biochemical Characterization Of Patients With Dihydrolipoamide Dehydrogenase Deficiency, Parith Wongkittichote, Sanmati R Cuddapah, Stephen R Master, Dorothy K Grange, Dennis Dietzen, Stephen M Roper, Rebecca D Ganetzky

2020-Current year OA Pubs

Dihydrolipoamide dehydrogenase (DLD; E3) oxidizes lipoic acid. Restoring the oxidized state allows lipoic acid to act as a necessary electron sink for the four mitochondrial keto-acid dehydrogenases: pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, branched-chain α-keto-acid dehydrogenase, and 2-oxoadipate dehydrogenase. DLD deficiency (DLDD) is caused by biallelic pathogenic variants in

Ergosterol Distribution Controls Surface Structure Formation And Fungal Pathogenicity, Hau Lam Choy, Elizabeth A. Gaylord, Tamara L. Doering

2020-Current year OA Pubs

Ergosterol, the major sterol in fungal membranes, is critical for defining membrane fluidity and regulating cellular processes. Although ergosterol synthesis has been well defined in model yeast, little is known about sterol organization in the context of fungal pathogenesis. We identified a retrograde sterol transporter, Ysp2, in the opportunistic fungal pathogen

Loss Of Stearoyl-Coa Desaturase 2 Disrupts Inflammatory Response In Macrophages, Joseph B. Lin, Amy Mora, Tzu Jui Wang, Andrea Santeford, Darksha Usmani, Marianne M. Ligon, Indira U. Mysorekar, Rajendra S. Apte

2020-Current year OA Pubs

Macrophages are innate immune cells that patrol tissues and are the first responders to detect infection. They orchestrate the host immune response in eliminating invading pathogens and the subsequent transition from inflammation to tissue repair. Macrophage dysfunction contributes to age-related pathologies, including low-grade inflammation in advanced age that is termed "inflammaging." Our laboratory has previously identified that macrophage expression of a fatty acid desaturase, stearoyl-CoA desaturase 2 (SCD2), declines with age. Herein, we delineate the precise cellular effects of SCD2 deficiency in murine macrophages. We found that deletion of

Bcl6, Irf2, And Notch2 Promote Nonclassical Monocyte Development, Kevin W O'Connor, Tiantian Liu, Sunkyung Kim, Carlos G Briseño, Katia Georgopoulos, Theresa L Murphy, Kenneth M Murphy

2020-Current year OA Pubs

Ly6C

Entry Receptor Ldlrad3 Is Required For Venezuelan Equine Encephalitis Virus Peripheral Infection And Neurotropism Leading To Pathogenesis In Mice, Natasha M Kafai, Hana Janova, Matthew D Cain, Yael Alippe, Stefanie Muraro, Alan Sariol, Michelle Elam-Noll, Robyn S Klein, Michael S Diamond

2020-Current year OA Pubs

Venezuelan equine encephalitis virus (VEEV) is an encephalitic alphavirus responsible for epidemics of neurological disease across the Americas. Low-density lipoprotein receptor class A domain-containing 3 (LDLRAD3) is a recently reported entry receptor for VEEV. Here, using wild-type and Ldlrad3-deficient mice, we define a critical role for LDLRAD3 in controlling steps in VEEV infection, pathogenesis, and neurotropism. Our analysis shows that LDLRAD3 is required for efficient VEEV infection and pathogenesis prior to and after central nervous system invasion. Ldlrad3-deficient mice survive intranasal and intracranial VEEV inoculation and show reduced infection of neurons in different brain regions. As LDLRAD3 is a determinant …

Genetic Modifiers Of Mendelian Monogenic Collagen Iv Nephropathies In Humans And Mice, Constantinos Deltas, Gregory Papagregoriou, Stavroula F Louka, Apostolos Malatras, Frances Flinter, Daniel P Gale, Susie Gear, Oliver Gross, Julia Hoefele, Rachel Lennon, Jeffrey H Miner, Alessandra Renieri, Judy Savige, A Neil Turner

2020-Current year OA Pubs

Familial hematuria is a clinical sign of a genetically heterogeneous group of conditions, accompanied by broad inter- and intrafamilial variable expressivity. The most frequent condition is caused by pathogenic (or likely pathogenic) variants in the collagen-IV genes,

Microglial Rev-Erbα Regulates Inflammation And Lipid Droplet Formation To Drive Tauopathy In Male Mice, Jiyeon Lee, Julie M Dimitry, Jong Hee Song, Minsoo Son, Patrick W Sheehan, Melvin W King, G Travis Tabor, Young Ah Goo, Mitchell A Lazar, Leonard Petrucelli, Erik S Musiek

2020-Current year OA Pubs

Alzheimer's disease, the most common age-related neurodegenerative disease, is characterized by tau aggregation and associated with disrupted circadian rhythms and dampened clock gene expression. REV-ERBα is a core circadian clock protein which also serves as a nuclear receptor and transcriptional repressor involved in lipid metabolism and macrophage function. Global REV-ERBα deletion has been shown to promote microglial activation and mitigate amyloid plaque formation. However, the cell-autonomous effects of microglial REV-ERBα in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male …

Sustainable Development For Mobile Health Apps Using The Human-Centered Design Process, Qingfan An, Marjorie M Kelley, Audra Hanners, Po-Yin Yen

2020-Current year OA Pubs

Well-documented scientific evidence indicates that mobile health (mHealth) apps can improve the quality of life, relieve symptoms, and restore health for patients. In addition to improving patients' health outcomes, mHealth apps reduce health care use and the cost burdens associated with disease management. Currently, patients and health care providers have a wide variety of choices among commercially available mHealth apps. However, due to the high resource costs and low user adoption of mHealth apps, the cost-benefit relationship remains controversial. When compared to traditional expert-driven approaches, applying human-centered design (HCD) may result in more useable, acceptable, and effective mHealth apps. In …

The Proteome Of Extracellular Vesicles Of The Lung Fluke Paragonimus Kellicotti Produced In Vitro And In The Lung Cyst, Lucia S Di Maggio, Kerstin Fischer, Devyn Yates, Kurt C Curtis, Bruce A Rosa, John Martin, Petra Erdmann-Gilmore, Robert S W Sprung, Makedonka Mitreva, R Reid Townsend, Gary J Weil, Peter U Fischer

2020-Current year OA Pubs

Paragonimiasis is a zoonotic, food-borne trematode infection that affects 21 million people globally. Trematodes interact with their hosts via extracellular vesicles (EV) that carry protein and RNA cargo. We analyzed EV in excretory-secretory products (ESP) released by Paragonimus kellicotti adult worms cultured in vitro (EV ESP) and EV isolated from lung cyst fluid (EV CFP) recovered from infected gerbils. The majority of EV were approximately 30-50 nm in diameter. We identified 548 P. kellicotti-derived proteins in EV ESP by mass spectrometry and 8 proteins in EV CFP of which 7 were also present in EV ESP. No parasite-derived proteins were …

Transcranial Focused Ultrasound-Induced Blood‒Brain Barrier Opening In Mice Without Shaving Hairs, Lu Xu, Yan Gong, Chih-Yen Chien, Eric Leuthardt, Hong Chen

2020-Current year OA Pubs

Acoustic coupling through hairs remains a challenge to performing transcranial-focused ultrasound procedures. Here, we demonstrated that this challenge could be addressed by using oil as the coupling medium, leveraging oil's high affinity to hairs due to their inherent hydrophobicity. We compared focused ultrasound-induced blood-brain barrier opening (FUS-BBBO) outcomes in mice under three coupling conditions: oil with hairs ("oil + hairs"), ultrasound gel with hair shaving ("ultrasound gel + no hair"), and ultrasound gel with hairs ("ultrasound gel + hairs"). The quality of the coupling was evaluated by [Formula: see text]-weighted magnetic resonance imaging (MRI) and passive cavitation detection (PCD). The …

Vegf-B Prevents Excessive Angiogenesis By Inhibiting Fgf2/Fgfr1 Pathway, Chunsik Lee, David M Ornitz, Et Al.

2020-Current year OA Pubs

Although VEGF-B was discovered as a VEGF-A homolog a long time ago, the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups. Notwithstanding, drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases. It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms. Using comprehensive in vitro and in vivo methods and models, we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting …

Defining The Roles Of Pyruvate Oxidation, Tca Cycle, And Mannitol Metabolism In Methicillin-Resistant Staphylococcus Aureus Catheter-Associated Urinary Tract Infection, Santosh Paudel, Sarah Guedry, Chloe L P Obernuefemann, Scott J. Hultgren, Jennifer N. Walker, Ritwij Kulkarni

2020-Current year OA Pubs

Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of complicated urinary tract infection (UTI) associated with the use of indwelling urinary catheters. Previous reports have revealed host and pathogen effectors critical for MRSA uropathogenesis. Here, we sought to determine the significance of specific metabolic pathways during MRSA UTI. First, we identified four mutants from the Nebraska transposon mutant library in the MRSA JE2 background that grew normally in rich medium but displayed significantly reduced growth in pooled human urine (HU). This prompted us to transduce the uropathogenic MRSA 1369 strain with the transposon mutants in

Brain-Derived Neurotrophic Factor Dysregulation As An Essential Pathological Feature In Huntington's Disease: Mechanisms And Potential Therapeutics, Andrew Speidell, Noman Bin Abid, Hiroko Yano

2020-Current year OA Pubs

Brain-derived neurotrophic factor (BDNF) is a major neurotrophin whose loss or interruption is well established to have numerous intersections with the pathogenesis of progressive neurological disorders. There is perhaps no greater example of disease pathogenesis resulting from the dysregulation of BDNF signaling than Huntington's disease (HD)-an inherited neurodegenerative disorder characterized by motor, psychiatric, and cognitive impairments associated with basal ganglia dysfunction and the ultimate death of striatal projection neurons. Investigation of the collection of mechanisms leading to BDNF loss in HD highlights this neurotrophin's importance to neuronal viability and calls attention to opportunities for therapeutic interventions. Using electronic database searches …

Mechanical Stiffness And Anisotropy Measured By Mre During Brain Development In The Minipig, Shuaihu Wang, Charlotte A Guertler, Ruth J Okamoto, Curtis L Johnson, Matthew D J Mcgarry, Philip V Bayly

2020-Current year OA Pubs

The relationship between brain development and mechanical properties of brain tissue is important, but remains incompletely understood, in part due to the challenges in measuring these properties longitudinally over time. In addition, white matter, which is composed of aligned, myelinated, axonal fibers, may be mechanically anisotropic. Here we use data from magnetic resonance elastography (MRE) and diffusion tensor imaging (DTI) to estimate anisotropic mechanical properties in six female Yucatan minipigs at ages from 3 to 6 months. Fiber direction was estimated from the principal axis of the diffusion tensor in each voxel. Harmonic shear waves in the brain were excited …

Discovery And Targeting Of A Noncanonical Mechanism Of Sarcoma Resistance To Adi-Peg20 Mediated By The Microenvironment, Leonard C Rogers, Jeff C Kremer, Caitlyn B Brashears, Zongtao Lin, Alliny C S Bastos, Adriana Baker, Nicole Fettig, Dong Zhou, Kooresh I Shoghi, Carina A Dehner, John S A Chrisinger, Benjamin A Garcia, Toshinao Oyama, Brian A Van Tine, Et Al.

2020-Current year OA Pubs

PURPOSE: Many cancers lack argininosuccinate synthetase 1 (ASS1), the rate-limiting enzyme of arginine biosynthesis. This deficiency causes arginine auxotrophy, targetable by extracellular arginine-degrading enzymes such as ADI-PEG20. Long-term tumor resistance has thus far been attributed solely to ASS1 reexpression. This study examines the role of ASS1 silencing on tumor growth and initiation and identifies a noncanonical mechanism of resistance, aiming to improve clinical responses to ADI-PEG20.

EXPERIMENTAL DESIGN: Tumor initiation and growth rates were measured for a spontaneous Ass1 knockout (KO) murine sarcoma model. Tumor cell lines were generated, and resistance to arginine deprivation therapy was studied in vitro and …

Risk-Adapted Treatment Strategies With Pre-Irradiation Chemotherapy In Pediatric Medulloblastoma: Outcomes From The Polish Pediatric Neuro-Oncology Group, Marta Perek-Polnik, Anne Cochrane, Jinli Wang, Marzanna Chojnacka, Monika Drogosiewicz, Iwona Filipek, Ewa Swieszkowska, Magdalena Tarasinska, Wiesława Grajkowska, Joanna Trubicka, Paweł Kowalczyk, Bożenna Dembowska-Bagińskai, Mohamed S Abdelbaki

2020-Current year OA Pubs

Craniospinal irradiation (CSI) has been a major component of the standard of care treatment backbone for childhood medulloblastoma. However, chemotherapy regimens have varied based on protocol, patient age, and molecular subtyping. In one of the largest studies to date, we analyzed treatment outcomes in children with newly-diagnosed medulloblastoma treated with pre-irradiation chemotherapy followed by risk-adapted radiotherapy and maintenance chemotherapy. A total of 153 patients from the Polish Pediatric Neuro-Oncology Group were included in the analysis. The median age at diagnosis was 8.0 years, and median follow-up time was 6.4 years. Sixty-seven patients were classified as standard-risk and eighty-six as high-risk. …

Rho Enhancers Play Unexpectedly Minor Roles In Rhodopsin Transcription And Rod Cell Integrity, Chi Sun, Philip A Ruzycki, Shiming Chen

2020-Current year OA Pubs

Enhancers function with a basal promoter to control the transcription of target genes. Enhancer regulatory activity is often studied using reporter-based transgene assays. However, unmatched results have been reported when selected enhancers are silenced in situ. In this study, using genomic deletion analysis in mice, we investigated the roles of two previously identified enhancers and the promoter of the Rho gene that codes for the visual pigment rhodopsin. The Rho gene is robustly expressed by rod photoreceptors of the retina, and essential for the subcellular structure and visual function of rod photoreceptors. Mutations in RHO cause severe vision loss in …

Er-Mitochondria Contacts And Cholesterol Metabolism Are Disrupted By Disease-Associated Tau Protein, Leonora Szabo, Nadia Cummins, Paolo Paganetti, Alex Odermatt, Andreas Papassotiropoulos, Celeste Karch, Jürgen Götz, Anne Eckert, Amandine Grimm

2020-Current year OA Pubs

Abnormal tau protein impairs mitochondrial function, including transport, dynamics, and bioenergetics. Mitochondria interact with the endoplasmic reticulum (ER) via mitochondria-associated ER membranes (MAMs), which coordinate and modulate many cellular functions, including mitochondrial cholesterol metabolism. Here, we show that abnormal tau loosens the association between the ER and mitochondria in vivo and in vitro. Especially, ER-mitochondria interactions via vesicle-associated membrane protein-associated protein (VAPB)-protein tyrosine phosphatase-interacting protein 51 (PTPIP51) are decreased in the presence of abnormal tau. Disruption of MAMs in cells with abnormal tau alters the levels of mitochondrial cholesterol and pregnenolone, indicating that conversion of cholesterol into pregnenolone is impaired. …

Positron Emission Tomography And Magnetic Resonance Imaging Methods And Datasets Within The Dominantly Inherited Alzheimer Network (Dian), Nicole S Mckay, Brian A Gordon, Russ C Hornbeck, Aylin Dincer, Shaney Flores, Sarah J Keefe, Nelly Joseph-Mathurin, Peter R Millar, Beau M Ances, Charles D Chen, Alisha Daniels, Diana A Hobbs, Kelley Jackson, Deborah Koudelis, Parinaz Massoumzadeh, Austin Mccullough, Michael L Nickels, Farzaneh Rahmani, Laura Swisher, Qing Wang, Carlos Cruchaga, Jason Hassenstab, Celeste Karch, Eric Mcdade, Richard J Perrin, Chengjie Xiong, John C Morris, Randall J Bateman, Tammie L S Benzinger, Et Al.

2020-Current year OA Pubs

The Dominantly Inherited Alzheimer Network (DIAN) is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). ADAD arises from mutations occurring in three genes. Offspring from ADAD families have a 50% chance of inheriting their familial mutation, so non-carrier siblings can be recruited for comparisons in case-control studies. The age of onset in ADAD is highly predictable within families, allowing researchers to estimate an individual's point in the disease trajectory. These characteristics allow candidate AD biomarker measurements to be reliably mapped during the preclinical phase. Although ADAD represents a small proportion of AD cases, understanding neuroimaging-based changes that occur during …

Scca1/Serpinb3 Suppresses Antitumor Immunity And Blunts Therapy-Induced T Cell Responses Via Stat-Dependent Chemokine Production, Liyun Chen, Victoria Shi, Songyan Wang, Lulu Sun, Rebecca Freeman, Jasmine Yang, Matthew J. Inkman, Subhajit Ghosh, Fiona Ruiz, Kay Jayachandran, Yi Huang, Jingqin Luo, Jin Zhang, Pippa Cosper, Clifford J Luke, Perry W. Grigsby, Julie K. Schwarz, Stephanie Markovina, Et Al.

2020-Current year OA Pubs

Patients with cancer who have high serum levels of squamous cell carcinoma antigen 1 (SCCA1, now referred to as SERPINB3) commonly experience treatment resistance and have a poor prognosis. Despite being a clinical biomarker, the modulation of SERPINB3 in tumor immunity is poorly understood. We found positive correlations of SERPINB3 with CXCL1, CXCL8 (CXCL8/9), S100A8, and S100A9 (S100A8/A9) myeloid cell infiltration through RNA-Seq analysis of human primary cervical tumors. Induction of SERPINB3 resulted in increased CXCL1/8 and S100A8/A9 expression, which promoted monocyte and myeloid-derived suppressor cell (MDSC) migration in vitro. In mouse models, Serpinb3a tumors showed increased MDSC and tumor-associated …

Csf Mtbr-Tau243 Is A Specific Biomarker Of Tau Tangle Pathology In Alzheimer's Disease, Kanta Horie, Nicolas R Barthélemy, Yan Li, Yingxin He, Benjamin Saef, Charles D Chen, Hong Jiang, Chihiro Sato, Brian A Gordon, Tammie L S Benzinger, David M Holtzman, John C Morris, Suzanne E Schindler, Randall J Bateman, Et Al.

2020-Current year OA Pubs

Aggregated insoluble tau is one of two defining features of Alzheimer's disease. Because clinical symptoms are strongly correlated with tau aggregates, drug development and clinical diagnosis need cost-effective and accessible specific fluid biomarkers of tau aggregates; however, recent studies suggest that the fluid biomarkers currently available cannot specifically track tau aggregates. We show that the microtubule-binding region (MTBR) of tau containing the residue 243 (MTBR-tau243) is a new cerebrospinal fluid (CSF) biomarker specific for insoluble tau aggregates and compared it to multiple other phosphorylated tau measures (p-tau181, p-tau205, p-tau217 and p-tau231) in two independent cohorts (BioFINDER-2, n = 448; and …