Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders.

The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Using exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with myristic acid alkyne (YnMyr) chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), aged 1-50 years, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%) and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%) and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%) and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each) as well as hypertrophy of the clava (24%) were common neuroimaging findings. Acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localization and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-myristoylation was similarly affected in acbd6-deficient zebrafish and X. tropicalis models, including Fus, Marcks and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders.

Correction: The Knowledge Translation Status in Selected Eastern-Mediterranean Universities and Research Institutes.

[This corrects the article DOI: 10.1371/journal.pone.0103732.].

The knowledge translation status in selected Eastern-Mediterranean universities and research institutes.

BACKGROUND: A serious worldwide effort to strengthen research based knowledge translation (KT) has begun in recent years and some countries, particularly developed ones, are trying to incorporate KT in their health and health research systems. Keeping in mind the recent economic depression and the need to perform more efficient research, we aimed to assess and compare the KT status of selected health research institutes in the Eastern Mediterranean Regions' countries, and to identify their strengths and weaknesses in the field. METHODS: After finding the focal points that would steer the focus group discussions (FGDs) and help complete the 'Self Assessment Tool for Research Institutes' (SATORI) tool, each focal point held two FGDs in which researchers, research authorities and other individuals specified in detail further in the study were held. The scores obtained by each institute were evaluated quantitatively, and the transcriptions were analyzed qualitatively with OpenCode software. RESULTS: For ease of analysis the 50 items of the SATORI were classified into 7 main domains: 'priority setting', 'research quality and timeliness', 'researchers' KT capacities', 'facilities and pre-requisites of KT', 'processes and regulations supporting KT', 'interaction with research users', and 'promoting and evaluating the use of knowledge'. Based on the scoring system, the strongest domain was 'research quality and timeliness'. 'Priority setting' was the weakest domain of all. The remaining domains were more or less equal in strength and were not in a favorable state. The qualitative findings confirmed the quantitative findings. CONCLUSIONS: The main problem, it seems, is that a KT climate does not exist in the region. And despite the difference in the contexts, there are many similarities in the region's institutes included in this study. Collaborative efforts can play a role in creating this climate by steering countries towards KT and suggesting regional strategic directions according to their needs.

Detection p53 gene deletion in hematological malignancies using fluorescence in situ hybridization: a pilot study. .

P53 as a tumor suppressor gene plays a major role in cancer development, it is essential for cell growth regulation and apoptosis. The deletion of p53 is known to be associated with aggressive diseases in several hematological malignancies. The evidence indicated that p53 deletions can be acquired as a result of chemotherapy. Therefore, a follow-up study for p53 gene deletion by fluorescence in situ hybridization technique (FISH) was carried out for the patients group who affected with different hematological malignancies before and after chemotherapy. The main goals from screening of p53 deletion were to assess the correlation between p53 deletion and chemotherapy resistance, overall median survival and chromosomal abnormalities. It is concluded from the present study that p53 deletion has a cardinal effect on the clinical outcome (chemotherapy resistance, overall median survival) and outcome of chromosomal abnormalities (quality and quantity of chromosomal abnormalities) of the patients who were affected with hematological malignancies before and after chemotherapy.

Molecular characterization of glucose-6-phosphate dehydrogenase deficient variants in Baghdad city - Iraq.

BACKGROUND: Although G6PD deficiency is the most common genetically determined blood disorder among Iraqis, its molecular basis has only recently been studied among the Kurds in North Iraq, while studies focusing on Arabs in other parts of Iraq are still absent. METHODS: A total of 1810 apparently healthy adult male blood donors were randomly recruited from the national blood transfusion center in Baghdad. They were classified into G6PD deficient and non-deficient individuals based on the results of methemoglobin reduction test (MHRT), with confirmation of deficiency by subsequent enzyme assays. DNA from deficient individuals was studied using a polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP) for four deficient molecular variants, namely G6PD Mediterranean (563 C→T), Chatham (1003 G→A), A- (202 G→A) and Aures (143 T→C). A subset of those with the Mediterranean variant, were further investigated for the 1311 (C→T) silent mutation. RESULTS: G6PD deficiency was detected in 109 of the 1810 screened male individuals (6.0%). Among 101 G6PD deficient males molecularly studied, the Mediterranean mutation was detected in 75 cases (74.3%), G6PD Chatham in 5 cases (5.0%), G6PD A- in two cases (2.0%), and G6PD Aures in none. The 1311 silent mutation was detected in 48 out of the 51 G6PD deficient males with the Mediterranean variant studied (94.1%). CONCLUSIONS: Three polymorphic variants namely: the Mediterranean, Chatham and A-, constituted more than 80% of G6PD deficient variants among males in Baghdad. Iraq. This observation is to some extent comparable to other Asian Arab countries, neighboring Turkey and Iran.

Immunohistochemical expression of epidermal growth factor receptor (EGFR) in oral squamous cell carcinoma in relation to proliferation, apoptosis, angiogenesis and lymphangiogenesis.

OBJECTIVES: Squamous cell carcinoma (SCC) is by far the most common malignant neoplasm of the oral cavity. A number of etiologic factors have been implicated in its development. During the past few decades, a particular focus has been placed on the investigation of valid biomarkers predictive of cancer behavior and cervical lymph node metastasis in head and neck Squamous cell carcinoma (HNSCC).The present study was designed to investigate the expression of epidermal growth factor in these tumors in relation to proliferation, apoptosis, angiogenesis and lymphangiogenesis. MATERIALS AND METHODS: Immunohistochemical (IHC) evaluation of epidermal growth factor receptor (EGFR) expression in 40 retrospective OSCC specimens and its correlation with proliferating cell nuclear antigen (PCNA), antiapoptotic antibody (P53), vascular endothelial growth factor (VEGF), and D2-40 monoclonal antibodies (Mab), in relation to the clinicopathological parameters. RESULTS: Data revealed positive EGFR immunoreactivity in 35(87.5%) cases. There was a statistically significant correlation regarding EGFR extent score with respect to intratumoral lymphatic vessel density (ILVD) (r = 0.35) as well as EGFR intensity score with respect to ILVD and peritumoral lymphatic vessel density (PLVD) (r = 0.33, r = 0.36 respectively). EGFR expression was not correlated with the clinicopathological parameters. CONCLUSIONS: EGFR is expressed by most of the cases. EGFR correlation with D2- 40 positive lymphatic vessels suggests a higher tendency of OSCC for lymphatic dissemination. Lack of correlation among the studied markers suggests their independent effect on tumor behavior.