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Sarm1 Acts Downstream Of Neuroinflammatory And Necroptotic Signaling To Induce Axon Degeneration, Kwang Woo Ko, Jeffrey Milbrandt, Aaron Diantonio

Open Access Publications

Neuroinflammation and necroptosis are major contributors to neurodegenerative disease, and axon dysfunction and degeneration is often an initiating event. SARM1 is the central executioner of pathological axon degeneration. Here, we demonstrate functional and mechanistic links among these three pro-degenerative processes. In a neuroinflammatory model of glaucoma, TNF-α induces SARM1-dependent axon degeneration, oligodendrocyte loss, and subsequent retinal ganglion cell death. TNF-α also triggers SARM1-dependent axon degeneration in sensory neurons via a noncanonical necroptotic signaling mechanism. MLKL is the final executioner of canonical necroptosis; however, in axonal necroptosis, MLKL does not directly trigger degeneration. Instead, MLKL induces loss of the axon survival …

Dopamine D2 Receptor Signaling On Imsns Is Required For Initiation And Vigor Of Learned Actions, Shana M Augustin, Gabriel C Loewinger, Timothy J O'Neal, Alexxai V Kravitz, David M Lovinger

Open Access Publications

Striatal dopamine D2 receptors (D2Rs) are important for motor output. Selective deletion of D2Rs from indirect pathway-projecting medium spiny neurons (iMSNs) impairs locomotor activities in a task-specific manner. However, the role of D2Rs in the initiation of motor actions in reward seeking and taking is not fully understood, and there is little information about how receptors contribute under different task demands and with different outcome types. The iMSN-D2Rs modulate neuronal activity and synaptic transmission, exerting control on circuit functions that may play distinct roles in action learning and performance. Selective deletion of D2Rs on iMSNs resulted in slower action initiation …

Fragment Screening Targeting Ebola Virus Nucleoprotein C-Terminal Domain Identifies Lead Candidates, David J Aceti, Hamza Ahmed, William M Westler, Chao Wu, Hesam Dashti, Marco Tonelli, Hamid Eghbalnia, Gaya K Amarasinghe, John L Markley

Open Access Publications

The Ebola Virus is a causative agent of viral hemorrhagic fever outbreaks and a potential global health risk. The outbreak in West Africa (2013-2016) led to 11,000+ deaths and 30,000+ Ebola infected individuals. The current outbreak in the Democratic Republic of Congo (DRC) with 3000+ confirmed cases and 2000+ deaths attributed to Ebola virus infections provides a reminder that innovative countermeasures are still needed. Ebola virus encodes 7 open reading frames (ORFs). Of these, the nucleocapsid protein (eNP) encoded by the first ORF plays many significant roles, including a role in viral RNA synthesis. Here we describe efforts to target …

Deconvolving The Contributions Of Cell-Type Heterogeneity On Cortical Gene Expression, Ellis Patrick, Mariko Taga, Ayla Ergun, Bernard Ng, William Casazza, Maria Cimpean, Christina Yung, Julie A. Schneider, David A. Bennett, Chris Gaiteri, Philip L. De Jager, Elizabeth M. Bradshaw, Sara Mostafavi

Open Access Publications

Complexity of cell-type composition has created much skepticism surrounding the interpretation of bulk tissue transcriptomic studies. Recent studies have shown that deconvolution algorithms can be applied to computationally estimate cell-type proportions from gene expression data of bulk blood samples, but their performance when applied to brain tissue is unclear. Here, we have generated an immunohistochemistry (IHC) dataset for five major cell-types from brain tissue of 70 individuals, who also have bulk cortical gene expression data. With the IHC data as the benchmark, this resource enables quantitative assessment of deconvolution algorithms for brain tissue. We apply existing deconvolution algorithms to brain …

Radiation Causes Tissue Damage By Dysregulating Inflammasome-Gasdermin D Signaling In Both Host And Transplanted Cells, Jianqiu Xiao, Chun Wang, Juo-Chin Yao, Yael Alippe, Tong Yang, Dustin Kress, Kai Sun, Kourtney L. Kostecki, Joseph B. Monahan, Deborah J. Veis, Yousef Abu-Amer, Daniel C. Link, Gabriel Mbalaviele

Open Access Publications

Radiotherapy is a commonly used conditioning regimen for bone marrow transplantation (BMT). Cytotoxicity limits the use of this life-saving therapy, but the underlying mechanisms remain poorly defined. Here, we use the syngeneic mouse BMT model to test the hypothesis that lethal radiation damages tissues, thereby unleashing signals that indiscriminately activate the inflammasome pathways in host and transplanted cells. We find that a clinically relevant high dose of radiation causes severe damage to bones and the spleen through mechanisms involving the NLRP3 and AIM2 inflammasomes but not the NLRC4 inflammasome. Downstream, we demonstrate that gasdermin D (GSDMD), the common effector of …

Mapping Geographical Inequalities In Oral Rehydration Therapy Coverage In Low-Income And Middle-Income Countries, 2000-17, Local Burden Of Disease Diarrhoea Collaborators, Ziyad Al-Aly, Et Al

Open Access Publications

BACKGROUND: Oral rehydration solution (ORS) is a form of oral rehydration therapy (ORT) for diarrhoea that has the potential to drastically reduce child mortality; yet, according to UNICEF estimates, less than half of children younger than 5 years with diarrhoea in low-income and middle-income countries (LMICs) received ORS in 2016. A variety of recommended home fluids (RHF) exist as alternative forms of ORT; however, it is unclear whether RHF prevent child mortality. Previous studies have shown considerable variation between countries in ORS and RHF use, but subnational variation is unknown. This study aims to produce high-resolution geospatial estimates of relative …

Postmenopausal Hormone Therapy And Colorectal Cancer Risk By Molecularly Defined Subtypes And Tumor Location, Julia D. Labadie, Yin Cao, Et Al

Open Access Publications

Background: Postmenopausal hormone therapy (HT) is associated with a decreased colorectal cancer (CRC) risk. As CRC is a heterogeneous disease, we evaluated whether the association of HT and CRC differs across etiologically relevant, molecularly defined tumor subtypes and tumor location.

Methods: We pooled data on tumor subtypes (microsatellite instability status, CpG island methylator phenotype status,

Results: Among postmenopausal women, ever HT use was associated with a 38% reduction in overall CRC risk (OR =0.62, 95% CI = 0.56 to 0.69). This association was similar according to microsatellite instability, CpG island methylator phenotype and

Conclusions: We observed a strong inverse association …

The Personality Profile Of Chronic Alcohol Dependent Patients With Comorbid Gambling Disorder Symptoms, Ildikó Kovács, Ildikó Katalin Pribék, Ildikó Demeter, Sándor Rózsa, Zoltán Janka, Zsolt Demetrovics, Bálint Andó

Open Access Publications

BACKGROUND AND AIMS: The importance of personality characteristics in the diagnosis and treatment of gambling disorder (GD) and alcohol use disorder (AUD) is often highlighted in scientific literature. This study aimed to test predictions about the associations of temperament and character in chronic AUD patients with comorbid GD symptoms and without them.

METHODS: Chronic AUD patients enrolled from an inpatient clinic were divided in two groups based on cluster analysis, AUD patients with (AUD + GD group: n = 30) and without (AUD group: n = 68) GD symptoms. Severity of GD symptoms and personality dimensions (Cloninger's Temperament and Character …

Virus Infection Is Controlled By Hematopoietic And Stromal Cell Sensing Of Murine Cytomegalovirus Through Sting, Sytse J. Piersma, Jennifer Poursine-Laurent, Liping Yang, Glen N. Barber, Bijal A. Parikh, Wayne M. Yokoyama

Open Access Publications

Recognition of DNA viruses, such as cytomegaloviruses (CMVs), through pattern-recognition receptor (PRR) pathways involving MyD88 or STING constitute a first-line defense against infections mainly through production of type I interferon (IFN-I). However, the role of these pathways in different tissues is incompletely understood, an issue particularly relevant to the CMVs which have broad tissue tropisms. Herein, we contrasted anti-viral effects of MyD88 versus STING in distinct cell types that are infected with murine CMV (MCMV). Bone marrow chimeras revealed STING-mediated MCMV control in hematological cells, similar to MyD88. However, unlike MyD88, STING also contributed to viral control in non-hematological, stromal …

The "Secret Sauce" For A Mentored Training Program: Qualitative Perspectives Of Trainees In Implementation Research For Cancer Control, Rebekah R Jacob, Angeline Gacad, Christine Pfund, Margaret Padek, David A Chambers, Jon F Kerner, Anne Sales, Maureen Dobbins, Shiriki Kumanyika, Ross C Brownson

Open Access Publications

BACKGROUND: Mentored training approaches help build capacity for research through mentoring networks and skill building activities. Capacity for dissemination and implementation (D&I) research in cancer is needed and mentored training programs have been developed. Evaluation of mentored training programs through quantitative approaches often provides us with information on "what" improved for participants. Qualitative approaches provide a deeper understanding of "how" programs work best.

METHODS: Qualitative interviews were conducted with 21 fellows of the National Cancer Institute-funded Mentored Training for Dissemination and Implementation in Cancer to gain understanding of their experiences with mentoring received during the program. Fellows were selected from …

Transcriptional Profiling Reveals Altered Biological Characteristics Of Chorionic Stem Cells From Women With Gestational Diabetes, Liyun Chen, Chung-Teng Wang, Nicholas R Forsyth, Pensee Wu

Open Access Publications

BACKGROUND: Gestational diabetes (GDM) is a common complication of pregnancy. The impact of pregnancy complications on placental function suggests that extraembryonic stem cells in the placenta may also be affected during pregnancy. Neonatal tissue-derived stem cells, with the advantages of their differentiation capacity and non-invasive isolation processes, have been proposed as a promising therapeutic avenue for GDM management through potential cell therapy approaches. However, the influence of GDM on autologous stem cells remains unclear. Thus, studies that provide comprehensive understanding of stem cells isolated from women with GDM are essential to guide future clinical applications.

METHODS: Human chorionic membrane-derived stem …

Duodenal Microbiota In Stunted Undernourished Children With Enteropathy, Robert Y Chen, Vanderlene L Kung, Matthew C Hibberd, Janaki Guruge, Blanda Di Luccia, Kazi Ahsan, Elizabeth Kennedy, Jesus Santiago-Borges, Michael J Barratt, Jeffrey I Gordon, Et Al

Open Access Publications

BACKGROUND: Environmental enteric dysfunction (EED) is an enigmatic disorder of the small intestine that is postulated to play a role in childhood undernutrition, a pressing global health problem. Defining the incidence of this disorder, its pathophysiological features, and its contribution to impaired linear and ponderal growth has been hampered by the difficulty in directly sampling the small intestinal mucosa and microbial community (microbiota).

METHODS: In this study, among 110 young children (mean age, 18 months) with linear growth stunting who were living in an urban slum in Dhaka, Bangladesh, and had not benefited from a nutritional intervention, we performed endoscopy …

The Brief Case: "Not Positive" Or "Not Sure"-Covid-19-Negative Results In A Symptomatic Patient, Bijal A Parikh, Thomas C Bailey, Patrick G Lyons, Neil W Anderson

Open Access Publications

No abstract provided.

Characterization Of A Multicenter Pediatric-Hydrocephalus Shunt Biobank, Jacob Gluski, Paul Zajciw, Prashant Hariharan, Amanda Morgan, Diego M Morales, Andrew Jea, William Whitehead, Neena Marupudi, Steven Ham, Sandeep Sood, James P Mcallister Ii, David D Limbrick Jr, Carolyn A Harris

Open Access Publications

BACKGROUND: Pediatric hydrocephalus is a devastating and costly disease. The mainstay of treatment is still surgical shunting of cerebrospinal fluid (CSF). These shunts fail at a high rate and impose a significant burden on patients, their families and society. The relationship between clinical decision making and shunt failure is poorly understood and multifaceted, but catheter occlusion remains the most frequent cause of shunt complications. In order to investigate factors that affect shunt failure, we have established the Wayne State University (WSU) shunt biobank.

METHODS: To date, four hospital centers have contributed various components of failed shunts and CSF from patients …

Single-Subject Grey Matter Network Trajectories Over The Disease Course Of Autosomal Dominant Alzheimer's Disease, Lisa Vermunt, Guoqiao Wang, Aylin Dincer, Shaney Flores, Sarah J Keefe, Carlos Cruchaga, Jason Hassenstab, Celeste M Karch, Eric Mcdade, John C Morris, Richard J Perrin, Chengjie Xiong, Randall J Bateman, Tammie L S Benzinger, Brian A Gordon, Et Al

Open Access Publications

Structural grey matter covariance networks provide an individual quantification of morphological patterns in the brain. The network integrity is disrupted in sporadic Alzheimer's disease, and network properties show associations with the level of amyloid pathology and cognitive decline. Therefore, these network properties might be disease progression markers. However, it remains unclear when and how grey matter network integrity changes with disease progression. We investigated these questions in autosomal dominant Alzheimer's disease mutation carriers, whose conserved age at dementia onset allows individual staging based upon their estimated years to symptom onset. From the Dominantly Inherited Alzheimer Network observational cohort, we selected …

An Important Role For Cd4 + T Cells In Adaptive Immunity To Toxoplasma Gondii In Mice Lacking The Transcription Factor Batf3, Roxane Tussiwand, Michael S Behnke, Nicole M Kretzer, Gary E Grajales-Reyes, Theresa L Murphy, Robert D Schreiber, Kenneth M Murphy, L David Sibley

Open Access Publications

Immunity to

Selective Dorsal Rhizotomy For The Treatment Of Spastic Triplegic Cerebral Palsy, T. S. Park, Susan Joh, Deanna M. Walter, Matthew B. Dobbs

Open Access Publications

Background Spastic triplegia is a recognized subtype of cerebral palsy (CP). In the course of treating spastic triplegic children with selective dorsal rhizotomy (SDR), we found that some children who had "minimal or mild involvement" in the stronger arm improved strikingly after undergoing SDR. Some of them became independent ambulators, which was an outcome that is not usually achieved in spastic quadriplegic children. However, the literature currently contains no data on the natural clinical course and the effects of CP interventions on spastic triplegia. Objectives Our aim was to elucidate the clinical characteristics of spastic triplegia and the effects of …

Expert Consensus On The Management Of Adverse Events And Prescribing Practices Associated With The Treatment Of Patients Taking Pirfenidone For Idiopathic Pulmonary Fibrosis: A Delphi Consensus Study, Franck F Rahaghi, Zeenat Safdar, Anne Whitney Brown, Joao A De Andrade, Kevin R Flaherty, Robert J Kaner, Christopher S King, Maria L Padilla, Imre Noth, Mary Beth Scholand, Adrian Shifren, Steven D Nathan

Open Access Publications

BACKGROUND: In patients with idiopathic pulmonary fibrosis (IPF) treated with pirfenidone (Esbriet®, Genentech USA, Inc. South San Francisco, CA.), effectively managing treatment-related adverse events (AEs) may improve adherence. Due to a lack of clinical evidence and expertise, managing these AEs can be challenging for patients and physicians alike. In the absence of evidence, consensus recommendations from physicians experienced in using pirfenidone to treat IPF are beneficial.

METHODS: Using a modified Delphi process, expert recommendations were developed by a panel of physicians experienced with using pirfenidone for IPF. Over three iterations, panelists developed and refined a series of statements on the …

Molecular And Clinicopathologic Features Of Gliomas Harboring Ntrk Fusions, Matthew Torre, Sonika Dahiya, Et Al

Open Access Publications

Fusions involving neurotrophic tyrosine receptor kinase (NTRK) genes are detected in ≤2% of gliomas and can promote gliomagenesis. The remarkable therapeutic efficacy of TRK inhibitors, which are among the first Food and Drug Administration-approved targeted therapies for NTRK-fused gliomas, has generated significant clinical interest in characterizing these tumors. In this multi-institutional retrospective study of 42 gliomas with NTRK fusions, next generation DNA sequencing (n = 41), next generation RNA sequencing (n = 1), RNA-sequencing fusion panel (n = 16), methylation profile analysis (n = 18), and histologic evaluation (n = 42) were performed. All infantile NTRK-fused gliomas (n = 7) …

Analysis Of Single-Cell Rnaseq Identifies Transitional States Of T Cells Associated With Hepatocellular Carcinoma, Yanying Yang, Fangming Liu, Weiren Liu, Mingyue Ma, Jie Gao, Yan Lu, Li-Hao Huang, Xiaoying Li, Yinghong Shi, Xiangdong Wang, Duojiao Wu

Open Access Publications

BACKGROUND: Exhausted T cells and regulatory T cells (Tregs) comprise diverse subsets of tumor immunosuppressive microenvironment that play key roles in tumor progress. Understanding subset diversity in T cells is a critical question for developing cancer immunotherapy.

METHODS: A total of 235 specimens from surgical resections of hepatocellular carcinoma (HCC) patients were examined for infiltration of exhausted T cell (Tex) in tumor and adjacent tissue. We conducted deep single-cell targeted immune profiling on CD3

RESULTS: We observed transitional differentiation of exhausted CD8

CONCLUSIONS: T cell exhaustion is a progressive process, and the gene-expression profiling displayed T cell exhaustion and anergy …

Physical Robustness And Resilience Among Long-Lived Female Siblings: A Comparison With Sporadic Long-Livers, Angéline Galvin, Svetlana Ukraintseva, Konstantin Arbeev, Mary Feitosa, Kaare Christensen

Open Access Publications

Long-lived individuals are central in studies of healthy longevity. However, few pro-longevity factors have been identified, presumably because of "phenocopies", i.e. individuals that live long by chance. Familial longevity cases may include less phenocopies than sporadic cases and provide better insights into longevity mechanisms. Here we examined whether long-lived female siblings have a better ability to avoid diseases at ages 65+ (proxy for "robustness") and/or survive to extreme ages (proxy for "resilience") compared to sporadic long-livers. A total of 1,156 long-lived female siblings were selected from three nationwide Danish studies and age-matched with sporadic long-lived female controls. Outcomes included cumulative …

Inhibition Of Fatty Acid Oxidation Promotes Macrophage Control Of Mycobacterium Tuberculosis, Pallavi Chandra, Li He, Matthew Zimmerman, Guozhe Yang, Stefan Köster, Mireille Ouimet, Han Wang, Kathyrn J Moore, Véronique Dartois, Joel D Schilling, Jennifer A Philips

Open Access Publications

Macrophage activation involves metabolic reprogramming to support antimicrobial cellular functions. How these metabolic shifts influence the outcome of infection by intracellular pathogens remains incompletely understood.

Defining A Research Agenda For Layperson Prehospital Hemorrhage Control: A Consensus Statement, Eric Goralnick, Erin Andrade, Et Al

Open Access Publications

Importance: Trauma is the leading cause of death for US individuals younger than 45 years, and uncontrolled hemorrhage is a major cause of trauma mortality. The US military's medical advancements in the field of prehospital hemorrhage control have reduced battlefield mortality by 44%. However, despite support from many national health care organizations, no integrated approach to research has been made regarding implementation, epidemiology, education, and logistics of prehospital hemorrhage control by layperson immediate responders in the civilian sector.

Objective: To create a national research agenda to help guide future work for prehospital hemorrhage control by laypersons.

Evidence Review: The 2-day, …

Epigenomics And Genotype-Phenotype Association Analyses Reveal Conserved Genetic Architecture Of Complex Traits In Cattle And Human, Shuli Liu, Ying Yu, Shengli Zhang, John B Cole, Albert Tenesa, Ting Wang, Tara G Mcdaneld, Li Ma, George E Liu, Lingzhao Fang

Open Access Publications

BACKGROUND: Lack of comprehensive functional annotations across a wide range of tissues and cell types severely hinders the biological interpretations of phenotypic variation, adaptive evolution, and domestication in livestock. Here we used a combination of comparative epigenomics, genome-wide association study (GWAS), and selection signature analysis, to shed light on potential adaptive evolution in cattle.

RESULTS: We cross-mapped 8 histone marks of 1300 samples from human to cattle, covering 178 unique tissues/cell types. By uniformly analyzing 723 RNA-seq and 40 whole genome bisulfite sequencing (WGBS) datasets in cattle, we validated that cross-mapped histone marks captured tissue-specific expression and methylation, reflecting tissue-relevant …

Clinical Teaching: An Evidence-Based Guide To Best Practices From The Council Of Emergency Medicine Residency Directors, Sreeja Natesan, John Bailitz, Andrew King, Sara M Krzyzaniak, Sarah K Kennedy, Albert J Kim, Richard Byyny, Michael Gottlieb

Open Access Publications

Clinical teaching is the primary educational tool use to train learners from day one of medical school all the way to the completion of fellowship. However, concerns over time constraints and patient census have led to a decline in bedside teaching. This paper provides a critical review of the literature on clinical teaching with a focus on instructor teaching strategies, clinical teaching models, and suggestions for incorporating technology. Recommendations for instructor-related teaching factors include adequate preparation, awareness of effective teacher attributes, using evidence-based-knowledge dissemination strategies, ensuring good communication, and consideration of environmental factors. Proposed recommendations for potential teaching strategies include …

Whole Exome Sequencing Reveals The Maintained Polyclonal Nature From Primary To Metastatic Malignant Peripheral Nerve Sheath Tumor In Two Patients With Nf1, Abigail Godec, Reyka Jayasinghe, John S A Chrisinger, Bethany Prudner, Tyler Ball, Yuxi Wang, Divya Srihari, Madhurima Kaushal, Hilary Dietz, Xiaochun Zhang, Melike Pekmezci, Sonika Dahiya, Yu Tao, Jinqin Luo, Brian A Van Tine, Li Ding, David H Gutmann, Angela C Hirbe

Open Access Publications

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas with high metastatic rates and poor overall patient survival. There are currently no effective therapies, underscoring the pressing need to define the molecular etiologies that underlie MPNST progression. The aim of this study was to examine clonal progression and identify the molecular events critical for MPNST spread.

METHODS: In two patients with temporally and spatially distinct metastatic lesions, we employed whole exome sequencing (WES) to elucidate the genetic events of clonal progression, thus identifying the molecular events critical for MPNST spread.

RESULTS: First, we demonstrated shared clonal origins …

Association Of Interleukin 7 Immunotherapy With Lymphocyte Counts Among Patients With Severe Coronavirus Disease 2019 (Covid-19), Pierre Francois Laterre, Bruno François, Christine Collienne, Philippe Hantson, Robin Jeannet, Kenneth E. Remy, Richard S. Hotchkiss

Open Access Publications

No abstract provided.

Histopathology And Selective Biomarker Expression In Human Meibomian Glands, Lixing W Reneker, Rebecca T Irlmeier, Ying-Bo Shui, Ying Liu, Andrew J W Huang

Open Access Publications

BACKGROUND/AIMS: Meibomian gland dysfunction (MGD) is the most common form of evaporative dry eye disease, but its pathogenesis is poorly understood. This study examined the histopathological features of meibomian gland (MG) tissue from cadaver donors to identify potential pathogenic processes that underlie MGD in humans.

METHODS: Histological analyses was performed on the MGs in the tarsal plates dissected from four cadaver donors, two young and two old adults, including a 36-year-old female (36F) and three males aged 30, 63 and 64 years (30M, 63M and 64M).

RESULTS: The MGs of 36F displayed normal anatomy and structure, whereas the MGs of …

A Patient-Centred, Comprehensive Model For The Care For Heart Failure: The 360° Heart Failure Centre, Ilia G Halatchev, Jay R Mcdonald, Wen-Chin Wu

Open Access Publications

No abstract provided.

Predictors Of Worsening Neuropathy And Neuropathic Pain After 12 Years In People With Hiv, Ronald J Ellis, Monica Diaz, Ned Sacktor, Christina Marra, Ann C Collier, David B Clifford, Nigel Calcutt, Jerel A Fields, Robert K Heaton, Scott L Letendre, Cns Antiretroviral Therapy Effects Research (Charter) Study Group

Open Access Publications

OBJECTIVE: Distal sensory polyneuropathy (DSP) and neuropathic pain are important clinical concerns in virally suppressed people with HIV. We determined how these conditions evolved, what factors influenced their evolution, and their clinical impact.

METHODS: Ambulatory, community-dwelling HIV seropositive individuals were recruited at six research centers. Clinical evaluations at baseline and 12 years later determined neuropathy signs and distal neuropathic pain (DNP). Additional assessments measured activities of daily living and quality of life (QOL). Factors potentially associated with DSP and DNP progression included disease severity, treatment, demographics, and co-morbidities. Adjusted odds ratios were calculated for follow-up neuropathy outcomes.

RESULTS: Of 254 …