First person - Lena Marie Westermann [FIRST PERSON]

First person - Lena Marie Westermann [FIRST PERSON], ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers., ABSTRACT

First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Lena Marie Westermann is first author on ‘Imbalanced cellular metabolism compromises cartilage homeostasis and joint function in a mouse model of mucolipidosis type III gamma’, published in DMM. Lena Marie is an MD student in the lab of Dr Sandra Pohl at University Medical Center Hamburg-Eppendorf, Hamburg, Germany, investigating bone and connective tissue phenotypes in lysosomal storage disorders.

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Differential physiological roles for BIN1 isoforms in skeletal muscle development, function and regeneration...

Differential physiological roles for BIN1 isoforms in skeletal muscle development, function and regeneration..., ABSTRACT Skeletal muscle development and regeneration are tightly regulated processes. How the intracellular organization of muscle fibers is achieved during these steps is unclear., ABSTRACT

Skeletal muscle development and regeneration are tightly regulated processes. How the intracellular organization of muscle fibers is achieved during these steps is unclear. Here, we focus on the cellular and physiological roles of amphiphysin 2 (BIN1), a membrane remodeling protein mutated in both congenital and adult centronuclear myopathies (CNM), that is ubiquitously expressed and has skeletal muscle-specific isoforms. We created and characterized constitutive muscle-specific and inducible Bin1 homozygous and heterozygous knockout mice targeting either ubiquitous or muscle-specific isoforms. Constitutive Bin1-deficient mice died at birth from lack of feeding due to a skeletal muscle defect. T-tubules and other organelles were misplaced and altered, supporting a general early role for BIN1 in intracellular organization, in addition to membrane remodeling. Although restricted deletion of Bin1 in unchallenged adult muscles had no impact, the forced switch from the muscle-specific isoforms to the ubiquitous isoforms through deletion of the in-frame muscle-specific exon delayed muscle regeneration. Thus, ubiquitous BIN1 function is necessary for muscle development and function, whereas its muscle-specific isoforms fine tune muscle regeneration in adulthood, supporting that BIN1 CNM with congenital onset are due to developmental defects, whereas later onset may be due to regeneration defects.

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L-type voltage-gated calcium channel agonists mitigate hearing loss and modify ribbon synapse morphology in...

L-type voltage-gated calcium channel agonists mitigate hearing loss and modify ribbon synapse morphology in..., ABSTRACT The mariner (myo7aa–/–) mutant is a zebrafish model for Usher syndrome type 1 (USH1). To further characterize hair cell synaptic elements in myo7aa–/– mutants, we focused on the ribbon synapse and evaluated ultrastructure, number and distribution of immunolabeled ribbons, and postsynaptic densities., ABSTRACT

The mariner (myo7aa–/–) mutant is a zebrafish model for Usher syndrome type 1 (USH1). To further characterize hair cell synaptic elements in myo7aa–/– mutants, we focused on the ribbon synapse and evaluated ultrastructure, number and distribution of immunolabeled ribbons, and postsynaptic densities. By transmission electron microscopy, we determined that myo7aa–/– zebrafish have fewer glutamatergic vesicles tethered to ribbon synapses, yet maintain a comparable ribbon area. In myo7aa–/– hair cells, immunolocalization of Ctbp2 showed fewer ribbon-containing cells in total and an altered distribution of Ctbp2 puncta compared to wild-type hair cells. myo7aa–/– mutants have fewer postsynaptic densities – as assessed by MAGUK immunolabeling – compared to wild-type zebrafish. We quantified the circular swimming behavior of myo7aa–/– mutant fish and measured a greater turning angle (absolute smooth orientation). It has previously been shown that L-type voltage-gated calcium channels are necessary for ribbon localization and occurrence of postsynaptic density; thus, we hypothesized and observed that L-type voltage-gated calcium channel agonists change behavioral and synaptic phenotypes in myo7aa–/– mutants in a drug-specific manner. Our results indicate that treatment with L-type voltage-gated calcium channel agonists alter hair cell synaptic elements and improve behavioral phenotypes of myo7aa–/– mutants. Our data support that L-type voltage-gated calcium channel agonists induce morphological changes at the ribbon synapse – in both the number of tethered vesicles and regarding the distribution of Ctbp2 puncta – shift swimming behavior and improve acoustic startle response.

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Using systems medicine to identify a therapeutic agent with potential for repurposing in inflammatory bowel...

Using systems medicine to identify a therapeutic agent with potential for repurposing in inflammatory bowel..., ABSTRACT Inflammatory bowel diseases (IBDs) cause significant morbidity and mortality. Aberrant NF-B signalling is strongly associated with these conditions, and several established drugs influence the NF-B signalling network to exert their effect. This study aimed to identify drugs that alter NF-B signalling and could be repositioned for use in IBD., ABSTRACT

Inflammatory bowel diseases (IBDs) cause significant morbidity and mortality. Aberrant NF-B signalling is strongly associated with these conditions, and several established drugs influence the NF-B signalling network to exert their effect. This study aimed to identify drugs that alter NF-B signalling and could be repositioned for use in IBD. The SysmedIBD Consortium established a novel drug-repurposing pipeline based on a combination of in silico drug discovery and biological assays targeted at demonstrating an impact on NF-B signalling, and a murine model of IBD. The drug discovery algorithm identified several drugs already established in IBD, including corticosteroids. The highest-ranked drug was the macrolide antibiotic clarithromycin, which has previously been reported to have anti-inflammatory effects in aseptic conditions. The effects of clarithromycin effects were validated in several experiments: it influenced NF-B-mediated transcription in murine peritoneal macrophages and intestinal enteroids; it suppressed NF-B protein shuttling in murine reporter enteroids; it suppressed NF-B (p65) DNA binding in the small intestine of mice exposed to lipopolysaccharide; and it reduced the severity of dextran sulphate sodium-induced colitis in C57BL/6 mice. Clarithromycin also suppressed NF-B (p65) nuclear translocation in human intestinal enteroids. These findings demonstrate that in silico drug repositioning algorithms can viably be allied to laboratory validation assays in the context of IBD, and that further clinical assessment of clarithromycin in the management of IBD is required.


This article has an associated First Person interview with the joint first authors of the paper.

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Restoration of motor learning in a mouse model of Rett syndrome following long-term treatment with a novel...

Restoration of motor learning in a mouse model of Rett syndrome following long-term treatment with a novel..., A, ABSTRACT

Reduced expression of brain-derived neurotrophic factor (BDNF) and impaired activation of the BDNF receptor, tropomyosin receptor kinase B (TrkB; also known as Ntrk2), are thought to contribute significantly to the pathophysiology of Rett syndrome (RTT), a severe neurodevelopmental disorder caused by loss-of-function mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). Previous studies from this and other laboratories have shown that enhancing BDNF expression and/or TrkB activation in Mecp2-deficient mouse models of RTT can ameliorate or reverse abnormal neurological phenotypes that mimic human RTT symptoms. The present study reports on the preclinical efficacy of a novel, small-molecule, non-peptide TrkB partial agonist, PTX-BD4-3, in heterozygous female Mecp2 mutant mice, a well-established RTT model that recapitulates the genetic mosaicism of the human disease. PTX-BD4-3 exhibited specificity for TrkB in cell-based assays of neurotrophin receptor activation and neuronal cell survival and in in vitro receptor binding assays. PTX-BD4-3 also activated TrkB following systemic administration to wild-type and Mecp2 mutant mice and was rapidly cleared from the brain and plasma with a half-life of ~2 h. Chronic intermittent treatment of Mecp2 mutants with a low dose of PTX-BD4-3 (5 mg/kg, intraperitoneally, once every 3 days for 8 weeks) reversed deficits in two core RTT symptom domains – respiration and motor control – and symptom rescue was maintained for at least 24 h after the last dose. Together, these data indicate that significant clinically relevant benefit can be achieved in a mouse model of RTT with a chronic intermittent, low-dose treatment paradigm targeting the neurotrophin receptor TrkB.

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First person - Katie Lloyd and Stamatia Papoutsopoulou [FIRST PERSON]

First person - Katie Lloyd and Stamatia Papoutsopoulou [FIRST PERSON], ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers., ABSTRACT

First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Katie Lloyd and Stamatia Papoutsopoulou are co-first authors on ‘Using systems medicine to identify a therapeutic agent with potential for repurposing in inflammatory bowel disease’, published in DMM. Katie conducted the research described in this article while a postdoctoral research associate in Prof. Chris Probert's lab at the University of Liverpool, Liverpool, UK. She is now a lecturer in pharmacology at the University of Chester, Chester, UK. Her research focuses on personalising medicine by combining innovative experimental approaches to identify biomarkers of inflammatory disease, drug response and mechanisms of drug resistance, which consider complex factors such as inter-patient variability and co-morbidities. Stamatia conducted the research described in this article while a postdoctoral research associate in Werner Muller's lab at the University of Manchester, Manchester, UK. She is currently a postdoctoral research associate in the lab of Mark Pritchard at the University of Liverpool, Liverpool, UK, investigating the regulation of transcriptional responses during inflammation and the impact of environmental factors on them, and has just accepted the position of assistant professor at the University of Thessaly, Greece.

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Teleological role of L-2-hydroxyglutarate dehydrogenase in the kidney [RESEARCH ARTICLE]

Teleological role of L-2-hydroxyglutarate dehydrogenase in the kidney [RESEARCH ARTICLE], ABSTRACT L-2-hydroxyglutarate (L-2HG) is an oncometabolite found elevated in renal tumors. However, this molecule might have physiological roles that extend beyond its association with cancer, as L-2HG levels are elevated in response to hypoxia and during Drosophila larval development., ABSTRACT

L-2-hydroxyglutarate (L-2HG) is an oncometabolite found elevated in renal tumors. However, this molecule might have physiological roles that extend beyond its association with cancer, as L-2HG levels are elevated in response to hypoxia and during Drosophila larval development. L-2HG is known to be metabolized by L-2HG dehydrogenase (L2HGDH), and loss of L2HGDH leads to elevated L-2HG levels. Despite L2HGDH being highly expressed in the kidney, its role in renal metabolism has not been explored. Here, we report our findings utilizing a novel CRISPR/Cas9 murine knockout model, with a specific focus on the role of L2HGDH in the kidney. Histologically, L2hgdh knockout kidneys have no demonstrable histologic abnormalities. However, GC-MS metabolomics demonstrates significantly reduced levels of the TCA cycle intermediate succinate in multiple tissues. Isotope labeling studies with [U-13C] glucose demonstrate that restoration of L2HGDH in renal cancer cells (which lowers L-2HG) leads to enhanced incorporation of label into TCA cycle intermediates. Subsequent biochemical studies demonstrate that L-2HG can inhibit the TCA cycle enzyme α-ketoglutarate dehydrogenase. Bioinformatic analysis of mRNA expression data from renal tumors demonstrates that L2HGDH is co-expressed with genes encoding TCA cycle enzymes as well as the gene encoding the transcription factor PGC-1α, which is known to regulate mitochondrial metabolism. Restoration of PGC-1α in renal tumor cells results in increased L2HGDH expression with a concomitant reduction in L-2HG levels. Collectively, our analyses provide new insight into the physiological role of L2HGDH as well as mechanisms that promote L-2HG accumulation in disease states.

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Oleanolic acid ameliorates intestinal alterations associated with EAE

Oleanolic acid ameliorates intestinal alterations associated with EAE, Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease affecting the CNS. Recent studies have indicated that intestinal alterations play key pathogenic roles in the development of autoimmune dis..., Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease affecting the CNS. Recent studies have indicated that intestinal alterations play key pathogenic roles in the development of autoimmune dis..., admin,

Neuroprotective epi-drugs quench the inflammatory response and microglial/macrophage activation in a mouse...

Neuroprotective epi-drugs quench the inflammatory response and microglial/macrophage activation in a mouse..., Activation of NF-kappaB RelA deacetylated at the lysine residues, except the lysine 310, drives pro-apoptotic transcription in noxious brain ischemia. We showed that the sinergistic combination of the histone ..., Activation of NF-kappaB RelA deacetylated at the lysine residues, except the lysine 310, drives pro-apoptotic transcription in noxious brain ischemia. We showed that the sinergistic combination of the histone ..., admin,

CCL3 contributes to secondary damage after spinal cord injury

CCL3 contributes to secondary damage after spinal cord injury, Secondary damage after spinal cord injury (SCI) is characterized by a cascade of events including hemorrhage, apoptosis, oxidative stress, and inflammation which increase the lesion size which can influence th..., Secondary damage after spinal cord injury (SCI) is characterized by a cascade of events including hemorrhage, apoptosis, oxidative stress, and inflammation which increase the lesion size which can influence th..., admin,

Immunological classification of gliomas based on immunogenomic profiling

Immunological classification of gliomas based on immunogenomic profiling, Gliomas are heterogeneous in the tumor immune microenvironment (TIM). However, a classification of gliomas based on immunogenomic profiling remains lacking., Gliomas are heterogeneous in the tumor immune microenvironment (TIM). However, a classification of gliomas based on immunogenomic profiling remains lacking., admin,

Standardization and Personalized Medicine Using Quantitative EEG in Clinical Settings

Standardization and Personalized Medicine Using Quantitative EEG in Clinical Settings, Clinical EEG and Neuroscience, Ahead of Print. Two major trends have been dominant in health care in recent years. First, there is a growing consensus that standardization of health care procedures and methods can result in improved effectiveness and safety of treatments., Clinical EEG and Neuroscience, Ahead of Print.
Two major trends have been dominant in health care in recent years. First, there is a growing consensus that standardization of health care procedures and methods can result in improved effectiveness and safety of treatments. Second, there is increased interest in “personalized medicine,” which refers to the tailoring of treatments to individual patients. Here I discuss how these trends apply to the field of quantitative EEG (qEEG), where de-artifacted resting state EEGs of individuals are compared with a normative database in order to assess clinically meaningful deviations, which can be used for diagnostic procedures, to guide personalized treatment protocols, and to assess treatment effectiveness. Standardized and automated de-artifacting procedures are increasingly being used in scientific research and in clinical practice. The advantages of these procedures over manual de-artifacting will be discussed. The results of a systematic comparison between 2 commonly used qEEG databases show that these databases produce very comparable results, illustrating not only the validity and reliability of both databases but also the opportunity to move forward to a standardized use of qEEG in clinical practice. Finally, the standardization of qEEG interpretation as both a diagnostic and treatment selection tool provides an example of how qEEG can merge both personalized medicine and standardization in the treatment of psychological disorders., admin,

An allosteric interleukin-1 receptor modulator mitigates inflammation and photoreceptor toxicity in a model...

An allosteric interleukin-1 receptor modulator mitigates inflammation and photoreceptor toxicity in a model..., Inflammation and particularly interleukin-1β (IL-1β), a pro-inflammatory cytokine highly secreted by activated immune cells during early AMD pathological events, contribute significantly to retinal neurodegene..., Inflammation and particularly interleukin-1β (IL-1β), a pro-inflammatory cytokine highly secreted by activated immune cells during early AMD pathological events, contribute significantly to retinal neurodegene..., admin,

Neurophysiological Findings and Brain Injury Pattern in Patients on ECMO

Neurophysiological Findings and Brain Injury Pattern in Patients on ECMO, Clinical EEG and Neuroscience, Ahead of Print. Introduction. Brain injury is a major determinant of outcomes in extracorporeal membrane oxygenation (ECMO). Neurologic prognostication in ECMO has not been established., Clinical EEG and Neuroscience, Ahead of Print.
Introduction. Brain injury is a major determinant of outcomes in extracorporeal membrane oxygenation (ECMO). Neurologic prognostication in ECMO has not been established. Absent electroencephalogram (EEG) reactivity and absent N20 on somatosensory evoked potential (SSEP) are associated with poor outcome in other types of brain injuries, especially following cardiopulmonary arrest. It is currently known if the same criteria are applicable in patients on ECMO. Methods. Continuous EEG (cEEG) was performed for patients with a Glasgow Coma Scale (GCS) <8 and SSEP data were performed for patients with a motor GCS < 4 in a prospective observational cohort undergoing ECMO at a tertiary center. EEG variables including reactivity were collected. SSEPs were categorized into absence, delay, or presence of N20. Poor outcome was defined as cerebral performance category 3 to 5 at discharge. Results. We present 13 consecutive patients who underwent both cEEG and SSEP. The median time from cannulation to EEG and SSEP were 3 (interquartile range [IQR] = 1-6) and 5 (IQR = 2-7) days, respectively. All patients were in coma and 12 (92%) had poor outcomes. Ten (77%) underwent brain computed tomography, the findings of which explained coma in only 2. Patients (n = 12) with poor outcome had poor variability, absent reactivity, and lack of sleep features with diffusely slow theta-delta background on the EEG. Despite poor outcomes, all had relatively preserved or normal N20 responses. One patient with preserved reactivity and sleep features on the EEG and intact SSEP had a good outcome. Conclusions. Absent EEG reactivity with the preservation of SSEP N20 was associated with poor outcome in comatose ECMO patients. We advise caution in interpreting electrophysiological tests in prognosticating ECMO patients until the patterns and outcomes are better understood., admin,

Autism, Epilepsy, and Neuroregression: Photosensitivity on Electroencephalography Solved the Riddle

Autism, Epilepsy, and Neuroregression: Photosensitivity on Electroencephalography Solved the Riddle, Clinical EEG and Neuroscience, Volume 51, Issue 6, Page 399-402, November 2020. Autistic epileptiform regression is an uncommon but extensively described malady in children. The clinico-etiological spectrum of this entity ranges from electrical status epilepticus in sleep to various neurogenetic and neurodegenerative disorders., Clinical EEG and Neuroscience, Volume 51, Issue 6, Page 399-402, November 2020.
Autistic epileptiform regression is an uncommon but extensively described malady in children. The clinico-etiological spectrum of this entity ranges from electrical status epilepticus in sleep to various neurogenetic and neurodegenerative disorders. Identification of these disorders is crucial considering their therapeutic and prognostic implications. Simple investigations such as neuroimaging and electroencephalography with activation procedures can provide valuable diagnostic clues in resource-limited settings; facilitating targeted genetic/metabolic testing. Here we report a 3.5-year-old girl with autistic regression and epilepsy. Neuronal ceroid lipofuscinosis was suspected as her electroencephalogram showed photoparoxysmal response on low-frequency (1-3 Hz) intermittent photic stimulation. A deficient leukocyte tripeptidyl peptidase 1 enzyme confirmed the diagnosis of late infantile neuronal ceroid lipofuscinosis., admin,