👤 Esra Demir

Amyloid beta (Aβ) oligomers are thought to play an important role during development and progression of Alzheimer's disease (AD). Previously, we determined the Aβ oligomer concentrations in various AD mouse models and in human brain tissues of former AD patients. Here, we investigate which proteins are part of these Aβ oligomers, apart from Aβ itself. Because several oligomer-associated proteins have been implicated in mechanisms leading to AD pathology, identification of the Aβ oligomer proteome may provide insights into the formation of Aβ oligomers Show less

Cognitive impairment varies widely in bipolar disorder. Identifying cognitive subgroups and their biological correlates may improve understanding of the disorder. Brain-derived neurotrophic factor (BDNF) and C-reactive protein (CRP) are key candidates due to their roles in neuroplasticity and inflammation. The aim was to investigate cognitive subgroups in patients with bipolar disorder and their association with serum levels of BDNF and CRP. A cross-sectional study was conducted on 149 bipolar disorder patients and 48 healthy controls. Cognitive performance was assessed using a comprehensive battery of neuropsychological tests. Cluster analysis was performed to identify cognitive subgroups, followed by discriminant function analysis to validate the classification. Serum levels of BDNF and CRP were measured and compared across cognitive subgroups. Cluster analysis identified three cognitive subgroups: intact cognition, selectively impaired cognition (SIC) and globally impaired cognition (GIC). SIC exhibited the highest BDNF levels, while GIC demonstrated the highest CRP levels. CRP levels were negatively associated with performance across all cognitive domains. BDNF showed a negative correlation with verbal fluency, short-term memory and working memory. CRP levels exceeding 4.3 mg/L predicted global cognitive impairment with a sensitivity of 72.41% and specificity of 73.63%. Cognitive impairments in bipolar disorder patients can be classified into distinct subgroups, which are associated with serum levels of BDNF and CRP. These findings suggest that inflammation and neuroplasticity play key roles in the pathophysiology of cognitive decline in bipolar disorder, providing potential biomarkers for identifying patients at risk for severe cognitive impairments. Show less

This study investigated the effects of periodontitis (P) and non-surgical periodontal therapy (NSPT) on behavior, neurodegeneration, and neuroinflammation in rats with Alzheimer's disease (AD)-like pathology. AD-like pathology was induced in rats (n = 28) using STZ neurodegeneration model. Periodontitis was experimentally induced (n = 32), and half of which received NSPT with Chlorhexidine (CHX) gel. Behavioral assessment included the passive avoidance task (PA) and Morris water maze (MWM). Levels of NLRP3, phosphorylated tau (p-tau), and tau in the hippocampus, cerebrospinal fluid (CSF), and serum were measured by ELISA, while BACE1, IL1β, iNOS, and NF-κβ proteins were assessed by Western blotting. Rats in the AD and AD + P groups performed worse in behavioral tests compared to controls (p < 0.05), whereas the NSPT group showed similar performance to controls (p > 0.05). CSF p-tau levels were comparable between AD and AD + P groups, but the hippocampal p-tau/tau ratio was significantly higher in the AD + P group (p < 0.05). BACE1 levels were similar in P and AD groups. NLRP3 and iNOS levels did not show significant differences across groups. Notably, the NSPT group exhibited reduced NF-κβ levels (p < 0.05). Periodontitis may exacerbate AD-like molecular pathology, particularly by promoting tau hyperphosphorylation, while NSPT appears to mitigate disease progression and improve behavioral outcomes. Show less

High-density genomic data analyzed by accurate statistical methods are of potential to enlighten past breeding practices such as selection by unraveling fixed regions. In this study, four native Turkish sheep breeds (80 samples) were genotyped via 296.097 single nucleotide polymorphisms (SNPs) detected by double-digest restriction site-associated DNA (ddRADseq) library preparation combined with the Illumina HiSeq X Ten instrument in order to identify genes under selection pressure. A total of 32, 136, 133, and 119 protein-coding genes were detected under selection pressure by runs of homozygosity (ROH), integrated haplotype score (iHS), the ratio of extended haplotype homozygosity (Rsb), and fixation index (F Show less

Hereditary multiple osteochondromas is an autosomal dominant disorder caused by heterozygous pathogenic variants in EXT1 or EXT2. We aimed to evaluate the clinical and molecular findings of a Turkish cohort with hereditary multiple osteochondroma. Thirty-two patients aged 1.3-49.6 years from 22 families were enrolled. Genetic analyses were made by EXT1 and/or EXT2 sequencing and chromosomal microarray analyses. We found 17 intragenic pathogenic variants in EXT1 (13/17) and EXT2 (4/17), 12 of which are novel. Four probands had EXT1 deletions, including 2 patients with partial EXT1 microdeletions involving exons 2-11 and 5-11, and 2 patients with whole-gene deletions. In 21 variants, the frequency of truncating and missense variants was 76.1% and 23.8%, respectively. Two families had no detectable variants in EXT1 and EXT2. All patients had multiple osteochondromas at the long bones, mainly at the tibia, forearm, femur, and humerus. Bowing deformity of the forearms (9/32) and the lower extremities (2/32), and scoliosis (6/32) were observed. The clinical severity was not different between patients with EXT1 or EXT2 variants. One patient with an EXT2 variant and another with an EXT1 microdeletion had the most severe phenotype with class III disease. Four patients with no EXT1 or EXT2 variants had milder phenotypes. Intrafamilial variability in disease severity was not observed. We report a hereditary multiple osteochondroma cohort with clinical and molecular data including 12 novel intragenic variants in EXT1 or EXT2, and 4 microdeletions involving EXT1. Taken together, our data expand the existing knowledge of the phenotype-genotype spectrum in hereditary multiple osteochondroma. Show less

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilises the angiotensin-converting enzyme 2 (ACE2) transmembrane peptidase as cellular entry receptor. However, whether SARS-CoV-2 in the alveolar compartment is strictly ACE2-dependent and to what extent virus-induced tissue damage and/or direct immune activation determines early pathogenesis is still elusive. Spectral microscopy, single-cell/-nucleus RNA sequencing or ACE2 "gain-of-function" experiments were applied to infected human lung explants and adult stem cell derived human lung organoids to correlate ACE2 and related host factors with SARS-CoV-2 tropism, propagation, virulence and immune activation compared to SARS-CoV, influenza and Middle East respiratory syndrome coronavirus (MERS-CoV). Coronavirus disease 2019 (COVID-19) autopsy material was used to validate We provide evidence that alveolar ACE2 expression must be considered scarce, thereby limiting SARS-CoV-2 propagation and virus-induced tissue damage in the human alveolus. Instead, Collectively, our findings indicate that severe lung injury in COVID-19 probably results from a macrophage-triggered immune activation rather than direct viral damage of the alveolar compartment. Show less

Congenital myasthenic syndromes (CMS) are composed of numerous hereditary disorders involving genetic mutations in proteins essential to the integrity of neuromuscular transmission. The symptoms of CMS vary according to the age at onset of symptoms, and the type and severity of muscle weakness. Effective treatment and genetic counseling depend upon the underlying pathogenic molecular mechanism and subtype of CMS. A retrospective and cross-sectional study was performed with 16 patients with a genetically confirmed diagnosis of CMS to share our experience with clinical symptoms, demographic data, genetic variants, and treatments applied. Sixteen patients with a specific CMS genetic diagnosis (three novel mutations) were identified, including CHRNE (n = 7), DOK7 (n = 2), AGRN (n = 2), RAPSN (n = 1), CHRNA1 (n = 1), CHRNB1 (n = 1), CHAT (n = 1), and SCN4A (n = 1). Age at onset of symptoms ranged from the neonatal period to 12 years. Genetic diagnosis was confirmed between the ages of three months and 17 years. A significant delay was determined between the onset of symptoms and genetic diagnosis of the disease. This study highlights the importance of genetic testing in CMS. Due to the rarity of CMS, more cases will be recognized and reported as the use of laboratory and genetic testing accelerates. We hope that our experience will grow and contribute further to the literature as clinical follow-up and treatment increase. Show less

Idiopathic hypogonadotropic hypogonadism (IHH) is caused by dysfunction of the hypothalamic-pituitary-gonadal axis. DLG2 was recently implicated as a gene associated with delayed puberty and which may also contribute to IHH. The confirmation of the candidate puberty genes in independent IHH cohorts has become crucial due to the lack of proper genotype-phenotype segregations in reported pedigrees. Therefore, we aimed to screen DLG2 in patient variants in a large cohort of IHH patients. The present study included a total of 336 IHH patients from 290 independent families. The coding and flanking regions of DLG2 were screened for potentially important variants in the WES data. Candidate variants were evaluated in the -gnomAD and GME databases according to their allele frequencies, and only those with a frequency <0.0001 were considered rare. Detected variants were classified according to the ACMG/AMP criteria. We found 1 homozygous and 2 heterozygous missense variants in 3 independent pedigrees. Identified variants were found extremely rare or not reported in gnomAD. Two variants were categorized as "uncertain significance," and the other one was "likely pathogenic" according to the ACMG criteria. All patients were normosmic, and in 2 of the 3 families, there were no causal variants in other IHH-related genes. We detected 3 rare sequencing variants in DLG2 in 5 patients with IHH or delayed puberty in a large IHH cohort. Our results support the contention that the DLG2 mutations are associated with IHH in human puberty. Show less

We report two newborns with female external genitalia and bilateral inguinal swelling who were diagnosed with 17β-hydroxysteroid dehydrogenase type 3 deficiency, a rare cause of 46,XY disorder of sexual development. The first case had normal clitoral size and vaginal and urethral openings, palpable gonads in the inguinal region, low testosterone, and low levels of basal and GNRH-stimulated gonadotropin. The second case had similar external genitalia, low testosterone but borderline basal and normal stimulated gonadotropin levels. Low testosterone/androstenedione ratios (0.22 and 0.24, respectively; normal, >0.8) after human chorionic gonadotropin stimulation indicated 17β-hydroxysteroid dehydrogenase type 3 deficiency. HSD17B3 sequencing revealed a homozygous novel mutation (c.464A>C, p.H155P) in exon 6 in the first case and homozygous c.239G>A (p.R80Q) in exon 3 in the second. Show less