David A Pearce's research while affiliated with Sanford Research and other places

Publications (216)

Article
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Uncultured, unmodified, autologous, adipose-derived regenerative cells (UA-ADRCs) are a safe and effective treatment option for various musculoskeletal pathologies. However, it is unknown whether the composition of the final cell suspension systematically varies with the subject’s individual age, sex, body mass index and ethnicity. UA-ADRCs were is...
Preprint
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Objective: Symptomatic, partial-thickness rotator cuff tears (sPTRCT) are problematic. Management of sPTRCT with fresh, uncultured, unmodified, autologous, adipose-derived regenerative cells (UA-ADRCs) isolated from lipoaspirate at the point of care is safe and leads to improved shoulder function without adverse effects. This study tested the hypot...
Article
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Rare disease patients face many challenges including diagnostic delay, misdiagnosis and lack of therapies. However, early access to diagnosis and therapies can modify the management and the progression of diseases, which in return positively impacts patients, families and health care systems. The International Rare Diseases Research Consortium set...
Preprint
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Mouse models of CLN3 Batten disease, a rare lysosomal storage disorder with no cure, have improved our understanding of CLN3 biology and therapeutics through their ease of use and a consistent display of cellular pathology. However, the translatability of murine models is limited by disparities in anatomy, body size, life span, and inconsistent, su...
Article
CLN2 Batten disease is a lysosomal disorder in which pathogenic variants in CLN2 lead to reduced activity in the enzyme tripeptidyl peptidase 1. The disease typically manifests around 2 to 4 years of age with developmental delay, ataxia, seizures, inability to speak and walk, and fatality between 6 and 12 years of age. Multiple Cln2 mouse models ex...
Article
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We recently demonstrated that HCl-acidified drinking water, which is widely used in laboratory animal facilities, had some beneficial effects in the Cln3 −/− mouse model of juvenile Batten disease, a neurodegenerative lysosomal storage disorder ¹ . Here we tested if acidified drinking water has therapeutic effects in Cln1 R151X nonsense mutant mice...
Article
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(1) Background: Conclusions of meta-analyses of clinical studies may substantially influence opinions of prospective patients and stakeholders in healthcare. Nineteen meta-analyses of clinical studies on the management of primary knee osteoarthritis (pkOA) with stem cells, published between January 2020 and July 2021, came to inconsistent conclusio...
Preprint
Background: Conclusions of meta-analyses of clinical studies may substantially influence opinions of perspective patients and stakeholders in health care. Nineteen meta-analyses of clinical studies on the management of primary knee osteoarthritis (pkOA) with stem cells, published between January 2020 and July 2021, came to inconsistent conclusions...
Article
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Background Recently, the management of musculoskeletal disorders with the patients' own stem cells, isolated from the walls of small blood vessels, which can be found in great numbers in the adipose tissue, has received considerable attention. On the other hand, there are still misconceptions about these adipose-derived regenerative cells (ADRCs) t...
Preprint
Full-text available
Background: Recently, the management of musculoskeletal disorders with the patients' own stem cells, isolated from the walls of small blood vessels, which can be found in great numbers in the adipose tissue, has received considerable attention. On the other hand, there are still misconceptions about these adipose-derived regenerative cells (ADRCs)...
Preprint
Recently, the management of musculoskeletal disorders with the patients' own stem cells, isolated from the walls of small blood vessels, which can be found in great numbers in the adipose tissue, has received considerable attention. The use of these autologous, unmodified stem cells can be seamlessly integrated into modern orthopedic treatment conc...
Article
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Background Rare diseases (RD) are a diverse collection of more than 7–10,000 different disorders, most of which affect a small number of people per disease. Because of their rarity and fragmentation of patients across thousands of different disorders, the medical needs of RD patients are not well recognized or quantified in healthcare systems (HCS)...
Article
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Acidification of drinking water to a pH between 2.5 and 3.0 is widely used to prevent the spread of bacterial diseases in animal colonies. Besides hydrochloric acid (HCl), sulfuric acid (H 2 SO 4 ) is also used to acidify drinking water. Here we examined the effects of H 2 SO 4 -acidified drinking water (pH = 2.8) received from weaning (postnatal d...
Article
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Accumulated evidence indicates that the gut microbiota affects brain function and may be altered in neurological diseases. In this study, we analyzed the gut microbiota in Cln1R151X and Cln2R207X mice, models of the childhood neurodegenerative disorders, infantile CLN1 and late infantile CLN2 Batten diseases. Significant alterations were found in t...
Article
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Aim: The ambitious goals set by the International Rare Diseases Research Consortium (IRDiRC) by 2027 to fulfill the vision of providing diagnosis and treatments to rare diseases (RDs) patients within one year of coming to medical attention have been challenged by the COVID-19 pandemic. This article aims to identify the needs and challenges of the R...
Article
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CLN3 Batten disease (CLN3 disease) is a pediatric lysosomal storage disorder that presents with progressive blindness, motor and cognitive decline, seizures, and premature death. CLN3 disease results from mutations in CLN3 with the most prevalent mutation, a 966 bp deletion spanning exons 7–8, affecting ~ 75% of patients. Mouse models with complete...
Article
Medical innovation awards stand out as an important means to focus public attention on what matters in medical advancement. Traditional awards typically focus on celebrating medical innovators with either a track record of proven successes in new treatments or promising basic science breakthroughs still years away from reaching patients. Perhaps on...
Article
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CLN3 mutations cause the fatal neurodegenerative disorder, CLN3 Batten disease. The Cln3−/− mouse model displays characteristic features of the human disease including motor deficits. When mice received acidified drinking water (pH 2.5–2.9) instead of normal tap water (pH 8.4) for several generations, the motor skills of Cln3−/− mice normalized to...
Article
Batten disease (also known as neuronal ceroid lipofuscinoses) constitutes a family of devastating lysosomal storage disorders that collectively represent the most common inherited paediatric neurodegenerative disorders worldwide. Batten disease can result from mutations in 1 of 13 genes. These mutations lead to a group of diseases with loosely over...
Article
CLN3-Batten disease is an autosomal-recessive disorder that results from mutations in CLN3. In the vast majority of cases, disease onset occurs in early childhood, is characterized by progressive loss of vision, seizures and a failure in psychomotor development and is universally fatal by the third decade of life. Several mouse models of CLN3 have...
Data
Statistical results table from three-way ANOVAs—CBCs. (XLSX)
Data
No changes in metabolic parameters between control and Cln3Δex7/8 mutant mice at 5 months of age. Metabolic panels measuring blood levels of aspartate aminotransferase (A), alanine aminotransferase (B), alkaline phosphatase (C), albumin (D), total protein (E), sodium (F), potassium (G), sodium/potassium ratio (H), calcium (I), chloride (J), glucose...
Article
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CLN3-Batten disease is a rare, autosomal recessive disorder involving seizures, visual, motor and cognitive decline, and premature death. The Cln3Δex7/8 mouse model recapitulates several phenotypic characteristics of the most common 1.02kb disease-associated deletion. Identification of reproducible biomarker(s) to facilitate longitudinal monitoring...
Data
Statistical results table from two-way ANOVAs—CBCs. (XLSX)
Data
Animal groups and counts. List of all animal groups used in the study including animal number and the experiments in which they were included. Note that not all animals in the list were finally included in the analysis (e.g. mice were allocated to different tests, exclusion due to unstable recordings or insufficient quality criteria for neurophysio...
Data
Statistic report table. Table containing information regarding distribution, statistical analysis method, exact p values, n-values and number of biological replicates, mean, SD, SEM, median and confidence intervals, and Cohen’s d effect size for all experiments.
Article
Ataxia telangiectasia (AT) is a progressive multisystem autosomal recessive disorder caused by mutations in the AT-mutated (ATM) gene. Early onset AT in children is characterized by cerebellar degeneration, leading to motor impairment. Lung disease and cancer are the two most common causes of death in AT patients. Accelerated thymic involution may...
Article
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Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, an...
Article
Full-text available
Juvenile CLN3 (Batten) disease, a fatal, childhood neurodegenerative disorder, results from mutations in the CLN3 gene encoding a lysosomal/endosomal transmembrane protein. The exact physiological function of CLN3 is still unknown and it is unclear how CLN3 mutations lead to selective neurodegeneration. To study the tissue expression and subcellula...
Article
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Juvenile Batten disease (JBD) is an inherited disorder that is characterized by the development of blindness, seizures, and progressive motor, psychiatric, and cognitive impairment. A model of JBD expressing the predominant human mutation (Cln3∆ex7/8) has been explored. Dissociated brain cultures from Cln3∆ex7/8 knock-in mice were compared to wild...
Article
Importance Mutations in genes traditionally associated with syndromic retinal disease are increasingly found to cause nonsyndromic inherited retinal degenerations. Mutations in CLN3 are classically associated with juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease with early retinal degeneration and progressive neurologic det...
Data
Unaltered sphingomyelinase activity and selectively altered PPT1 activity in various Cln2R207X/R207X mouse tissues. Fluorogenic enzyme activity assays for sphingomyelinase (A) and PPT1 (B) were used to measure endogenous activity in five different tissues from 1-month-old Cln2+/+ (n = 3) and Cln2R207X/R207X (n = 3) mice. In the sphingomyelinase act...
Article
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The Neuronal Ceroid Lipofuscinoses (NCLs), also known as Batten disease, result from mutations in over a dozen genes. Although, adults are susceptible, the NCLs are frequently classified as pediatric neurodegenerative diseases due to their greater pediatric prevalence. Initial clinical presentation usually consists of either seizures or retinopathy...
Data
A significant portion of mitochondrial ATP synthase subunit c accumulation is localized to the lysosome. Cln2R207X/R207X cerebral sections immunostained with anti-subunit c (red) and anti-LAMP-1 (green) reveal co-localization. (TIF)
Data
Similar levels of anxiety in Cln2+/+ and Cln2R207X/R207X mice. The light/dark box test was used to assess for anxiety in 3-month-old Cln2+/+ (n = 14) and Cln2R207X/R207X (n = 20) mice. Both cohorts spent similar amounts of time in the dark. Columns and bars represent mean ± SEM. Statistical significance was determined using an unpaired t-test. (TIF...
Data
Hypereosinophilic inclusions and neurodegeneration in 4-month-old Cln2R207X/R207X mice. Tissues from Cln2+/+ (n = 3) and Cln2R207X/R207X (n = 3) mice were sectioned, hematoxylin/eosin stained, and evaluated by a veterinary pathologist under blinded conditions. The pathology report solely identified cerebral cellular hypereosinophilic inclusions (ar...
Data
Cerebellar layers of Cln2R207X/R207X mice display enhanced mitochondrial ATP synthase subunit c accumulation. Images of the molecular (ML) and granular (GL) cerebellar layers demonstrate accumulation of mitochondrial ATP synthase subunit c in Cln2R207X/R207X mice when compared to Cln2+/+ controls. Pronounced accumulation is present in the Purkinje...
Data
No signs of activated microglia at 3 months in Cln2R207X/R207X mice. (A) Superficial and deep cortical layers from 3-month-old Cln2+/+ and Cln2R207X/R207X mice show minimal differences in immunostaining for the microglial marker, Iba1. (B) Images from 3-month-old Cln2+/+ (n = 4) and Cln2R207X/R207X (n = 5) mice were blindly collected and analyzed f...
Article
Among Neuronal Ceroid Lipofuscinoses (NCLs), which are childhood fatal neurodegenerative disorders, the juvenile onset form (JNCL) is the most common. JNCL is caused by recessive mutations in the CLN3 gene. CLN3 encodes a lysosomal/endosomal transmembrane protein but its precise function is not completely known. We have previously reported that in...
Article
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The Neuronal Ceroid Lipofuscinoses (NCLs) are a family of autosomal recessive neurodegenerative disorders that annually affect 1:100,000 live births worldwide. This family of diseases results from mutations in one of 14 different genes that share common clinical and pathological etiologies. Clinically, the diseases are subcategorized into infantile...
Article
Infantile CLN1 disease, also known as infantile neuronal ceroid lipofuscinosis, is a fatal childhood neurodegenerative disorder caused by mutations in the CLN1 gene. CLN1 encodes a soluble lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1), and it is still unclear why neurons are selectively vulnerable to the loss of PPT1 enzyme activity in...
Article
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Neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of lysosomal storage disorders. NCLs include the rare autosomal recessive neurodegenerative disorder neuronal ceroid lipofuscinosis type 2 (CLN2) disease, caused by mutations in the tripeptidyl peptidase 1 (TPP1)/CLN2 gene and the resulting TPP1 enzyme deficiency. CLN2 disease most com...
Article
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Cystine and cysteine are important molecules for pathways such as redox signaling and regulation, and thus identifying cellular deficits upon deletion of the Saccharomyces cerevisiae cystine transporter Ers1p allows for a further understanding of cystine homeostasis. Previous complementation studies using the human ortholog suggest yeast Ers1p is a...
Article
Mutations of the CLN3 gene lead to juvenile neuronal ceroid lipofuscinosis (JNCL), an autosomal recessive lysosomal storage disorder that causes progressive neurodegeneration in children and adolescents. There is evidence of immune system involvement in pathology that has been only minimally investigated. We characterized bone marrow stem cell-deri...
Article
As the biomedical and biotechnology industries are two of the most prominent sources of new job creation in South Dakota, it is important to link these in- dustries to secondary STEM (science, technolog y, engineering, math) education through practices and concepts. Numerous studies have recommended not only depth in a teacher ’s subject area...
Article
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About 10% of inherited diseases are caused by nonsense mutations [Trends Mol Med 18 (2012) 688], and nonsense suppression drug therapy promoting translation through premature stop codons is an emerging therapeutic approach. Infantile neuronal ceroid lipofuscinosis (INCL), a childhood neurodegenerative disease, results from mutations in the CLN1 gen...
Article
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The process of developing effective science educators has been a long-standing objective of the broader education community. Numerous studies have recommended not only depth in a teacher's subject area but also a breadth of professional development grounded in constructivist principles, allowing for successful student-centered and inquiry-based ins...
Article
The neuronal ceroid lipofuscinoses (NCLs) are a group of neurodegenerative genetic diseases that primarily affect children and have no known cure. A unified clinical rating scale for the juvenile form of NCL (JNCL) has been developed, but it has not been validated in other subtypes and does not give a true measure of the pathophysiological changes...
Poster
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Background: CLN2 disorder is a lysosomal storage disorder resulting from TPP1 enzyme deficiency that causes progressive neurological degeneration and early mortality. CLN2 disorder is rare and often unsuspected, leading to delays in diagnosis. Methods: In late 2014, 18 international CLN2 experts (clinicians, academic researchers, and laboratory dir...
Article
Full-text available
Ataxia telangiectasia (AT) is a progressive multisystem disorder caused by mutations in the AT-mutated (ATM) gene. AT is a neurodegenerative disease primarily characterized by cerebellar degeneration in children leading to motor impairment. The disease progresses with other clinical manifestations including oculocutaneous telangiectasia, immune dis...
Article
Full-text available
Mutations in the CLN3 gene cause a fatal neurodegenerative disorder, juvenile CLN3 disease. Exploring the cause of the motor coordination deficit in the Cln3−/− mouse model of the disease we have previously found that attenuation of AMPA receptor activity in 1-month-old Cln3−/− mice significantly improves their motor coordination [20]. To elucidate...
Article
The fatal, primarily childhood neurodegenerative disorders, neuronal ceroid lipofuscinoses (NCLs), are currently associated with mutations in 13 genes. The protein products of these genes (CLN1 to CLN14) differ in their function and their intracellular localization. NCL-associated proteins have been localized mostly in lysosomes (CLN1, CLN2, CLN3,...
Article
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Mutations in the CLN3 gene cause a fatal neurodegenerative disorder: juvenile CLN3 disease, also known as juvenile Batten disease. The two most commonly utilized mouse models of juvenile CLN3 disease are Cln3-knockout (Cln3(-/-)) and Cln3(Δex7/8)-knock-in mice, the latter mimicking the most frequent disease-causing human mutation. To determine whic...
Article
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SV2A is a synaptic vesicle membrane protein expressed in neurons and endocrine cells and involved in the regulation of neurotransmitter release. Although the exact function of SV2A still remains elusive, it was identified as the specific binding site for levetiracetam, a second generation antiepileptic drug. Our sequence analysis demonstrates that...
Article
The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of autosomal recessive neurodegenerative disorders in children characterized by the progressive onset of seizures, blindness, motor and cognitive decline and premature death. Patients with mutations in CLN1 primarily manifest with infantile NCL (INCL or Haltia-Sant...
Article
Introduction: Batten disease, also called neuronal ceroid lipofuscinosis, describes a heterogeneous group of lysosomal storage disorders that are the most common inherited progressive neurodegenerative disorders in children. The disease is caused by mutations in the neuronal ceroid lipofusinoses (CLN) genes, which are mostly inherited in an autosom...
Article
Eukaryotic cells utilize various RNA quality control mechanisms to ensure high fidelity of gene expression, thus protecting against the accumulation of nonfunctional RNA and the subsequent production of abnormal peptides. Messenger RNAs (mRNAs) are largely responsible for protein production, and mRNA quality control is particularly important for pr...
Article
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The lysosome, an organelle central to macromolecule degradation and recycling, plays a pivotal role in normal cell processes, ranging from autophagy to redox regulation. Not surprisingly, lysosomes are an integral part of the renal epithelial molecular machinery that facilitates normal renal physiology. Two inherited diseases that manifest as kidne...
Article
The neuronal ceroid lipofuscinoses, collectively referred to as Batten disease, make up a group of inherited childhood disorders that result in blindness, motor and cognitive regression, brain atrophy, and seizures, ultimately leading to premature death. So far more than 10 genes have been implicated in different forms of the neuronal ceroid lipofu...
Article
The neuronal ceroid lipofuscinoses, a family of neurodegenerative lysosomal storage disorders, represent the most common cause of pediatric-onset neurodegeneration. The infantile form has a devastatingly early onset and one of the fastest-progressing disease courses. Despite decades of research, the molecular mechanisms driving neuronal loss in inf...
Article
Neuronal ceroid lipofuscinosis is the most common childhood neurodegenerative disorder in the world, with an incidence of 1 in 100 000 live births. More than 400 mutations in at least 14 different genes are linked to multiple clinical variants. These progressive genetic disorders primarily manifest in the central nervous system due to an extensive...
Article
The neuronal ceroid lipofuscinoses are the most common autosomal recessive neurodegenerative disorders in children, with a worldwide incidence of 1 in 100 000 live births. Multiple clinical variants are caused by more than 400 mutations in at least 14 different genes. These progressive genetic disorders primarily manifest in the central nervous sys...
Article
The neuronal ceroid lipofuscinoses, collectively the most common neurodegenerative disorders of childhood, are primarily caused by an autosomal recessive genetic mutation leading to a lysosomal storage disease. Clinically, these diseases manifest at varying ages of onset, and associated symptoms include cognitive decline, movement disorders, seizur...
Article
We examined flurothyl gas-induced seizure latencies and phenotype in 2 mouse models of neuronal ceroid lipofuscinoses: the nclf (Cln6 mutant) variant late-infantile model and the mnd (Cln8 mutant) Northern epilepsy model. Mnd mice on postnatal days 35 to 42 had increased latency to loss of posture compared with wild-type controls. Nclf, mnd, and wi...
Article
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Several studies have shown that environmental factors can affect the outcome of behavioral experiments, shedding doubts on the inter-laboratory reproducibility of behavioral test results. When our laboratory moved from the University of Rochester, Rochester, NY, to Sanford Research in Sioux Falls, SD, our mouse colony was also transferred and the n...
Article
Full-text available
Juvenile CLN3 disease (formerly known as juvenile neuronal ceroid lipofuscinosis) is a fatal childhood neurodegenerative disorder caused by mutations in the CLN3 gene. CLN3 encodes a putative lysosomal transmembrane protein with unknown function. Previous cell culture studies using CLN3-overexpressing vectors and/or anti-CLN3 antibodies with questi...
Data
A fraction of myc-CLN3 is localized to late endosomes. BHK clone 19 myc-CLN3 expressing cells were grown under isotonic (300 mOsm) conditions. Late endosomes were pulse-chase labeled according to a method developed to label late endosomes in BHK cells [57]. Cells grown on poly-D-lysine coated coverslips were incubated with Alexa Fluor 488-labeled d...
Article
Neuronal ceroid lipofuscinosis (NCL), commonly referred to as Batten disease, is a group of autosomal recessive neurodegenerative diseases of childhood characterized by seizures, blindness, motor and cognitive decline, and premature death. Currently, there are over 400 known mutations in fourteen different genes, leading to five overlapping clinica...
Article
Full-text available
Tripeptidyl-peptidase 1 (TPP1) null or residual activity occurs in neuronal ceroid lipofuscinosis (NCL) with underlying TPP1/CLN2 mutations. A survey of 25 South American CLN2 affected individuals enabled the differentiation of two phenotypes: classical late-infantile and variant juvenile, each in approximately 50% of patients, with residual TPP1 a...