Ifenprodil Intracerebrally Offers Neuroprotection against 6-OHDA-Induced Toxicity in SD-Rats via Enhancing Autophagy Function

The progressive decline of dopamine neurons in the substantia nigra is the main pathogenic change in Parkinson's disease (PD). Studies have found that excessive excitement of glutamatergic neurons causes intracellular calcium overload and induces autophagy impairment, which is one of the main mechanisms of dopamine neuron damage. The neuroprotective effect of Ifenprodil against 6-OHDA-injured mice was studied in this study. Ifenprodil was administered intraperitoneally (i.p.) or intracerebrally to rats who had a nigral-striatum pathway lesioned by 6-OHDA stereotactic brain injection. The ability to move was evaluated. The survival of dopamine neurons in the nigral was determined using HE staining, while TH-positive expression was measured using immunohistochemistry. Western Blot was used to examine the expression of CaM protein and light chain 3 (LC3), Beclin-1, BNIP3LNix, and p62. The results revealed that Ifenprodil improves motor function in 6-OHDA rats, and intracerebral injection is more effective than systemic administration. The same results also found in HE and IHC. Ifenprodil enhanced LC3II, BNIP3LNix, and Beclin-1 while decreasing p62, p-CaMKII, and β-Ca expression. In addition, Ifenprodil reduced the activation of microglia caused by 6-OHDA. Overall, the findings imply that Ifenprodil intracerebrally may protect against Parkinson's disease via modulating autophagy-related proteins during 6-OHDA-induced toxicity.

Complex Phenotypic Presentation of Syndromic Hearing Loss Deciphered as Three Separate Clinical Entities: How Genetic Testing Guides Final Diagnosis

<b><i>Background:</i></b> Genetically determined prelingual hearing loss (HL) may occur in an isolated or syndromic form. <b><i>Objective:</i></b> The aim of the study was to unravel the genetic cause of medical problems in a 21-year-old woman, whose phenotypic presentation extended beyond Stickler syndrome and included enlarged vestibular aqueduct (EVA) and persistent microhematuria. <b><i>Methods and Results:</i></b> After sequencing of clinical exome, a known de novo <i>COL2A1</i> pathogenic variant (c.1833+1G&#x3e;A, p.?) causative for Stickler syndrome and one paternally inherited pathogenic change in <i>COL4A5</i> (c.1871G&#x3e;A, p.Gly624Asp) causative for X-linked Alport syndrome were found. No pathogenic variants, including those within the <i>SLC26A4</i> 5′ region (Caucasian EVA haplotype), explaining the development of EVA, were identified. <b><i>Conclusions:</i></b> The study reveals a multilocus genomic variation in one individual and provides a molecular diagnosis of two HL syndromes that co-occur in the proband independent of each other. For the third entity, EVA, no etiological factor was identified. Our data emphasize the relevance of detailed clinical phenotyping for accurate genotype interpretation. Focus on broadening the phenotypic spectrum of known genetic syndromes may actually obscure patients with multiple molecular diagnoses.

Cloning, expression and enzyme activity delineation of two novel CANT1 mutations: the disappearance of dimerization may indicate the change of protein conformation and even function

Background Desbuquois dysplasia (DBQD) was a rare autosomal recessive skeletal dysplasia. Calcium activated nucleotidase 1 (CANT1) mutation was identified as a common pathogenic change for DBQD type 1 and Kim variant but not for DBQD type 2. To our knowledge, all patients with DBQD type 1 currently found could be explained by mutations in the CANT1 gene, but mutations in the CANT1 gene might not be directly diagnosed as DBQD type 1. Results We have identified two novel CANT1 mutations (mut1: c.594G > A [p.Trp198*], mut2: c.734C > T [p.Pro245Leu]) in three children from a family of Chinese origin for the first time. Two of the three children could be diagnosed as typical DBQD type 1 and one child could not be diagnosed as DBQD type 1 based on the clinical data we had. To further clarify the effect of the two mutations of the CANT1 gene, we studied the CANT1 gene expression and detected the protein secretion and nucleotide enzyme activity through cDNA cloning and expression vectors construction for wild and mutant types. The mut1 was a nonsense mutation which could lead to premature termination and produced the truncated bodies; The CANT1 dimer of mut2 was significantly reduced and even undetectable. The extracellular secretion of mut1 was extremely high while mut2 was significantly reduced compared with the wild type. And mut1 and mut2 also could result in a significant reduction in the activity of CANT1 nucleotidease. From the results we could deduce that the two mutations of the CANT1 gene were the causes of the two cases in this study. Conclusions Regarding the particularity of the cases reported in this study, the pathogenesis of CANT1 might be more complicated. The genetic and phenotype of three children with the same genetic background need to be further studied. Larger cohort of patients was needed to establish genotype–phenotype correlations in DBQD.

A MUTATION FOR PATHOGENICITY IN PUCCINIA GRAMINIS TRITICI

A pathogenic change, explainable only on the assumption of mutation, has occurred in a uredial culture of race 52 of Puccinia graminis Tritici, which had previously remained constant in pathogenicity for nearly two years. The mutation appears to have taken place during a six-month period of storage of the urediospores in a refrigerator maintained at a temperature of about 8 °C. When cultured in the greenhouse, at the end of this period, the rust appeared to be a mixture of race 52 and a hitherto undescribed physiologic race, with the latter predominating. The original culture was left in storage for a further period of four months, after which it gave rise to a pure culture of the new race without any indication of the presence of race 52. The new race has been assigned the number 178.