Digital Commons Network^™

Seasonal Nitrogen Remobilization And The Role Of Auxin Transport In Poplar Trees, Gen Li, Rongshoung Lin, Chioma Egekwu, Joshua Blakeslee, Jinshan Lin, Emily Pettengill, Angus S Murphy, Wendy A Peer, Nazrul Islam, Benjamin A Babst, Fei Gao, Sergey Komarov, Yuan-Chuan Tai, Gary D Coleman

2020-Current year OA Pubs

Seasonal nitrogen (N) cycling in Populus, involves bark storage proteins (BSPs) that accumulate in bark phloem parenchyma in the autumn and decline when shoot growth resumes in the spring. Little is known about the contribution of BSPs to growth or the signals regulating N remobilization from BSPs. Knockdown of BSP accumulation via RNAi and N sink manipulations were used to understand how BSP storage influences shoot growth. Reduced accumulation of BSPs delayed bud break and reduced shoot growth following dormancy. Further, 13N tracer studies also showed that BSP accumulation is an important factor in N partitioning from senescing leaves to …

Interleukin-22 Inhibits Respiratory Syncytial Virus Production By Blocking Virus-Mediated Subversion Of Cellular Autophagy, Sudipta Das, Claudette St Croix, Misty Good, Jie Chen, Jinming Zhao, Sanmei Hu, Mark Ross, Michael M Myerburg, Joseph M Pilewski, John Williams, Sally E Wenzel, Jay K Kolls, Anuradha Ray, Prabir Ray

Open Access Publications

Respiratory syncytial virus (RSV) infection can cause severe bronchiolitis in infants requiring hospitalization, whereas the elderly and immunocompromised are prone to RSV-induced pneumonia. RSV primarily infects lung epithelial cells. Given that no vaccine against RSV is currently available, we tested the ability of the epithelial-barrier protective cytokine interleukin-22 (IL-22) to control RSV production. When used in a therapeutic modality, IL-22 efficiently blunted RSV production from infected human airway and alveolar epithelial cells and IL-22 administration drastically reduced virus titer in the lungs of infected newborn mice. RSV infection resulted in increased expression of LC3B, a key component of the cellular …

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 …

A Pip2 Substitute Mediates Voltage Sensor-Pore Coupling In Kcnq Activation, Yongfeng Liu, Nien-Du Yang, Et Al.

2020-Current year OA Pubs

KCNQ family K

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

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) …

Fam20b-Catalyzed Glycosaminoglycans Control Murine Tooth Number By Restricting Fgfr2b Signaling, Jingyi Wu, Ling Li, David M Ornitz, Et Al

Open Access Publications

BACKGROUND: The formation of supernumerary teeth is an excellent model for studying the molecular mechanisms that control stem/progenitor cell homeostasis needed to generate a renewable source of replacement cells and tissues. Although multiple growth factors and transcriptional factors have been associated with supernumerary tooth formation, the regulatory inputs of extracellular matrix in this regenerative process remains poorly understood.

RESULTS: In this study, we present evidence that disrupting glycosaminoglycans (GAGs) in the dental epithelium of mice by inactivating FAM20B, a xylose kinase essential for GAG assembly, leads to supernumerary tooth formation in a pattern reminiscent of replacement teeth. The dental epithelial …

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 …

Collaborative, Multidisciplinary Evaluation Of Cancer Variants Through Virtual Molecular Tumor Boards Informs Local Clinical Practices, Shruti Rao, Beth Pitel, Alex H Wagner, Simina M Boca, Matthew Mccoy, Ian King, Samir Gupta, Ben Ho Park, Jeremy L Warner, James Chen, Peter K Rogan, Debyani Chakravarty, Malachi Griffith, Obi L Griffith, Subha Madhavan

2020-Current year OA Pubs

PURPOSE: The cancer research community is constantly evolving to better understand tumor biology, disease etiology, risk stratification, and pathways to novel treatments. Yet the clinical cancer genomics field has been hindered by redundant efforts to meaningfully collect and interpret disparate data types from multiple high-throughput modalities and integrate into clinical care processes. Bespoke data models, knowledgebases, and one-off customized resources for data analysis often lack adequate governance and quality control needed for these resources to be clinical grade. Many informatics efforts focused on genomic interpretation resources for neoplasms are underway to support data collection, deposition, curation, harmonization, integration, and analytics …

Proteogenomic Characterization Reveals Therapeutic Vulnerabilities In Lung Adenocarcinoma, Michael A. Gillette, Song Cao, Yize Li, Wen-Wei Liang, Michael C Wendl, Ramaswamy Govindan, Et Al.

2020-Current year OA Pubs

To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization of 110 tumors and 101 matched normal adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, and acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, and gender. Proteomic and phosphoproteomic data illuminated biology downstream of copy number aberrations, somatic mutations, and fusions and identified therapeutic vulnerabilities associated with driver events involving KRAS, EGFR, and ALK. Immune subtyping revealed a complex landscape, reinforced the association of STK11 with immune-cold behavior, and underscored a potential immunosuppressive role of neutrophil degranulation. …

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.

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 …

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 …

Transcriptomes From German Shepherd Dogs Reveal Differences In Immune Activity Between Atopic Dermatitis Affected And Control Skin, K Tengvall, K Bergvall, M Olsson, B Ardesjö-Lundgren, F H G Farias, M Kierczak, Å Hedhammar, K Lindblad-Toh, G Andersson

2020-Current year OA Pubs

Canine atopic dermatitis (CAD) is an inflammatory and pruritic allergic skin disease with both genetic and environmental risk factors described. We performed mRNA sequencing of non-lesional axillary skin biopsies from nine German shepherd dogs. Obtained RNA sequences were mapped to the dog genome (CanFam3.1) and a high-quality skin transcriptome was generated with 23,510 expressed gene transcripts. Differentially expressed genes (DEGs) were defined by comparing three controls to five treated CAD cases. Using a leave-one-out analysis, we identified seven DEGs: five known to encode proteins with functions related to an activated immune system (CD209, CLEC4G, LOC102156842 (lipopolysaccharide-binding protein-like), LOC480601 (regakine-1-like), LOC479668 …

Diagnosis And Management Of Malignant Peripheral Nerve Sheath Tumors: Current Practice And Future Perspectives, Bethany C Prudner, Tyler Ball, Richa Rathore, Angela C Hirbe

2020-Current year OA Pubs

One of the most common malignancies affecting adults with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome is the malignant peripheral nerve sheath tumor (MPNST), a highly aggressive sarcoma that typically develops from benign plexiform neurofibromas. Approximately 8-13% of individuals with NF1 will develop MPNST during young adulthood. There are few therapeutic options, and the vast majority of people with these cancers will die within 5 years of diagnosis. Despite efforts to understand the pathogenesis of these aggressive tumors, the overall prognosis remains dismal. This manuscript will review the current understanding of the cellular and molecular progression of MPNST, diagnostic …

Disease And Treatment Patterns Among Patients With Pouch-Related Conditions In A Cohort Of Large Tertiary Care Inflammatory Bowel Disease Centers In The United States, Edward L Barnes, Laura Raffals, Millie D Long, Gaurav Syal, Maia Kayal, Ashwin Ananthakrishnan, Benjamin Cohen, Joel Pekow, Parakkal Deepak, Jean-Frederic Colombel, Hans H Herfarth, Robert S Sandler

2020-Current year OA Pubs

BACKGROUND: Gaps exist in our understanding of the clinical course of pouch-related disorders.

METHODS: We evaluated baseline disease activity and longitudinal treatment patterns among patients with inflammatory conditions of the pouch.

RESULTS: Among 468 patients with an ileal pouch-anal anastomosis (IPAA), 94 (20%) had acute pouchitis, 96 (21%) had chronic pouchitis, and 192 (41%) had Crohn disease of the pouch. Following an IPAA, 38% of patients were treated with a biologic and 11% underwent inflammatory bowel disease- or bowel-related surgery.

CONCLUSIONS: Treatment patterns after IPAA indicate that pouch-related disorders have a significant impact on individual patients and the healthcare system.

The Society For Immunotherapy Of Cancer Consensus Statement On Immunotherapy For The Treatment Of Multiple Myeloma, Nina Shah, Ravi Vij, Et Al

2020-Current year OA Pubs

Outcomes in multiple myeloma (MM) have improved dramatically in the last two decades with the advent of novel therapies including immunomodulatory agents (IMiDs), proteasome inhibitors and monoclonal antibodies. In recent years, immunotherapy for the treatment of MM has advanced rapidly, with the approval of new targeted agents and monoclonal antibodies directed against myeloma cell-surface antigens, as well as maturing data from late stage trials of chimeric antigen receptor CAR T cells. Therapies that engage the immune system to treat myeloma offer significant clinical benefits with durable responses and manageable toxicity profiles, however, the appropriate use of these immunotherapy agents can …

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.

Clinical Outcomes Of Patients With Advanced Synovial Sarcoma Or Myxoid/Round Cell Liposarcoma Treated At Major Cancer Centers In The United States, Seth M Pollack, Neeta Somaiah, Dejka M Araujo, Mihaela Druta, Brian A Van Tine, Melissa A Burgess, Sant P Chawla, Mahesh Seetharam, Scott H Okuno, Chet Bohac, Michael Chen, Sergey Yurasov, Steven Attia

Open Access Publications

BACKGROUND: Outcomes data regarding advanced synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are limited, consisting primarily of retrospective series and post hoc analyses of clinical trials.

METHODS: In this multi-center retrospective study, data were abstracted from the medical records of 350 patients from nine sarcoma centers throughout the United States and combined into a registry. Patients with advanced/unresectable or metastatic SS (n = 249) or MRCL (n = 101) who received first-line systemic anticancer therapy and had records of tumor imaging were included. Overall survival (OS), time to next treatment, time to distant metastasis, and progression-free survival (PFS) were …

Driving Factors Of Preterm Birth Risk In Adolescents, Marta J. Perez, Jen J. Chang, Lorene A. Temming, Ebony B. Carter, Julia D. López, Methodius G. Tuuli, George A. Macones, Molly J. Stout

Open Access Publications

No abstract provided.

Comparative Genomics And Transcriptomics Of 4 Paragonimus Species Provide Insights Into Lung Fluke Parasitism And Pathogenesis, Bruce A. Rosa, Young-Jun Choi, Samantha N. Mcnulty, Hyeim Jung, John Martin, Takeshi Agatsuma, Hiromu Sugiyama, Thanh Hoa Le, Pham Ngoc Doanh, Wanchai Maleewong, David Blair, Paul J. Brindley, Peter U. Fischer, Makedonka Mitreva

Open Access Publications

BACKGROUND: Paragonimus spp. (lung flukes) are among the most injurious foodborne helminths, infecting ∼23 million people and subjecting ∼292 million to infection risk. Paragonimiasis is acquired from infected undercooked crustaceans and primarily affects the lungs but often causes lesions elsewhere including the brain. The disease is easily mistaken for tuberculosis owing to similar pulmonary symptoms, and accordingly, diagnostics are in demand.

RESULTS: We assembled, annotated, and compared draft genomes of 4 prevalent and distinct Paragonimus species: Paragonimus miyazakii, Paragonimus westermani, Paragonimus kellicotti, and Paragonimus heterotremus. Genomes ranged from 697 to 923 Mb, included 12,072-12,853 genes, and were 71.6-90.1% complete according …

Lathosterol Oxidase (Sterol C-5 Desaturase) Deletion Confers Resistance To Amphotericin B And Sensitivity To Acidic Stress In Leishmania Major, Yu Ning, Cheryl Frankfater, Fong-Fu Hsu, Rodrigo P Soares, Camila A Cardoso, Paula M Nogueira, Noelia Marina Lander, Roberto Docampo, Kai Zhang

Open Access Publications

Lathosterol oxidase (LSO) catalyzes the formation of the C-5-C-6 double bond in the synthesis of various types of sterols in mammals, fungi, plants, and protozoa. In

The Endosymbiont Wolbachia Rebounds Following Antibiotic Treatment, Emma L. Gunderson, Young-Jun Choi, Makedonka Mitreva, Et Al.

Open Access Publications

Antibiotic treatment has emerged as a promising strategy to sterilize and kill filarial nematodes due to their dependence on their endosymbiotic bacteria, Wolbachia. Several studies have shown that novel and FDA-approved antibiotics are efficacious at depleting the filarial nematodes of their endosymbiont, thus reducing female fecundity. However, it remains unclear if antibiotics can permanently deplete Wolbachia and cause sterility for the lifespan of the adult worms. Concerns about resistance arising from mass drug administration necessitate a careful exploration of potential Wolbachia recrudescence. In the present study, we investigated the long-term effects of the FDA-approved antibiotic, rifampicin, in the Brugia pahangi …

Brainstorm: A Multi-Institutional Phase 1/2 Study Of Rrx-001 In Combination With Whole Brain Radiation Therapy For Patients With Brain Metastases, Michelle M Kim, Christina I Tsien, Et Al

Open Access Publications

PURPOSE: To determine the recommended phase 2 dose of RRx-001, a radiosensitizer with vascular normalizing properties, when used with whole-brain radiation therapy (WBRT) for brain metastases and to assess whether quantitative changes in perfusion magnetic resonance imaging (MRI) after RRx-001 correlate with response.

METHODS AND MATERIALS: Five centers participated in this phase 1/2 trial of RRx-001 given once pre-WBRT and then twice weekly during WBRT. Four dose levels were planned (5 mg/m

RESULTS: Between 2015 and 2017, 31 patients were enrolled. Two patients dropped out before any therapy. Median age was 60 years (range, 30-76), and 12 were male. The …

The Effect Of Thermal Therapy On The Blood-Brain Barrier And Blood-Tumor Barrier, Bhuvic Patel, Peter H Yang, Albert H Kim

Open Access Publications

The blood-brain and blood-tumor barriers represent highly specialized structures responsible for tight regulation of molecular transit into the central nervous system. Under normal circumstances, the relative impermeability of the blood-brain barrier (BBB) protects the brain from circulating toxins and contributes to a brain microenvironment necessary for optimal neuronal function. However, in the context of tumors and other diseases of central nervous system, the BBB and the more recently appreciated blood-tumor barrier (BTB) represent barriers that prevent effective drug delivery. Overcoming both barriers to optimize treatment of central nervous system diseases remains the subject of intense scientific investigation. Although many newer …

Robust Principal Component Analysis For Accurate Outlier Sample Detection In Rna-Seq Data, Xiaoying Chen, Bo Zhang, Ting Wang, Azad Bonni, Guoyan Zhao

Open Access Publications

BACKGROUND: High throughput RNA sequencing is a powerful approach to study gene expression. Due to the complex multiple-steps protocols in data acquisition, extreme deviation of a sample from samples of the same treatment group may occur due to technical variation or true biological differences. The high-dimensionality of the data with few biological replicates make it challenging to accurately detect those samples, and this issue is not well studied in the literature currently. Robust statistics is a family of theories and techniques aim to detect the outliers by first fitting the majority of the data and then flagging data points that …