etrimental effect of white matter hyperintensities on parkinsonian motor symptoms is more relevant and independent for axial motor impairments in the status of mildly decreased striatal dopamine transporter availability. © 2021 International Parkinson and Movement Disorder Society.
  The Progressive Supranuclear Palsy Rating Scale is a prospectively validated physician-rated measure of disease severity for progressive supranuclear palsy. We hypothesized that, according to experts' opinion, individual scores of items would differ in relevance for patients' quality of life, functionality in daily living, and mortality. Thus, changes in the score may not equate to clinically meaningful changes in the patient's status.
 
  The aim of this work was to establish a condensed modified version of the scale focusing on meaningful disease milestones.
 
  Sixteen movement disorders experts evaluated each scale item for its capacity to capture disease milestones (0=no, 1=moderate, 2=severe milestone). Items not capturing severe milestones were eliminated. Remaining items were recalibrated in proportion to milestone severity by collapsing across response categories that yielded identical milestone severity grades.  https://www.selleckchem.com/products/Enzastaurin.html  Items with low sensitivity to change were eliminated, based on power calculations using longitudinal 12-month follow-up data from 86 patients with possible or probable progressive supranuclear palsy.
 
  The modified scale retained 14 items (yielding 0-2 points each). The items were rated as functionally relevant to disease milestones with comparable severity. The modified scale was sensitive to change over 6 and 12 months and of similar power for clinical trials of disease-modifying therapy as the original scale (achieving 80% power for two-sample t test to detect a 50% slowing with n=41 and 25% slowing with n=159 at 12 months).
 
  The modified Progressive Supranuclear Palsy Rating Scale may serve as a clinimetrically sound scale to monitor disease progression in clinical trials and routine. © 2021 International Parkinson and Movement Disorder Society.
 The modified Progressive Supranuclear Palsy Rating Scale may serve as a clinimetrically sound scale to monitor disease progression in clinical trials and routine. © 2021 International Parkinson and Movement Disorder Society.Trypanosoma and Leishmania parasites cause devastating tropical diseases resulting in serious global health consequences. These organisms have complex life cycles with mammalian hosts and insect vectors. The parasites must, therefore, survive in different environments, demanding rapid physiological and metabolic changes. These responses depend upon regulation of gene expression, which primarily occurs posttranscriptionally. Altering the composition or conformation of RNA through nucleotide modifications is one posttranscriptional mechanism of regulating RNA fate and function, and modifications including N6-methyladenosine (m6A), N1-methyladenosine (m1A), N5-methylcytidine (m5C), N4-acetylcytidine (ac4C), and pseudouridine (Ψ), dynamically regulate RNA stability and translation in diverse organisms. Little is known about RNA modifications and their machinery in Trypanosomatids, but we hypothesize that they regulate parasite gene expression and are vital for survival. Here, we identified Trypanosomatid homologs for writers of m1A, m5C, ac4C, and Ψ and analyze their evolutionary relationships. We systematically review the evidence for their functions and assess their potential use as therapeutic targets. This work provides new insights into the roles of these proteins in Trypanosomatid parasite biology and treatment of the diseases they cause and illustrates that Trypanosomatids provide an excellent model system to study RNA modifications, their molecular, cellular, and biological consequences, and their regulation and interplay.tRNA molecules are post-transcriptionally modified by tRNA modification enzymes. Although composed of different chemistries, more than 40 types of human tRNA modifications play pivotal roles in protein synthesis by regulating tRNA structure and stability as well as decoding genetic information on mRNA. Many tRNA modifications are conserved among all three kingdoms of life, and aberrations in various human tRNA modification enzymes cause life-threatening diseases. Here, we describe the class of diseases and disorders caused by aberrations in tRNA modifications as 'tRNA modopathies'. Aberrations in over 50 tRNA modification enzymes are associated with tRNA modopathies, which most frequently manifest as dysfunctions of the brain and/or kidney, mitochondrial diseases, and cancer. However, the molecular mechanisms that link aberrant tRNA modifications to human diseases are largely unknown. In this review, we provide a comprehensive compilation of human tRNA modification functions, tRNA modification enzyme genes, and tRNA modopathies, and we summarize the elucidated pathogenic mechanisms underlying several tRNA modopathies. We will also discuss important questions that need to be addressed in order to understand the molecular pathogenesis of tRNA modopathies.
  Congenital cervical spinal muscular atrophy (CCSMA) is a rare, nonprogressive, neurogenic disorder characterized by symmetric arthrogryposis and motor deficits mainly confined to upper extremities. Since its first proposal by Darwish et al. 39years ago, only few cases have ever been reported. Vascular insult to the anterior horn of cervical spinal cord during fetal development was speculated to be the cause, however, the exact pathogenesis is still not well understood.
 
  In this study, whole-exome sequencing (WES) and copy number variation (CNV) analysis were conducted on a definitive CCSMA patient, confirmed by the clinical manifestations and other supplementary examinations.
 
  On physical examination, the patient was mainly characterized by symmetric, congenital, nonprogressive contractures, hypotonia, and muscle weakness mainly confined to the upper limbs, which were further supported by MRI and electromyography. Neuromuscular biopsy of the deltoid muscle demonstrated the type 1 myofiber predominance without any infiltration of inflammatory cells.