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Emerging therapeutics in Huntington's Disease.

Expert Opin Emerg Drugs 2021 Jul 28. Epub 2021 Jul 28.

NYU Langone's Fresco Institute for Parkinson's & Movement Disorders.

Introduction: Huntington's Disease is a neurodegenerative disease that is characterized by motor dysfunction, behavioral/psychiatric symptoms, and cognitive impairment. Because of the lack of availability of curative or disease modifying treatments, much of clinical practice in HD care to date has focused on symptomatic treatment. Recent work has created optimism surrounding possible emerging disease modifying therapeutics. Read More

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Mesenchymal Stem Cell Sheet Promotes Functional Recovery and Palliates Neuropathic Pain in a Subacute Spinal Cord Injury Model.

Stem Cells Int 2021 9;2021:9964877. Epub 2021 Jul 9.

Department of Neurosurgery, Graduate School of Medicine, Hokkaido University, Japan.

Stem cell therapy has been shown to reverse the sequelae of spinal cord injury (SCI). Although the ideal treatment route remains unknown, providing a large number of stem cells to the injured site using less invasive techniques is critical to achieving maximal recovery. This study was conducted to determine whether administration of bone marrow stem cell (BMSC) sheet made on its own without a scaffold is superior to intramedullary cell transplantation in a rat subacute SCI model. Read More

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Accelerated expansion of pathogenic mitochondrial DNA heteroplasmies in Huntington's disease.

Proc Natl Acad Sci U S A 2021 Jul;118(30)

Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853;

Mitochondrial dysfunction is found in the brain and peripheral tissues of patients diagnosed with Huntington's disease (HD), an irreversible neurodegenerative disease of which aging is a major risk factor. Mitochondrial function is encoded by not only nuclear DNA but also DNA within mitochondria (mtDNA). Expansion of mtDNA heteroplasmies (coexistence of mutated and wild-type mtDNA) can contribute to age-related decline of mitochondrial function but has not been systematically investigated in HD. Read More

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5-HTT Deficiency in Male Mice Affects Healing and Behavior after Myocardial Infarction.

J Clin Med 2021 Jul 14;10(14). Epub 2021 Jul 14.

Comprehensive Heart Failure Center, University Hospital of Würzburg, 97078 Würzburg, Germany.

Anxiety disorders and depression are common comorbidities in cardiac patients. Mice lacking the serotonin transporter (5-HTT) exhibit increased anxiety-like behavior. However, the role of 5-HTT deficiency on cardiac aging, and on healing and remodeling processes after myocardial infarction (MI), remains unclear. Read More

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Sex differences in adaptation to intermittent post-exercise sauna bathing in trained middle-distance runners.

Sports Med Open 2021 Jul 23;7(1):51. Epub 2021 Jul 23.

School of Sport Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, UK.

Background: The purpose of this study was to investigate the effect of sex on the efficacy of intermittent post-exercise sauna bathing to induce heat acclimation and improve markers of temperate exercise performance in trained athletes.

Methods: Twenty-six trained runners (16 female; mean ± SD, age 19 ± 1 years, V̇O F: 52.6 ± 6. Read More

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Individuals with Autistic Traits Exhibit Heightened Alexithymia But Intact Interoceptive-Exteroceptive Sensory Integration.

J Autism Dev Disord 2021 Jul 20. Epub 2021 Jul 20.

Neuropsychology and Applied Cognitive Neuroscience Laboratory, CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, 100101, China.

Interoceptive accuracy has been widely measured using the Heartbeat Tracking Test (HTT). We devised the novel paradigm of Interoception-Exteroception Synchronicity Judgement (IESJ) task to assess participants' interoceptive accuracy, exteroceptive accuracy, and the balancing score which reflected the ability to allocate attentions between interoceptive and exteroceptive signals. This study administered the behavioural paradigms of the HTT and the IESJ as well as other self-report scales to 119 typically-developing youths. Read More

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Total thyroidectomy can still remain the method of choice in some Bethesda III cases.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2021 Jul 20. Epub 2021 Jul 20.

Institute of Pathology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.

Background: The latest WHO classification of tumours of endocrine organs defines new units of borderline thyroid tumours (BTT). The aim of our study was to evaluate ultrasonographic and cytological features, mutation profile and surgery treatment in rare thyroid tumours.

Methods: An analysis of 8 BTT out of 487 patients, who underwent thyroid surgery between June 2016 and June 2020. Read More

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SQSTM1/p62 droplet -mediated autophagosome formation:insights into Huntington disease.

Autophagy 2021 Jul 19:1-4. Epub 2021 Jul 19.

Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China.

Huntington disease (HD) manifests a unique macroautophagy/autophagy defect: the presense of cytosolic autophagosomes without substrates or so-called "empty" autophagosomes. It was proposed that mutant HTT (huntingtin; mHTT) disrupts cargo recognition by the selective autophagy receptor SQSTM1/p62 thus leading to the failure of cargo sequestration by phagophores, the precursors to autophagosomes. Here we looked at recent discoveries that liquid-like SQSTM1 droplets can serve as platforms for autophagosome formation, and discussed possible alternative mechanisms for "empty" autophagosome formation in HD inspired by these findings. Read More

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Procedure for assessing patients referred to the UK's military Heat Illness Clinic: a case series.

BMJ Mil Health 2021 Jul 15. Epub 2021 Jul 15.

Institute of Naval Medicine, Gosport, UK.

Introduction: The UK military operates a Heat Illness Clinic (HIC) to aid the return to exercise, training and occupational duty recommendations for individuals who have suffered exertional heat illness or heatstroke. This paper describes the process of assessment and reports representative data from n=22 patients referred to the HIC.

Method: The assessment included clinical consultation, and measurement of maximal oxygen consumption (V̇Omax) and a heat tolerance test (HTT) conducted on a treadmill in an environmental chamber with an air temperature of 34°C and 44% relative humidity. Read More

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Accumulation of Endogenous Mutant Huntingtin in Astrocytes Exacerbates Neuropathology of Huntington Disease in Mice.

Mol Neurobiol 2021 Jul 12. Epub 2021 Jul 12.

Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China.

Selective neuronal accumulation of misfolded proteins is a key step toward neurodegeneration in a wide range of neurodegenerative diseases, including Huntington's (HD) diseases. Our recent studies suggest that Hsp70-binding protein 1 (HspBP1), an Hsp70/CHIP inhibitor that reduces protein folding, is highly expressed in neuronal cells and accounts for the accumulation of the HD protein huntingtin (HTT) in neuronal cells. To further determine the role of HspBP1 in regulation of mutant protein accumulation, we investigated whether increasing expression of HspBP1 in glial cells can also induce the accumulation of endogenous mutant HTT in glial cells and yield non-cell-autonomous toxic effects. Read More

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Macromolecular crowding in solution alters huntingtin interaction and aggregation at interfaces.

Colloids Surf B Biointerfaces 2021 Jul 7;206:111969. Epub 2021 Jul 7.

The C. Eugene Bennett Department of Chemistry, West Virginia University, 217 Clark Hall, Morgantown, WV 26506, United States; Rockefeller Neurosciences Institutes, West Virginia University, 1 Medical Center Dr., P.O. Box 9303, Morgantown, WV 26505, United States; Department of Neuroscience, West Virginia University, 1 Medical Center Dr., P.O. Box 9303, Morgantown, WV 26505, United States. Electronic address:

Huntington's disease (HD) is a fatal neurodegenerative disease caused by an extended polyglutamine (polyQ) domain within the first exon of the huntingtin protein (htt). PolyQ expansion directly invokes the formation of a heterogenous mixture of toxic htt aggregates, including fibrils and oligomers. While htt is a cytosolic protein, it also associates with numerous membranous surfaces within the cell, leading to altered organelle morphology and dysfunction. Read More

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Small, Seeding-Competent Huntingtin Fibrils Are Prominent Aggregate Species in Brains of zQ175 Huntington's Disease Knock-in Mice.

Front Neurosci 2021 22;15:682172. Epub 2021 Jun 22.

Neuroproteomics, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.

The deposition of mutant huntingtin (mHTT) protein aggregates in neurons of patients is a pathological hallmark of Huntington's disease (HD). Previous investigations in cell-free and cell-based disease models showed mHTT exon-1 (mHTTex1) fragments with pathogenic polyglutamine (polyQ) tracts (>40 glutamines) to self-assemble into highly stable, β-sheet-rich protein aggregates with a fibrillar morphology. HD knock-in mouse models have not been extensively studied with regard to mHTT aggregation. Read More

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Using Monozygotic Twins to Dissect Common Genes in Posttraumatic Stress Disorder and Migraine.

Front Neurosci 2021 22;15:678350. Epub 2021 Jun 22.

Centre for Genomics and Personalised Health, School of Biomedical Science, Faculty of Health, Queensland University of Technology, Kelvin Grove, QLD, Australia.

Epigenetic mechanisms have been associated with genes involved in Posttraumatic stress disorder (PTSD). PTSD often co-occurs with other health conditions such as depression, cardiovascular disorder and respiratory illnesses. PTSD and migraine have previously been reported to be symptomatically positively correlated with each other, but little is known about the genes involved. Read More

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Diagnosis and management of hyalinizing trabecular tumor of the thyroid: a single-institution experience.

Endocr J 2021 Jul 6. Epub 2021 Jul 6.

Departments of Surgery, Kuma Hospital, Kobe, Hyogo 650-0011, Japan.

Hyalinizing trabecular tumor (HTT) of the thyroid is a mostly benign disease. Its cytological and pathological diagnosis is often difficult, because HTT cells and papillary thyroid carcinoma (PTC) cells share similar features (e.g. Read More

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Cell-intrinsic glial pathology is conserved across human and murine models of Huntington's disease.

Cell Rep 2021 Jul;36(1):109308

Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA; Center for Translational Neuromedicine, University of Copenhagen Faculty of Health, Copenhagen 2200, Denmark; Neuroscience Center, Rigshospitalet-Copenhagen University Hospital, Copenhagen, Denmark. Electronic address:

Glial pathology is a causal contributor to the striatal neuronal dysfunction of Huntington's disease (HD). We investigate mutant HTT-associated changes in gene expression by mouse and human striatal astrocytes, as well as in mouse microglia, to identify commonalities in glial pathobiology across species and models. Mouse striatal astrocytes are fluorescence-activated cell sorted (FACS) from R6/2 and zQ175 mice, which respectively express exon1-only or full-length mHTT, and human astrocytes are generated either from human embryonic stem cells (hESCs) expressing full-length mHTT or from fetal striatal astrocytes transduced with exon1-only mHTT. Read More

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RNA-seq analysis reveals significant transcriptome changes in huntingtin-null human neuroblastoma cells.

BMC Med Genomics 2021 Jul 2;14(1):176. Epub 2021 Jul 2.

Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, 33431, USA.

Background: Huntingtin (Htt) protein is the product of the gene mutated in Huntington's disease (HD), a fatal, autosomal dominant, neurodegenerative disorder. Normal Htt is essential for early embryogenesis and the development of the central nervous system. However, the role of Htt in adult tissues is less defined. Read More

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Huntingtin and the Synapse.

Front Cell Neurosci 2021 15;15:689332. Epub 2021 Jun 15.

Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, NL, Canada.

Huntington disease (HD) is a monogenic disease that results in a combination of motor, psychiatric and cognitive symptoms. HD is caused by a CAG trinucleotide repeat expansion in the huntingtin () gene, which results in the production of a pathogenic mutant HTT protein (mHTT). Although there is no cure at present for HD, a number of RNA-targeting therapies have recently entered clinical trials which aim to lower mHTT production through the use of antisense oligonucleotides (ASOs) and RNAi. Read More

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Fear Extinction and Predictive Trait-Like Inter-Individual Differences in Rats Lacking the Serotonin Transporter.

Int J Mol Sci 2021 Jun 30;22(13). Epub 2021 Jun 30.

Behavioral Neuroscience, Experimental and Biological Psychology, Faculty of Psychology, Philipps-University of Marburg, Gutenberg-Str. 18, D-35032 Marburg, Germany.

Anxiety disorders are associated with a failure to sufficiently extinguish fear memories. The serotonergic system (5-hydroxytryptamine, 5-HT) with the 5-HT transporter (5-HTT, SERT) is strongly implicated in the regulation of anxiety and fear. In the present study, we examined the effects of SERT deficiency on fear extinction in a differential fear conditioning paradigm in male and female rats. Read More

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Purine Nucleotides Metabolism and Signaling in Huntington's Disease: Search for a Target for Novel Therapies.

Int J Mol Sci 2021 Jun 18;22(12). Epub 2021 Jun 18.

Department of Biochemistry, Medical University of Gdansk, 80-210 Gdansk, Poland.

Huntington's disease (HD) is a multi-system disorder that is caused by expanded CAG repeats within the exon-1 of the huntingtin () gene that translate to the polyglutamine stretch in the HTT protein. HTT interacts with the proteins involved in gene transcription, endocytosis, and metabolism. HTT may also directly or indirectly affect purine metabolism and signaling. Read More

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The Effect of CAG Repeats within the Non-Pathological Range in the HTT Gene on Cognitive Functions in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment.

Diagnostics (Basel) 2021 Jun 7;11(6). Epub 2021 Jun 7.

Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, 50139 Florence, Italy.

The Huntingtin gene (HTT) is within a class of genes containing a key region of CAG repeats. When expanded beyond 39 repeats, Huntington disease (HD) develops. Individuals with less than 35 repeats are not associated with HD. Read More

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Neuro-dermatological association between psoriasis and depression: an immune-mediated inflammatory process validating skin-brain axis theory.

AIMS Neurosci 2021 10;8(3):340-354. Epub 2021 Mar 10.

Department of Medicine, Rawalpindi Medical University, Pakistan.

Objective: Our study's motive was to recognize various immune-mediated inflammatory processes involved in the pathogenesis of depression and psoriasis and interlink between them based on inflammatory mediators.

Methods: A careful and comprehensive literature search was done through various databases like PubMed, Google Scholar, and EBSCO. A total of 56 studies were included in our study after careful screening. Read More

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Knockout of the Serotonin Transporter in the Rat Mildly Modulates Decisional Anhedonia.

Neuroscience 2021 08 25;469:31-45. Epub 2021 Jun 25.

Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, The Netherlands.

Serotonin transporter gene variance has long been considered an essential factor contributing to depression. However, meta-analyses yielded inconsistent findings recently, asking for further understanding of the link between the gene and depression-related symptoms. One key feature of depression is anhedonia. Read More

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Association Analysis of Chromosome X to Identify Genetic Modifiers of Huntington's Disease.

J Huntingtons Dis 2021 Jun 22. Epub 2021 Jun 22.

Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

Background: Huntington's disease (HD) is caused by an expanded (>35) CAG trinucleotide repeat in huntingtin (HTT). Age-at-onset of motor symptoms is inversely correlated with the size of the inherited CAG repeat, which expands further in brain regions due to somatic repeat instability. Our recent genetic investigation focusing on autosomal SNPs revealed that age-at-onset is also influenced by genetic variation at many loci, the majority of which encode genes involved in DNA maintenance/repair processes and repeat instability. Read More

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Impact of single or repeated short-term heat challenges mimicking summer heat waves on thermoregulatory responses and performances in finishing pigs.

David Renaudeau

Transl Anim Sci 2020 Oct 13;4(4):txaa192. Epub 2020 Oct 13.

PEGASE UMR1348, Physiologie, Environnement et Génétique pour l'Animal et les Systèmes d'Élevage, INRAE, Institut Agro, St Gilles, France.

The objectives of this study were to determine the effects of single or repeated short heat stress (HS) challenges that mimicked summer heat waves on performance and thermoregulatory responses in finishing pigs. A total of 45 crossbred castrated males were tested in three consecutive replicates of 15 pigs. Within each replicate, pigs were assigned to one of five treatments. Read More

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October 2020

A New Chemoenzymatic Semisynthetic Approach Provides Insight into the Role of Phosphorylation beyond Exon1 of Huntingtin and Reveals N-Terminal Fragment Length-Dependent Distinct Mechanisms of Aggregation.

J Am Chem Soc 2021 Jul 23;143(26):9798-9812. Epub 2021 Jun 23.

Laboratory of Molecular and Chemical Biology of Neurodegeneration, School of Life Sciences, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.

Huntington's disease is a neurodegenerative disorder caused by the expansion of a polyglutamine repeat (>36Q) in the N-terminal domain of the huntingtin protein (Htt), which renders the protein or fragments thereof more prone to aggregate and form inclusions. Although several Htt N-terminal fragments of different lengths have been identified within Htt inclusions, most studies on the mechanisms, sequence, and structural determinants of Htt aggregation have focused on the Httexon1 (Httex1). Herein, we investigated the aggregation properties of mutant N-terminal Htt fragments of various lengths (Htt171, Htt140, and Htt104) in comparison to mutant Httex1 (mHttex1). Read More

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Highlighting the clinical potential of HTT repeat expansions in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

Neuron 2021 06;109(12):1947-1948

Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD 21287, USA; Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London WC1N 1PJ, UK. Electronic address:

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Questioning the causality of HTT CAG-repeat expansions in FTD/ALS.

Neuron 2021 06;109(12):1945-1946

AP-HP, Genetic Department, University Hospital Pitié-Salpêtrière, Paris, France; Sorbonne University, Institut du Cerveau-Paris Brain Institute-ICM, INSERM, CNRS, Paris, France. Electronic address:

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Quantitative Exchange NMR-Based Analysis of Huntingtin-SH3 Interactions Suggests an Allosteric Mechanism of Inhibition of Huntingtin Aggregation.

J Am Chem Soc 2021 Jun 17;143(25):9672-9681. Epub 2021 Jun 17.

Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0520, United States.

Huntingtin polypeptides (htt), encoded by exon 1 of the gene and containing an expanded polyglutamine tract, form fibrils that accumulate within neuronal inclusion bodies, resulting in the fatal neurodegenerative condition known as Huntington's disease. Htt comprises three regions: a 16-residue N-terminal amphiphilic domain (NT), a polyglutamine tract of variable length (Q), and a polyproline-rich domain containing two polyproline tracts. The NT region of htt undergoes prenucleation transient oligomerization on the sub-millisecond time scale, resulting in a productive tetramer that promotes self-association and nucleation of the polyglutamine tracts. Read More

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The engineered expression of secreted HSPB5-Fc in CHO cells exhibits cytoprotection in vitro.

BMC Biotechnol 2021 Jun 14;21(1):39. Epub 2021 Jun 14.

Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital of Henan University, School of Basic Medical Sciences, Henan University, Jin-Ming Road, Kaifeng, 475004, China.

Background: HSPB5 is an ATP-independent molecular chaperone that is induced by heat shock or other proteotoxic stresses. HSPB5 is cytoprotective against stress both intracellularly and extracellularly. It acts as a potential therapeutic candidate in ischemia-reperfusion and neurodegenerative diseases. Read More

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Ribosome traffic jam in neurodegeneration: decoding hurdles in Huntington disease.

Cell Stress 2021 May 3;5(6):86-88. Epub 2021 May 3.

The Scripps Research Institute, Department of Neuroscience, Jupiter, FL, USA.

A ribosome typically moves at a particular rate on a given mRNA transcript to decode the nucleic acid information required to synthesize proteins. The speed and directionality of the ribosome movements during mRNA translation are determined by the mRNA sequence and structure and by various decoding factors. However, the molecular mechanisms of this remarkable movement during protein synthesis, or its relevance in brain disorders, remain unknown. Read More

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