Digital Commons Network^™

Mucosal Infection Rewires Tnfɑ Signaling Dynamics To Skew Susceptibility To Recurrence, Lu Yu, Valerie P. O'Brien, Jonathan Livny, Denise Dorsey, Nirmalya Bandyopadhyay, Marco Colonna, Michael G. Caparon, Elisha D.O. Roberson, Scott J. Hultgren, Thomas Hannan

Open Access Publications

A mucosal infectious disease episode can render the host either more or less susceptible to recurrent infection, but the specific mechanisms that tip the balance remain unclear. We investigated this question in a mouse model of recurrent urinary tract infection and found that a prior bladder infection resulted in an earlier onset of tumor necrosis factor-alpha (TNFɑ)-mediated bladder inflammation upon subsequent bacterial challenge, relative to age-matched naive mice. However, the duration of TNFɑ signaling activation differed according to whether the first infection was chronic (Sensitized) or self-limiting (Resolved). TNFɑ depletion studies revealed that transient early-phase TNFɑ signaling in Resolved mice …

Noroviruses Subvert The Core Stress Granule Component G3bp1 To Promote Viral Vpg-Dependent Translation, Myra Hosmillo, Jia Lu, Michael R. Mcallaster, James B. Eaglesham, Xinjie Wang, Edward Emmott, Patricia Domingues, Yasmin Chaudhry, Tim J. Fitzmaurice, Matthew K.H. Tung, Marc Dominik Panas, Gerald Mcinerney, Nicolas Locker, Craig B. Wilen, Ian G. Goodfellow

Open Access Publications

Knowledge of the host factors required for norovirus replication has been hindered by the challenges associated with culturing human noroviruses. We have combined proteomic analysis of the viral translation and replication complexes with a CRISPR screen, to identify host factors required for norovirus infection. The core stress granule component G3BP1 was identified as a host factor essential for efficient human and murine norovirus infection, demonstrating a conserved function across the

A Single-Nuclei Rna Sequencing Study Of Mendelian And Sporadic Ad In The Human Brain, Jorge L Del-Aguila, Zeran Li, Umber Dube, Kathie A Mihindukulasuriya, John P Budde, Maria Victoria Fernandez, Laura Ibanez, Joseph Bradley, Fengxian Wang, Kristy Bergmann, Richard Davenport, John C Morris, David M Holtzman, Richard J Perrin, Bruno A Benitez, Joseph Dougherty, Carlos Cruchaga, Oscar Harari

Open Access Publications

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. This neurodegenerative disorder is associated with neuronal death and gliosis heavily impacting the cerebral cortex. AD has a substantial but heterogeneous genetic component, presenting both Mendelian and complex genetic architectures. Using bulk RNA-seq from the parietal lobes and deconvolution methods, we previously reported that brains exhibiting different AD genetic architecture exhibit different cellular proportions. Here, we sought to directly investigate AD brain changes in cell proportion and gene expression using single-cell resolution.

METHODS: We generated unsorted single-nuclei RNA sequencing data from brain tissue. We leveraged the tissue donated from …

Toxoplasma Gondii Infection Drives Conversion Of Nk Cells Into Ilc1-Like Cells, Eugene Park, Swapneel Patel, Qiuling Wang, Prabhakar Andhey, Konstantin Zaitsev, Sophia Porter, Maxwell Hershey, Michael Bern, Beatrice Plougastel-Douglas, Patrick Collins, Marco Colonna, Kenneth M. Murphy, Eugene Oltz, Maxim Artyomov, L David Sibley, Wayne M. Yokoyama

Open Access Publications

Innate lymphoid cells (ILCs) were originally classified based on their cytokine profiles, placing natural killer (NK) cells and ILC1s together, but recent studies support their separation into different lineages at steady-state. However, tumors may induce NK cell conversion into ILC1-like cells that are limited to the tumor microenvironment and whether this conversion occurs beyond this environment remains unknown. Here, we describe

Association Of Baseline Inflammatory Biomarkers With Cancer Mortality In The Regards Cohort, Tomi Akinyemiju, Justin X. Moore, Maria Pisu, Michael Goodman, Virginia J. Howard, Monika Safford, Susan C. Gilchrist, Mary Cushman, Leann Long, Suzanne E. Judd

Open Access Publications

This study examines the association between inflammatory biomarkers and risk of cancer mortality by race. Data were obtained from 1,856 participants in the prospective REGARDS cohort who were cancer-free at baseline, and analyzed in relation to cancer mortality prospectively. Biomarkers were log-transformed and categorized into tertiles due to non-normal distributions, and Cox proportional hazard regression models were utilized to compute hazard ratios with 95% confidence intervals using robust sandwich methods. Individuals in the highest tertile of IL-6 had over a 12-fold increased risk of cancer mortality (HR: 12.97, 95% CI: 3.46-48.63); those in the highest tertile of IL-8 had over …

Measurement Repeatability Of 18 F-Fdg Pet/Ct Versus 18 F-Fdg Pet/Mri In Solid Tumors Of The Pelvis, Tyler J Fraum, Kathryn J Fowler, John P Crandall, Richard A Laforest, Amber Salter, Hongyu An, Michael A Jacobs, Perry W Grigsby, Farrokh Dehdashti, Richard L Wahl

Open Access Publications

Knowledge of the within-subject variability of

Analysis Of An Improved Cyanophora Paradoxa Genome Assembly, Dana C Price, Ursula W Goodenough, Robyn Roth, Jae-Hyeok Lee, Thamali Kariyawasam, Marek Mutwil, Camilla Ferrari, Fabio Facchinelli, Steven G Ball, Ugo Cenci, Cheong Xin Chan, Nicole E Wagner, Hwan Su Yoon, Andreas P M Weber, Debashish Bhattacharya

Open Access Publications

Glaucophyta are members of the Archaeplastida, the founding group of photosynthetic eukaryotes that also includes red algae (Rhodophyta), green algae, and plants (Viridiplantae). Here we present a high-quality assembly, built using long-read sequences, of the ca. 100 Mb nuclear genome of the model glaucophyte Cyanophora paradoxa. We also conducted a quick-freeze deep-etch electron microscopy (QFDEEM) analysis of C. paradoxa cells to investigate glaucophyte morphology in comparison to other organisms. Using the genome data, we generated a resolved 115-taxon eukaryotic tree of life that includes a well-supported, monophyletic Archaeplastida. Analysis of muroplast peptidoglycan (PG) ultrastructure using QFDEEM shows that PG is …

Novel Cell Adhesion/Migration Pathways Are Predictive Markers Of Hdac Inhibitor Resistance In Cutaneous T Cell Lymphoma, Jared M Andrews, Jennifer A Schmidt, Kenneth R Carson, Amy C Musiek, Neha Mehta-Shah, Jacqueline E Payton

Open Access Publications

BACKGROUND: Treatment for Cutaneous T Cell Lymphoma (CTCL) is generally not curative. Therefore, selecting therapy that is effective and tolerable is critical to clinical decision-making. Histone deacetylase inhibitors (HDACi), epigenetic modifier drugs, are commonly used but effective in only ~30% of patients. There are no predictive markers of HDACi response and the CTCL histone acetylation landscape remains unmapped. We sought to identify pre-treatment molecular markers of resistance in CTCL that progressed on HDACi therapy.

METHODS: Purified T cells from 39 pre/post-treatment peripheral blood samples and skin biopsies from 20 patients were subjected to RNA-seq and ChIP-seq for histone acetylation marks …

Precision Delivery Of Ras-Inhibiting Sirna To Kras Driven Cancer Via Peptide-Based Nanoparticles, Matthew S. Strand, Bradley A. Krasnick, Hua Pan, Xiuli Zhang, Ye Bi, Candace Brooks, Christopher Wetzel, Narendra Sankpal, Timothy Fleming, S Peter Goedegebuure, David G. Denardo, William E. Gillanders, William G. Hawkins, Samuel A. Wickline, Ryan C. Fields

Open Access Publications

Over 95% of pancreatic adenocarcinomas (PDACs), as well as a large fraction of other tumor types, such as colorectal adenocarcinoma, are driven by KRAS activation. However, no direct RAS inhibitors exist for cancer therapy. Furthermore, the delivery of therapeutic agents of any kind to PDAC in particular has been hindered by the extensive desmoplasia and resultant drug delivery challenges that accompanies these tumors. Small interfering RNA (siRNA) is a promising modality for anti-neoplastic therapy due to its precision and wide range of potential therapeutic targets. Unfortunately, siRNA therapy is limited by low serum half-life, vulnerability to intracellular digestion, and transient …

Spinal V2b Neurons Reveal A Role For Ipsilateral Inhibition In Speed Control, Rebecca A. Callahan, Richard Roberts, Mohini Sengupta, Yukiko Kimura, Shin-Ichi Higashijima, Martha W. Bagnall

Open Access Publications

The spinal cord contains a diverse array of interneurons that govern motor output. Traditionally, models of spinal circuits have emphasized the role of inhibition in enforcing reciprocal alternation between left and right sides or flexors and extensors. However, recent work has shown that inhibition also increases coincident with excitation during contraction. Here, using larval zebrafish, we investigate the V2b (Gata3+) class of neurons, which contribute to flexor-extensor alternation but are otherwise poorly understood. Using newly generated transgenic lines we define two stable subclasses with distinct neurotransmitter and morphological properties. These V2b subclasses synapse directly onto motor neurons with differential targeting …

Targeting Sporadic And Neurofibromatosis Type 1 (Nf1) Related Refractory Malignant Peripheral Nerve Sheath Tumors (Mpnst) In A Phase Ii Study Of Everolimus In Combination With Bevacizumab (Sarc016), Brigitte C. Widemann, Anglea C. Hirbe, Et Al

Open Access Publications

No abstract provided.

Ml277 Specifically Enhances The Fully Activated Open State Of Kcnq1 By Modulating Vsd-Pore Coupling, Panpan Hou, Jingyi Shi, Kelli Mcfarland White, Yuan Gao, Jianmin Cui

Open Access Publications

Upon membrane depolarization, the KCNQ1 potassium channel opens at the intermediate (IO) and activated (AO) states of the stepwise voltage-sensing domain (VSD) activation. In the heart, KCNQ1 associates with KCNE1 subunits to form I

Identification Of An Alternating-Access Dynamics Mutant Of Emre With Impaired Transport, Chao Wu, Samantha A Wynne, Nathan E Thomas, Eva-Maria Uhlemann, Christopher G Tate, Katherine A Henzler-Wildman

Open Access Publications

Proteins that perform active transport must alternate the access of a binding site, first to one side of a membrane and then to the other, resulting in the transport of bound substrates across the membrane. To better understand this process, we sought to identify mutants of the small multidrug resistance transporter EmrE with reduced rates of alternating access. We performed extensive scanning mutagenesis by changing every amino acid residue to Val, Ala, or Gly, and then screening the drug resistance phenotypes of the resulting mutants. We identified EmrE mutants that had impaired transport activity but retained the ability to bind …

A Sparse Covarying Unit That Describes Healthy And Impaired Human Gut Microbiota Development, Arjun S Raman, Jeanette L Gehrig, Siddarth Venkatesh, Hao-Wei Chang, Matthew C Hibberd, Sathish Subramanian, Michael J Barratt, Jeffrey I Gordon, Et Al

Open Access Publications

Characterizing the organization of the human gut microbiota is a formidable challenge given the number of possible interactions between its components. Using a statistical approach initially applied to financial markets, we measured temporally conserved covariance among bacterial taxa in the microbiota of healthy members of a Bangladeshi birth cohort sampled from 1 to 60 months of age. The results revealed an "ecogroup" of 15 covarying bacterial taxa that provide a concise description of microbiota development in healthy children from this and other low-income countries, and a means for monitoring community repair in undernourished children treated with therapeutic foods. Features of …

Effects Of Microbiota-Directed Foods In Gnotobiotic Animals And Undernourished Children, Jeanette L Gehrig, Siddarth Venkatesh, Hao-Wei Chang, Matthew C Hibberd, Vanderlene L Kung, Jiye Cheng, Robert Y Chen, Sathish Subramanian, Carrie A Cowardin, Martin F Meier, David O'Donnell, Michael Talcott, Larry D Spears, Clay F Semenkovich, Christopher Sawyer, Richard D Head, Michael J Barratt, Jeffrey I Gordon, Et Al

Open Access Publications

To examine the contributions of impaired gut microbial community development to childhood undernutrition, we combined metabolomic and proteomic analyses of plasma samples with metagenomic analyses of fecal samples to characterize the biological state of Bangladeshi children with severe acute malnutrition (SAM) as they transitioned, after standard treatment, to moderate acute malnutrition (MAM) with persistent microbiota immaturity. Host and microbial effects of microbiota-directed complementary food (MDCF) prototypes targeting weaning-phase bacterial taxa underrepresented in SAM and MAM microbiota were characterized in gnotobiotic mice and gnotobiotic piglets colonized with age- and growth-discriminatory bacteria. A randomized, double-blind controlled feeding study identified a lead MDCF …

A Stem-Cell-Derived Platform Enables Complete Cryptosporidium Development In Vitro And Genetic Tractability, Georgia Wilke, Lisa J Funkhouser-Jones, Yi Wang, Soumya Ravindran, Qiuling Wang, Wandy L Beatty, Megan T Baldridge, Kelli L Vandussen, Bang Shen, Mark S Kuhlenschmidt, Theresa B Kuhlenschmidt, William H Witola, Thaddeus S Stappenbeck, L. David Sibley

Open Access Publications

Despite being a frequent cause of severe diarrheal disease in infants and an opportunistic infection in immunocompromised patients, Cryptosporidium research has lagged due to a lack of facile experimental methods. Here, we describe a platform for complete life cycle development and long-term growth of C. parvum in vitro using "air-liquid interface" (ALI) cultures derived from intestinal epithelial stem cells. Transcriptomic profiling revealed that differentiating epithelial cells grown under ALI conditions undergo profound changes in metabolism and development that enable completion of the parasite life cycle in vitro. ALI cultures support parasite expansion > 100-fold and generate viable oocysts that are transmissible …

A Guinea Fowl Genome Assembly Provides New Evidence On Evolution Following Domestication And Selection In Galliformes, Alain Vignal, Simon Boitard, Noémie Thébault, Guiguigbaza-Kossigan Dayo, Valentine Yapi-Gnaore, Issaka Youssao Abdou Karim, Cécile Berthouly-Salazar, Nóra Pálinkás-Bodzsár, Daniel Guémené, Francoise Thibaud-Nissen, Wesley C Warren, Michèle Tixier-Boichard, Xavier Rognon

Open Access Publications

The helmeted guinea fowl Numida meleagris belongs to the order Galliformes. Its natural range includes a large part of sub-Saharan Africa, from Senegal to Eritrea and from Chad to South Africa. Archaeozoological and artistic evidence suggest domestication of this species may have occurred about 2,000 years BP in Mali and Sudan primarily as a food resource, although villagers also benefit from its capacity to give loud alarm calls in case of danger, of its ability to consume parasites such as ticks and to hunt snakes, thus suggesting its domestication may have resulted from a commensal association process. Today, it is …

Pituitary Adenoma In Pediatric And Adolescent Populations, Jie Chen, Robert E Schmidt, Sonika Dahiya

Open Access Publications

Pituitary adenomas are rare in children and adolescents and although mostly benign, they can sometimes be challenging to manage due to their locally invasive nature. In this study, we examined the clinicopathologic features of 42 pituitary adenomas in patients ≤21 years of age. The youngest patient was 8 years old (median age: 18 years), and the female-to-male ratio was 1.8:1. Five patients had recurrence after resection. There was no obvious difference between the recurrent rates in the typical (11.7%) and atypical adenomas (12.5%) based on the 2004 WHO classification. However, the recurrence rate was much higher in adenomas with an …

Peroxidasin Is A Novel Target Of Autoantibodies In Lupus Nephritis, Pallavi Manral, Selene Colon, Gautam Bhave, Ming-Hui Zhao, Sanjay Jain, Dorin-Bogdan Borza

Open Access Publications

No abstract provided.

A Multimodality Approach To Assessing Factor I Genetic Variants In Atypical Hemolytic Uremic Syndrome, Anuja Java, Nicola Pozzi, Latisha D Love-Gregory, Jonathan W Heusel, Yun Ju Sung, Zheng Hu, Paula Bertram, M Kathryn Liszewski, Laura M Cline, Zhen Ren, John P Atkinson

Open Access Publications

No abstract provided.

Unified Single-Cell Analysis Of Testis Gene Regulation And Pathology In Five Mouse Strains, Min Jung, Daniel Wells, Jannette Rusch, Suhaira Ahmad, Jonathan Marchini, Simon R. Myers, Donald F. Conrad

Open Access Publications

To fully exploit the potential of single-cell functional genomics in the study of development and disease, robust methods are needed to simplify the analysis of data across samples, time-points and individuals. Here we introduce a model-based factor analysis method, SDA, to analyze a novel 57,600 cell dataset from the testes of wild-type mice and mice with gonadal defects due to disruption of the genes

Intracellular Retention Of Mutant Lysyl Oxidase Leads To Aortic Dilation In Response To Increased Hemodynamic Stress, Vivian S Lee, Carmen M Halabi, Thomas J Broekelmann, Philip C Trackman, Nathan O Stitziel, Robert P Mecham

Open Access Publications

Heterozygous missense mutations in lysyl oxidase (LOX) are associated with thoracic aortic aneurysms and dissections. To assess how LOX mutations modify protein function and lead to aortic disease, we studied the factors that influence the onset and progression of vascular aneurysms in mice bearing a Lox mutation (p.M292R) linked to aortic dilation in humans. We show that mice heterozygous for the M292R mutation did not develop aneurysmal disease unless challenged with increased hemodynamic stress. Vessel dilation was confined to the ascending aorta although both the ascending and descending aortae showed changes in vessel wall structure, smooth muscle cell number and …

Reactive Microglia And Il1Β/Il-1r1-Signaling Mediate Neuroprotection In Excitotoxin-Damaged Mouse Retina, Levi Todd, Isabella Palazzo, Lilianna Suarez, Xiaoyu Liu, Leo Volkov, Thanh V Hoang, Warren A Campbell, Seth Blackshaw, Ning Quan, Andy J Fischer

Open Access Publications

BACKGROUND: Microglia and inflammation have context-specific impacts upon neuronal survival in different models of central nervous system (CNS) disease. Herein, we investigate how inflammatory mediators, including microglia, interleukin 1 beta (IL1β), and signaling through interleukin 1 receptor type 1 (IL-1R1), influence the survival of retinal neurons in response to excitotoxic damage.

METHODS: Excitotoxic retinal damage was induced via intraocular injections of NMDA. Microglial phenotype and neuronal survival were assessed by immunohistochemistry. Single-cell RNA sequencing was performed to obtain transcriptomic profiles. Microglia were ablated by using clodronate liposome or PLX5622. Retinas were treated with IL1β prior to NMDA damage and cell …

Eosinophils Downregulate Lung Alloimmunity By Decreasing Tcr Signal Transduction, Oscar Okwudiri Onyema, Yizhan Guo, Bayan Mahgoub, Qing Wang, Amir Manafi, Zhongcheng Mei, Anirban Banerjee, Dongge Li, Mark H. Stoler, Melissa T. Zaidi, Adam G. Schrum, Daniel Kreisel, Andrew E. Gelman, Elizabeth A. Jacobsen, Alexander Sasha Krupnick

Open Access Publications

Despite the accepted notion that granulocytes play a universally destructive role in organ and tissue grafts, it has been recently described that eosinophils can facilitate immunosuppression-mediated acceptance of murine lung allografts. The mechanism of eosinophil-mediated tolerance, or their role in regulating alloimmune responses in the absence of immunosuppression, remains unknown. Using lung transplants in a fully MHC-mismatched BALB/c (H2d) to C57BL/6 (H2b) strain combination, we demonstrate that eosinophils downregulate T cell-mediated immune responses and play a tolerogenic role even in the absence of immunosuppression. We further show that such downregulation depends on PD-L1/PD-1-mediated synapse formation between eosinophils and T cells. …

Vesicular Glutamatergic Transmission In Noise-Induced Loss And Repair Of Cochlear Ribbon Synapses, Kyunghee X. Kim, Shelby Payne, Aizhen Yang-Hood, Song-Zhe Li, Bethany Davis, Jason Carlquist, Babak V-Ghaffari, Jay A. Gantz, Dorina Kallogjeri, James A.J. Fitzpatrick, Kevin K. Ohlemiller, Keiko Hirose, Mark A. Rutherford

Open Access Publications

Noise-induced excitotoxicity is thought to depend on glutamate. However, the excitotoxic mechanisms are unknown, and the necessity of glutamate for synapse loss or regeneration is unclear. Despite absence of glutamatergic transmission from cochlear inner hair cells in mice lacking the vesicular glutamate transporter-3 (

Immunomodulatory Role Of Non-Neuronal Cholinergic Signaling In Myocardial Injury, Cibele Rocha-Resende, Carla Weinheimer, Geetika Bajpai, Luigi Adamo, Scot J. Matkovich, Joel Schilling, Philip M. Barger, Kory J. Lavine, Douglas L. Mann

Open Access Publications

Whereas prior studies have demonstrated an important immunomodulatory role for the neuronal cholinergic system in the heart, the role of the non-neuronal cholinergic system is not well understood. To address the immunomodulatory role of the non-neuronal cholinergic system in the heart we used a previously validated diphtheria toxin (DT)-induced cardiomyocyte ablation model (Rosa26-DTMlc2v-Cre mice). DT-injected Rosa26-DTMlc2v-Cre mice were treated with diluent or Pyridostigmine Bromide (PYR), a reversible cholinesterase inhibitor. PYR treatment resulted in increased survival and decreased numbers of MHC-IIlowCCR2+ macrophages in DT-injected Rosa26-DTMlc2v-Cre mice compared to diluent treated Rosa26-DTMlc2v-Cre mice. Importantly, the expression of CCL2/7 mRNA and protein was …

Expression Of Factor V By Resident Macrophages Boosts Host Defense In The Peritoneal Cavity, Nan Zhang, Rafael S. Czepielewski, Nicholas N. Jarjour, Emma C. Erlich, Ekaterina Esaulova, Brian T. Saunders, Steven P. Grover, Audrey C. Cleuren, George J. Broze, Brian T. Edelson, Nigel Mackman, Bernd H. Zinselmeyer, Gwendalyn J. Randolph

Open Access Publications

Macrophages resident in different organs express distinct genes, but understanding how this diversity fits into tissue-specific features is limited. Here, we show that selective expression of coagulation factor V (FV) by resident peritoneal macrophages in mice promotes bacterial clearance in the peritoneal cavity and serves to facilitate the well-known but poorly understood "macrophage disappearance reaction." Intravital imaging revealed that resident macrophages were nonadherent in peritoneal fluid during homeostasis. Bacterial entry into the peritoneum acutely induced macrophage adherence and associated bacterial phagocytosis. However, optimal control of bacterial expansion in the peritoneum also required expression of FV by the macrophages to form …

Phase Ii Trial Of Levocetirizine With Capecitabine And Bevacizumab To Overcome The Resistance Of Antiangiogenic Therapies In Refractory Metastatic Colorectal Cancer, Manik Amin, Monica Desai, Kathryn Trinkaus, Amberly Brown, Andrea Wang-Gillam, Benjamin Tan, Joel Picus, Steven Sorscher, Maureen Highkin, Kim Lears, Albert C. Lockhart

Open Access Publications

Background: Despite the clinical success of vascular endothelial growth factor (VEGF) blockade in metastatic colorectal cancers (mCRC), resistance to anti-angiogenic drugs invariably develops. IL-8 and other cytokines have been implicated in development of resistance to anti-angiogenic therapy. Levocetirizine is a second generation H1 antihistamine with anti-inflammatory and IL-8 suppression properties. We conducted a phase II trial combining levocetirizine with capecitabine and bevacizumab to potentially overcome anti-angiogenic therapy resistance in patients with refractory mCRC.

Methods: This was a single-center open-label prospective trial in refractory mCRC patients. Treatment consisted of oral capecitabine 850 mg/m

Results: Forty-seven patients were enrolled in the trial …

Peroxisomal Regulation Of Redox Homeostasis And Adipocyte Metabolism, Jingjing Liu, Wen Lu, Bimin Shi, Samuel Klein, Xiong Su

Open Access Publications

Peroxisomes are ubiquitous cellular organelles required for specific pathways of fatty acid oxidation and lipid synthesis, and until recently their functions in adipocytes have not been well appreciated. Importantly, peroxisomes host many oxygen-consumption reactions and play a major role in generation and detoxification of reactive oxygen species (ROS) and reactive nitrogen species (RNS), influencing whole cell redox status. Here, we review recent progress in peroxisomal functions in lipid metabolism as related to ROS/RNS metabolism and discuss the roles of peroxisomal redox homeostasis in adipogenesis and adipocyte metabolism. We provide a framework for understanding redox regulation of peroxisomal functions in adipocytes …

Genetic Approaches To Metabolic Bone Diseases, Fadil M Hannan, Paul J Newey, Michael P Whyte, Rajesh V Thakker

Open Access Publications

Metabolic bone diseases comprise a diverse group of disorders characterized by alterations in skeletal homeostasis, and are often associated with abnormal circulating concentrations of calcium, phosphate or vitamin D metabolites. These diseases commonly have a genetic basis and represent either a monogenic disorder due to a germline or somatic single gene mutation, or an oligogenic or polygenic disorder that involves variants in more than one gene. Germline single gene mutations causing Mendelian diseases typically have a high penetrance, whereas the genetic variations causing oligogenic or polygenic disorders are each associated with smaller effects with additional contributions from environmental factors. Recognition …