Publications by authors named "A Nazli Basak"

408 Publications

Label-Free Method Development for Hydroxyproline PTM Mapping in Human Plasma Proteome.

Protein J 2021 Apr 11. Epub 2021 Apr 11.

Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, 721302, India.

Post-translational modifications (PTMs) impart structural heterogeneities that can alter plasma proteins' functions in various pathophysiological processes. However, the identification and mapping of PTMs in untargeted plasma proteomics is still a challenge due to the presence of diverse components in blood. Here, we report a label-free method for identifying and mapping hydroxylated proteins using tandem mass spectrometry (MS/MS) in the human plasma sample. Our untargeted proteomics approach led us to identify 676 de novo sequenced peptides in human plasma that correspond to 201 proteins, out of which 11 plasma proteins were found to be hydroxylated. Among these hydroxylated proteins, Immunoglobulin A1 (IgA1) heavy chain was found to be modified at residue 285 (Pro to Hyp), which was further validated by MS/MS study. Molecular dynamics (MD) simulation analysis demonstrated that this proline hydroxylation in IgA1 caused both local and global structural changes. Overall, this study provides a comprehensive understanding of the protein profile containing Hyp PTMs in human plasma and shows the future perspective of identifying and discriminating Hyp PTM in the normal and the diseased proteomes.
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http://dx.doi.org/10.1007/s10930-021-09984-7DOI Listing
April 2021

Should Iliac Wing Screws Be Included in Long Segment Dynamic Stabilization?

Cureus 2021 Feb 24;13(2):e13543. Epub 2021 Feb 24.

Neurosurgery, Koç University School of Medicine, Istanbul, TUR.

Background In this article, clinical satisfaction and radiological results are discussed in a series of patients where the iliac wings participate in dynamic stabilization. Dynamic stabilization is an effective alternative surgical treatment method, especially in clinical pictures that go with pain due to minor instabilities. Practically the unique surgical instrument used in multilevel instabilities is the Dynesys system. The most important drawback of the Dynesys system is that the S1 screws become loose in time. In this article, our aim is to find solution to S1 insufficiency by extension of the system to the iliac wings. Methods Nineteen patients (eight females, 11 males) with a mean age of 54.16 were included in the study. Patients had multilevel (level 2 and above) instability, iliac wings were included in the stabilized segments, and Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) were used for patient follow-up. Results First year results showed a significant improvement in VAS and ODI. Regarding the complications, infection developed in one patient, loosening in the proximal iliac wing in one patient, and both S1 and iliac proximals in one patient, but no clinical findings were encountered. Conclusion When more than two levels of dynamic systems are used in chronic instability, especially in the elderly patients, S1 screws are loosened. In these patients, if the iliac bones are also included in stabilization, this problem is solved successfully. However unfortunately, Dynesys system does not have a screw suitable for the iliac bones.
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http://dx.doi.org/10.7759/cureus.13543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009454PMC
February 2021

Investigating the Efficacy of Adhesive Tape for Drilling Carbon Fibre Reinforced Polymers.

Materials (Basel) 2021 Mar 30;14(7). Epub 2021 Mar 30.

School of Mechanical Engineering, Shandong University of Technology, Zibo 255000, Shandong, China.

In the present research work, an effort has been made to explore the potential of using the adhesive tapes while drilling CFRPs. The input parameters, such as drill bit diameter, point angle, Scotch tape layers, spindle speed, and feed rate have been studied in response to thrust force, torque, circularity, diameter error, surface roughness, and delamination occurring during drilling. It has been found that the increase in point angle increased the delamination, while increase in Scotch tape layers reduced delamination. The surface roughness decreased with the increase in drill diameter and point angle, while it increased with the speed, feed rate, and tape layer. The best low roughness was obtained at 6 mm diameter, 130° point angle, 0.11 mm/rev feed rate, and 2250 rpm speed at three layers of Scotch tape. The circularity error initially increased with drill bit diameter and point angle, but then decreased sharply with further increase in the drill bit diameter. Further, the circularity error has non-linear behavior with the speed, feed rate, and tape layer. Low circularity error has been obtained at 4 mm diameter, 118° point angle, 0.1 mm/rev feed rate, and 2500 RPM speed at three layers of Scotch tape. The low diameter error has been obtained at 6 mm diameter, 130° point angle, 0.12 mm/rev feed rate, and 2500 rpm speed at three layer Scotch tape. From the optical micro-graphs of drilled holes, it has been found that the point angle is one of the most effective process parameters that significantly affects the delamination mechanism, followed by Scotch tape layers as compared to other parameters such as drill bit diameter, spindle speed, and feed rate.
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http://dx.doi.org/10.3390/ma14071699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037845PMC
March 2021

Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking.

Brain 2021 Apr;144(3):769-780

Department of Genetics, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh, 11211, Kingdom of Saudi Arabia.

Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function.
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http://dx.doi.org/10.1093/brain/awaa459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041041PMC
April 2021

Microstructural responses of Zirconia materials to in-situ SEM nanoindentation.

J Mech Behav Biomed Mater 2021 Mar 10;118:104450. Epub 2021 Mar 10.

School of Mechanical Engineering, The University of Adelaide, Adelaide, 5005, SA, Australia. Electronic address:

Development of optimal shaping processes for pre-sintered and sintered zirconia materials requires a fundamental understanding of damage and deformation mechanisms at small-scale contacts with diamond tools. This paper reports on responses of zirconia materials with distinct microstructures to nanoindentation associated with diamond machining using a Berkovich diamond indenter. In-situ nanoindentation was performed in a scanning electron microscope (SEM) and in-process filmed to record small contact events. Indentation morphology was SEM-mapped at high-magnifications. Although both pre-sintered porous and sintered dense zirconia materials mechanically revealed the quasi-plastic behavior in indentation, there were distinct responses of the two materials to quasi-plasticity at the microstructural level. For pre-sintered porous zirconia, the quasi-plasticity was attributed to shear faults resulting from breaking pore networks as microstructurally discrete interfaces, to lead to compression, fragmentation, pulverization and microcracking of zirconia crystals in indentation imprints. In contrast, sintered dense zirconia had shear band-induced quasi-plastic deformation, accompanied with localized tensile microfracture. A material index associated with the mechanical properties ranked the lower quasi-plasticity for pre-sintered porous zirconia than its sintered dense state, predicting more machining-induced damage in the former than the latter. Significantly higher indentation imprint volumes induced in indented pre-sintered porous zirconia than sintered dense state previses higher machining efficiency for the former than the latter. The microstructure-dependent indentation mechanisms provide the fundamental knowledge into micromechanics of abrasive machining of zirconia materials and may lead to a new microstructural design for zirconia materials to achieve a balanced machining efficiency and damage control.
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http://dx.doi.org/10.1016/j.jmbbm.2021.104450DOI Listing
March 2021

Hypopharynx injury in anterior cervical discectomy: Failure of surgical repair: Case report.

Neurocirugia (Astur) 2021 Mar 9. Epub 2021 Mar 9.

Neurosurgery Department, American Hospital, Istanbul, Turkey.

Hypopharynx injury is a very rare complication of the anterior cervical spine surgery. It is imperative that the complication is managed appropriately with a multidisciplinary approach. In this case, 52 year old male patient underwent C3-4, C4-5, and C5-6 anterior cervical microdiscectomy with interbody fusion and anterior cervical plate surgery. Patient was discharged on the postoperative day 2 with full recovery. During the first follow up at week 1, the patient was found to have leakage of sputum from the incision line. Radiological imaging studies revealed a hypopharynx fistula. First prophylactic course of antibiotic therapy was given; upon persistent leakage from the incision site, it was deemed appropriate to perform hypopharynx repair surgery. However, surgical treatment was not successful, and leakage continued. Thereupon, a controlled sterile environment for secondary granulation was created. Eventually, the leakage was stopped with antibiotic and supporting treatment at the end of week 6. The patient was closely followed for one year. During the one year follow up, the patient did not have any complaints, such as discharge, nor he had any infections. The use of methylene blue in the diagnosis of esophagus perforation, which has high mortality and morbidity rate, provided great benefit. The risk of infection was prevented by creating a sterile environment with a mini colostomy bag.
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http://dx.doi.org/10.1016/j.neucir.2020.12.007DOI Listing
March 2021

The Complex Genetic Landscape of Hereditary Ataxias in Turkey and Implications in Clinical Practice.

Mov Disord 2021 Feb 24. Epub 2021 Feb 24.

Suna and İnan Kıraç Foundation, Neurodegeneration Research Laboratory, KUTTAM, School of Medicine, Koç University, İstanbul, Turkey.

Background: The genetic and epidemiological features of hereditary ataxias have been reported in several populations; however, Turkey is still unexplored. Due to high consanguinity, recessive ataxias are more common in Turkey than in Western European populations.

Objective: To identify the prevalence and genetic structure of hereditary ataxias in the Turkish population.

Methods: Our cohort consisted of 1296 index cases and 324 affected family members. Polymerase chain reaction followed by Sanger sequencing or fragment analysis were performed to screen for the trinucleotide repeat expansions in families with a dominant inheritance pattern, as well as in sporadic cases. The expansion in the frataxin (FXN) gene was tested in all autosomal recessive cases and in sporadic cases with a compatible phenotype. Whole-exome sequencing was applied to 251 probands, selected based on the family history, age of onset, and phenotype.

Results: Mutations in known ataxia genes were identified in 30% of 1296 probands. Friedreich's ataxia was found to be the most common recessive ataxia in Turkey, followed by autosomal recessive spastic ataxia of Charlevoix-Saguenay. Spinocerebellar ataxia types 2 and 1 were the most common dominant ataxias. Whole-exome sequencing was performed in 251 probands with an approximate diagnostic yield of 50%. Forty-eight novel variants were found in a plethora of genes, suggesting a high heterogeneity. Variants of unknown significance were discussed in light of clinical data.

Conclusion: With the large sample size recruited across the country, we consider that our results provide an accurate picture of the frequency of hereditary ataxias in Turkey. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28518DOI Listing
February 2021

Chitosan Channels Stuffed with Mesenchyme Originated Stem/Progenitor Cells for Renovate Axonal Regeneration in Complete Spinal Cord Transection.

Turk Neurosurg 2021 ;31(2):189-198

Koc University Hospital, Department of Neurological Surgery, Istanbul, Turkey.

Aim: To examine the implantation of chitosan channels stuffed with mesenchyme-originated stem/progenitor cells (MSPCs) derived from adult rats in a spinal cord transection model. The level of axonal regeneration, the effect of chitosan channels on the survival of MSPCs, and the functional recovery results were also evaluated.

Material And Methods: Chitosan channels stuffed with MSPCs were implanted at the level of T8 in a transected rat spinal cord. MSPCs were harvested from the pelvic bone marrow of adult rats, and the MSPC?chitosan channel group was compared with three control groups. The axonal regeneration capacity, the effect of chitosan channels on the survival of MSPCs, and the functional recovery results were compared among four groups. The survival of MSPCs was evaluated using histopathological techniques and electron microscopy, axonal regeneration/germination was evaluated by confocal microscopy, and locomotor function was assessed for 4 weeks using the Basso, Beattie, and Bresnahan locomotor score.

Results: The MSPC-chitosan channel group exhibited enhanced survival of transplanted MSPCs compared with MSPCs transplanted directly into the lesion cavity, although no significant difference was detected in locomotor function between the treatment and control groups. The MSPC-chitosan channel group demonstrated thicker myelination of axons than the other groups.

Conclusion: Chitosan channels promoted the survival of transplanted MSPCs and created a tissue bridge after complete spinal cord transection. They also induced axonal regeneration and germination. No significant improvement in functional recovery was found between the groups.
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http://dx.doi.org/10.5137/1019-5149.JTN.29489-20.5DOI Listing
January 2021

Functional characterization of thermotolerant microbial consortium for lignocellulolytic enzymes with central role of Firmicutes in rice straw depolymerization.

Sci Rep 2021 Feb 4;11(1):3032. Epub 2021 Feb 4.

Department of Biotechnology, University of North Bengal, Raja Rammohunpur, P.O.-NBU, Siliguri, West Bengal, 734013, India.

Rice (Oryza sativa L.) straw, an agricultural waste of high yield, is a sustainable source of fermentable sugars for biofuel and other chemicals. However, it shows recalcitrance to microbial catalysed depolymerization. We herein describe development of thermotolerant microbial consortium (RSV) from vermicompost with ability to degrade rice straw and analysis of its metagenome for bacterial diversity, and lignocellulolytic carbohydrate active enzymes (CAZymes) and their phylogenetic affiliations. RSV secretome exhibited cellulases and hemicellulases with higher activity at 60 °C. It catalysed depolymerization of chemical pretreated rice straw as revealed by scanning electron microscopy and saccharification yield of 460 mg g rice straw. Microbial diversity of RSV was distinct from other compost habitats, with predominance of members of phyla Firmicutes, Proteobacteria and Bacteroidetes; and Pseudoclostridium, Thermoanaerobacterium, Chelatococcus and Algoriphagus being most abundant genera. RSV harboured 1389 CAZyme encoding ORFs of glycoside hydrolase, carbohydrate esterase, glycosyl transferase, carbohydrate binding module and auxiliary activity functions. Microorganisms of Firmicutes showed central role in lignocellulose deconstruction with importance in hemicellulose degradation; whereas representatives of Proteobacteria and Bacteroidetes contributed to cellulose and lignin degradation, respectively. RSV consortium could be a resource for mining thermotolerant cellulolytic bacteria or enzymes and studying their synergism in deconstruction of chemically pretreated rice straw.
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http://dx.doi.org/10.1038/s41598-021-82163-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862241PMC
February 2021

Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease.

Neurology 2021 03 25;96(9):e1369-e1382. Epub 2021 Jan 25.

From the Department of Neurodegenerative Diseases (A.T., S.R., L.S., M. Synofzik), Hertie-Institute for Clinical Brain Research and Center of Neurology, and German Center for Neurodegenerative Diseases (DZNE) (A.T., S.R., L.S., M. Synofzik), University of Tübingen, Germany; MRC Centre for Neuromuscular Diseases (A.C., N.D., H.H.), Department of Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, UCL Queen Square Institute of Neurology, London, UK; Department of Brain and Behaviour Sciences (A.C.), University Pavia, Italy; Department of Neurology (J.F., T.K.), University Hospital Bonn; German Center for Neurodegenerative Diseases (DZNE) (J.F., H.J., T.K.), Bonn; Department of Neurology (H.J.), University Hospital of Heidelberg; Department of Psychiatry, Psychotherapy and Psychosomatics (A.M.H., D.R.), University of Halle, Germany; Département de Neurologie (S.M., M.A.), Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg; Department of Neurology (A.E.-L.), APHP, CHU de Bicêtre; French National Reference Center for Rare Neuropathies (NNERF) (A.E.-L.); Inserm U1195 and Paris-Sud University (A.E.-L.), Le Kremlin Bicêtre, France; Medical Faculty (S.E.), Department of Neurology, Uludag University, Bursa, Turkey; University of Zurich (V.C.S., A.A.T.); Department of Neurology (V.C.S., A.A.T.), University Hospital Zurich, Switzerland; Institute of Medical Genetics and Applied Genomics (M. Sturm, T.B.H.) and Center for Rare Diseases (T.B.H.), University of Tübingen, Germany; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) (N.V.-D., H.P.); INSERM (N.V.-D., H.P.), U1258; CNRS (N.V.-D., H.P.), UMR7104, Illkirch; Université de Strasbourg (H.P.), France; Department of Neurology (B.P.v.d.W.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; Department of Neurology (M.P.), Karolinska University Hospital; Department of Clinical Neuroscience (M.P.), Karolinska Institute, Stockholm, Sweden; Department of Neurology (D.T.), Essen University Hospital, University of Duisburg-Essen, Essen; Department of Medical Statistics (R.-D.H.), RWTH Aachen University, Germany; Department of Neurology (J.G.), Hospital Universitario Miguel Servet. Zaragoza, Spain; Department of Neurology (M. Strupp), University Hospital, and German Center for Vertigo and Balance Disorders (M.Strupp), Ludwig Maximilians University, Munich, Germany; Neurology Service (G.M.), Hospital Unversitario Central de Asturias (HUCA), SESPA, Oviedo, Spain; Department of Neurosciences and Reproductive and Odontostomatological Sciences (A.F.), Federico II University Naples, Italy; Institute of Genetics and Molecular and Cellular Biology (M.A.), INSERM-U964/CNRS-UMR7104, University of Strasbourg, Illkirch; Strasbourg Federation of Translational Medicine (M.A.), University of Strasbourg, Strasbourg, France; Service of Neurology (J.I.), University Hospital "Marqués de Valdecilla (IDIVAL)," University of Cantabria, "Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)," Santander, Spain; and Suna and Inan Kıraç Foundation (A.N.B.), Neurodegeneration Research Laboratory, KUTTAM, Koç University School of Medicine, Istanbul, Turkey.

Objective: To delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of replication factor complex subunit 1 (RFC1) repeat expansions, recently identified as causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS).

Methods: Multimodal repeat screening (PCR, Southern blot, whole-exome/genome sequencing-based approaches) combined with cross-sectional and longitudinal deep phenotyping in (1) cross-European cohort A (70 families) with ≥2 features of CANVAS or ataxia with chronic cough (ACC) and (2) Turkish cohort B (105 families) with unselected late-onset ataxia.

Results: Prevalence of RFC1 disease was 67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and 100% in ACC. RFC1 disease was also identified in Western and Eastern Asian individuals and even by whole-exome sequencing. Visual compensation, sensory symptoms, and cough were strong positive discriminative predictors (>90%) against RFC1-negative patients. The phenotype across 70 RFC1-positive patients was mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia (28%) (overlap with cerebellar-type multiple system atrophy [MSA-C]), postural instability (49%), slow vertical saccades (17%), and chorea or dystonia (11%). Ataxia progression was ≈1.3 Scale for the Assessment and Rating of Ataxia points per year (32 cross-sectional, 17 longitudinal assessments, follow-up ≤9 years [mean 3.1 years]) but also included early falls, variable nonlinear phases of MSA-C-like progression (SARA points 2.5-5.5 per year), and premature death. Treatment trials require 330 (1-year trial) and 132 (2-year trial) patients in total to detect 50% reduced progression.

Conclusions: RFC1 disease is frequent and occurs across continents, with CANVAS and ACC as highly diagnostic phenotypes yet as variable, overlapping clusters along a continuous multisystemic disease spectrum, including MSA-C-overlap. Our natural history data help to inform future RFC1 treatment trials.

Classification Of Evidence: This study provides Class II evidence that RFC1 repeat expansions are associated with CANVAS and ACC.
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http://dx.doi.org/10.1212/WNL.0000000000011528DOI Listing
March 2021

A combined clinical and computational approach to understand the SOD1-mediated pathogenesis of rapidly progressive familial amyotrophic lateral sclerosis.

Acta Neurol Belg 2021 Jan 9. Epub 2021 Jan 9.

Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

Here, we aim to provide a comprehensive clinical and biomolecular description of familial amyotrophic lateral sclerosis (fALS) in a 25-year-old female patient with respect to the SOD1 genotype. The clinical diagnosis of the disease was based on family history, neurological examination, electroneurophysiological studies, and revised El Escorial criteria. The heterozygous presence of the A4T mutation in the proband was confirmed by PCR coupled with Sanger sequencing of exon 1 of the SOD1 gene. The mutation was introduced in silico into the three-dimensional structure of the native protein. After energy minimization and quality assessment, non-covalent interactions around threonine-4 and changes in protein stability were calculated computationally. The patient differed widely in age at onset, initial neurological symptoms and findings, and survival time from her kindred, in which several members are affected. SOD1-linked fALS in this case had bulbar involvement at onset, a combination of lower and upper motor neuron signs and showed rapid progression. Unlike alanine-4, threonine-4 failed to engage in hydrophobic interactions with the vicinal non-polar amino acids. The overall fold of the modeled SOD1 mutant remained intact, but unfolding free energy estimations disclosed a decrease in the protein's stability. We report a phenotypically distinct patient with fALS due to the SOD1 mutation and further expand the largest pedigree ever published for SOD1-linked fALS. Genotype‒phenotype correlation in fALS is complex, and it demands detailed clinical investigation and advanced scientific research. Awareness of the broadened phenotypic spectrum might potentially enhance the diagnosis and genetic counseling of fALS.
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http://dx.doi.org/10.1007/s13760-020-01588-9DOI Listing
January 2021

Effective use of CT by surgeons in acute appendicitis diagnosis.

Ulus Travma Acil Cerrahi Derg 2021 01;27(1):43-49

Department of General Surgery, Fatih Sultan Mehmet Training and Research Hospital, İstanbul-Turkey.

Background: Acute appendicitis (AA) still maintains its prominence among general surgical emergencies, and the risk of developing AA is 8.6% for men and 6.7% for women. The clinical diagnosis of acute appendicitis has a rate of approximately 20% false positive and false-negative. Ultrasound (US) and Computed Tomography (CT) are the imaging methods most utilized in this field. The present study aims to determine the relationship between the evaluation results of the clinician who examined the patient and the radiologist's evaluation in the evaluation of cross-sectional imaging tests for the diagnosis of acute appendicitis.

Methods: In this study, the records of 1891 patients who underwent an appendectomy in the General Surgery Clinic of Fatih Sultan Mehmet Training and Research Hospital between January 2010 and 2017 were reviewed retrospectively. From the file of the patients who underwent appendectomy with acute appendicitis and whose appendix was reported as normal in CT results, clinical examination findings of the patient in the emergency department and CT evaluation results of the relevant surgeon (Compatible with acute appendicitis, normal appendix or appendix could not be visualised) were recorded.

Results: Of the 1891 patients, who underwent appendectomy on suspicion of acute appendicitis, 1478 had CT scans for diagnosis and 145 were reported as normal by radiologists. In the evaluations by surgeons of these CT results all reported as normal by radiologists, 105 (%) 72,4) were compatible with acute appendicitis, while 18 (12.4%) were considered normal. In 22 (15.2%) patients, appendix could not be the visualized by surgeons. 70.0% of the cases with Lymphoid hyperplasia - fibrous obliteration pathology result; 73.8% of the cases with acute appendicitis; 75.6% of those with phlegmonousappendicitis and 64.0% of those with gangrenous/perforated appendicitis were diagnosed as appendicitis by CT evaluation performed by a general surgeon.

Conclusion: Diagnostic accuracy rates increase significantly when the CT results are interpreted by the physician performing the clinical evaluation of the patient. The chance of reaching the correct diagnosis will increase with gaining the ability to interpret abdominal cross-sectional imaging techniques during general surgery specialty training.
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http://dx.doi.org/10.14744/tjtes.2020.13359DOI Listing
January 2021

A dual-therapy approach for the treatment of biofilm-mediated Salmonella gallbladder carriage.

PLoS Pathog 2020 12 28;16(12):e1009192. Epub 2020 Dec 28.

Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.

Asymptomatic carriage of Salmonella Typhi continues to facilitate the transmission of typhoid fever, resulting in 14 million new infections and 136,000 fatalities each year. Asymptomatic chronic carriage of S. Typhi is facilitated by the formation of biofilms on gallstones that protect the bacteria from environmental insults and immune system clearance. Here, we identified two unique small molecules capable of both inhibiting Salmonella biofilm growth and disrupting pre-formed biofilm structures without affecting bacterial viability. In a mouse model of chronic gallbladder Salmonella carriage, treatment with either compound reduced bacterial burden in the gallbladder by 1-2 logs resulting in bacterial dissemination to peripheral organs that was associated with increased mortality. Co-administration of either compound with ciprofloxacin not only enhanced compound efficacy in the gallbladder by a further 1-1.5 logs for a total of 3-4.5 log reduction, but also prevented bacterial dissemination to peripheral organs. These data suggest a dual-therapy approach targeting both biofilm and planktonic populations can be further developed as a safe and efficient treatment of biofilm-mediated chronic S. Typhi infections.
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http://dx.doi.org/10.1371/journal.ppat.1009192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793255PMC
December 2020

Immunoglobulin-fold containing bacterial adhesins: molecular and structural perspectives in host tissue colonization and infection.

FEMS Microbiol Lett 2021 Feb;368(2)

School of Bioscience, Indian Institute of Technology Kharagpur, Kharagpur-721302, West Bengal, India.

Immunoglobulin (Ig) domains are one of the most widespread protein domains encoded by the human genome and are present in a large array of proteins with diverse biological functions. These Ig domains possess a central structure, the immunoglobulin-fold, which is a sandwich of two β sheets, each made up of anti-parallel β strands, surrounding a central hydrophobic core. Apart from humans, proteins containing Ig-like domains are also distributed in a vast selection of organisms including vertebrates, invertebrates, plants, viruses and bacteria where they execute a wide array of discrete cellular functions. In this review, we have described the key structural deviations of bacterial Ig-folds when compared to the classical eukaryotic Ig-fold. Further, we have comprehensively grouped all the Ig-domain containing adhesins present in both Gram-negative and Gram-positive bacteria. Additionally, we describe the role of these particular adhesins in host tissue attachment, colonization and subsequent infection by both pathogenic and non-pathogenic Escherichia coli as well as other bacterial species. The structural properties of these Ig-domain containing adhesins, along with their interactions with specific Ig-like and non Ig-like binding partners present on the host cell surface have been discussed in detail.
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http://dx.doi.org/10.1093/femsle/fnaa220DOI Listing
February 2021

Two cases of early-onset autosomal recessive spastic ataxia of Charlevoix-Saguenay diagnosed in adulthood.

Clin Neurol Neurosurg 2021 Feb 8;201:106423. Epub 2020 Dec 8.

Ankara University, Faculty of Medicine, Talatpasa Street 82 Altindag, 06310, Ankara, Turkey.

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http://dx.doi.org/10.1016/j.clineuro.2020.106423DOI Listing
February 2021

Methods and variables in Electrical discharge machining of titanium alloy - A review.

Heliyon 2020 Dec 14;6(12):e05554. Epub 2020 Dec 14.

Department of Mechanical Engineering, Indian Institute of Technology Bombay, India.

Titanium alloys are difficult to machine using conventional methods, therefore, nonconventional processes are often chosen in many applications. Electrical discharge machining (EDM) is one of those nonconventional processes that is used frequently for shaping titanium alloys with their respective pros and cons. However, a good understanding of this process is very difficult to achieve as research results are not properly connected and presented. Therefore, this study investigates different types of EDM processes such as, wire EDM, die-sink EDM, EDM drill and hybrid EDM used to machine titanium alloys. Machining mechanism, tool electrode, dielectric, materials removal rate (MRR), and surface integrity of all these processes are critically analysed and correlated based on the evidence accessible in literature. Machining process suffer from lower material removal rate and high tool wear while applied on titanium alloys. Formation of recast layer, heat affected zone and tool wear is common in all types of EDM processes. Additional challenge in wire EDM of titanium alloys is wire breakage under severe machining conditions. The formation of TiC and TiO are noticed in recast layer depending on the type of dielectrics. Removal of debris from small holes during EDM drilling is a challenge. All these restricts the applications EDMed titanium alloys in high-tech applications such as, aerospace and biomedical areas. Most of these challenges come up due to extraordinary properties such as, low thermal conductivity, high melting point and high hardness, of titanium alloys. Though hybrid EDM has been introduced and there is some work on simulation of EDM process, further developments in EDM of this alloy is required for widening the application of this methods.
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http://dx.doi.org/10.1016/j.heliyon.2020.e05554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736727PMC
December 2020

Structural, Dynamic, and Functional Characterization of a DnaX Mini-intein Derived from Provides Important Insights into Intein-Mediated Catalysis of Protein Splicing.

Biochemistry 2020 12 8;59(50):4711-4724. Epub 2020 Dec 8.

School of Bioscience, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal 721302, India.

Protein splicing is a self-catalyzed post-translational modification in which the intein enzyme excises itself from a precursor protein and ligates the flanking sequences to produce a mature protein. We report the solution structure of a 136-residue DnaX mini-intein enzyme derived from the cyanobacterium . This sequence adopts a well-defined globular structure and forms a horseshoe-shaped fold commonly found in the HINT (hedgehog intein) topology. Backbone dynamics and hydrogen exchange experiments revealed conserved motions on various time scales, which is proposed to be a characteristic of the intein fold. Interestingly, several dynamic motions were found in symmetrically equivalent positions within the protein structure, which might be a consequence of the symmetrical intein fold. In cell splicing activity showed that DnaX mini-intein is a highly active enzyme. The precursor protein was not detected at any timepoint of the assay. Apart from the splicing reaction, catalytic cleavage at the N- and C-termini of the precursor protein was also observed. To determine the roles of the catalytic residues in splicing and cleavage reactions, all combinations of alanine mutations of these residues were generated and functionally characterized. This in-depth analysis revealed cooperativity between these catalytic residues, which suppresses the N- and C-terminal cleavage reactions and enhances the yield of the spliced product. Overall, this study provides a thorough structural, dynamic, and functional characterization of a new intein sequence and adds to the collection of these unique enzymes that have found tremendous applications in biochemistry and biotechnology.
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http://dx.doi.org/10.1021/acs.biochem.0c00828DOI Listing
December 2020

Novel variants broaden the phenotypic spectrum of PLEKHG5-associated neuropathies.

Eur J Neurol 2021 Apr 17;28(4):1344-1355. Epub 2020 Dec 17.

Department of Neuromuscular Diseases, Iranian Centre of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.

Background And Purpose: Pathogenic variants in PLEKHG5 have been reported to date to be causative in three unrelated families with autosomal recessive intermediate Charcot-Marie-Tooth disease (CMT) and in one consanguineous family with spinal muscular atrophy (SMA). PLEKHG5 is known to be expressed in the human peripheral nervous system, and previous studies have shown its function in axon terminal autophagy of synaptic vesicles, lending support to its underlying pathogenetic mechanism. Despite this, there is limited knowledge of the clinical and genetic spectrum of disease.

Methods: We leverage the diagnostic utility of exome and genome sequencing and describe novel biallelic variants in PLEKHG5 in 13 individuals from nine unrelated families originating from four different countries. We compare our phenotypic and genotypic findings with a comprehensive review of cases previously described in the literature.

Results: We found that patients presented with variable disease severity at different ages of onset (8-25 years). In our cases, weakness usually started proximally, progressing distally, and can be associated with intermediate slow conduction velocities and minor clinical sensory involvement. We report three novel nonsense and four novel missense pathogenic variants associated with these PLEKHG5-associated neuropathies, which are phenotypically spinal muscular atrophy (SMA) or intermediate Charcot-Marie-Tooth disease.

Conclusions: PLEKHG5-associated neuropathies should be considered as an important differential in non-5q SMAs even in the presence of mild sensory impairment and a candidate causative gene for a wide range of hereditary neuropathies. We present this series of cases to further the understanding of the phenotypic and molecular spectrum of PLEKHG5-associated diseases.
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http://dx.doi.org/10.1111/ene.14649DOI Listing
April 2021

A novel PNPLA6 mutation in a Turkish family with intractable Holmes tremor and spastic ataxia.

Neurol Sci 2021 Apr 18;42(4):1535-1539. Epub 2020 Nov 18.

Suna and İnan Kıraç Foundation, Neurodegeneration Research Laboratory, KUTTAM, Koç University, School of Medicine, Istanbul, Turkey.

Autosomal recessive cerebellar ataxias are a group of rare neurological diseases with a genetic origin. Recently, the mutations in the PNPLA6 gene were suggested to lead to ataxia and also to other specific syndromes such as Boucher-Neuhauser (ataxia, hypogonadism, and chorioretinal dystrophy) or Gordon-Holmes Syndromes (ataxia, hypogonadism, and brisk reflexes) within a broad spectrum of neurodegenerative diseases. Here we report three patients from a single-family with a novel pathogenic mutation in the PNPLA6 gene which led to predominantly spastic-ataxia, and intractable Holmes tremor. The PNPLA6-related disease should be considered in the differential diagnosis of spastic-ataxias even in the absence of chorioretinal dystrophy, and hypogonadotropic hypogonadism. Further studies should unravel the factors which account for the phenotypic variability present in patients with PNPLA6 gene mutations.
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http://dx.doi.org/10.1007/s10072-020-04869-6DOI Listing
April 2021

Magneto-Rheological Fluid Assisted Abrasive Nanofinishing of β-Phase Ti-Nb-Ta-Zr Alloy: Parametric Appraisal and Corrosion Analysis.

Materials (Basel) 2020 Nov 16;13(22). Epub 2020 Nov 16.

Mechanical Engineering Department, Shree Guru Gobind Singh Tricentenary University, Gurugram 122505, India.

The present work explores the potential of magneto-rheological fluid assisted abrasive finishing (MRF-AF) for obtaining precise surface topography of an in-house developed β-phase Ti-Nb-Ta-Zr (TNTZ) alloy for orthopedic applications. Investigations have been made to study the influence of the concentration of carbonyl iron particles (CIP), rotational speed (Nt), and working gap (Gp) in response to material removal (MR) and surface roughness (Ra) of the finished sample using a design of experimental technique. Further, the corrosion performance of the finished samples has also been analyzed through simulated body fluid (SBF) testing. It has been found that the selected input process parameters significantly influenced the observed MR and Ra values at 95% confidence level. Apart from this, it has been found that Gp and Nt exhibited the maximum contribution in the optimized values of the MR and Ra, respectively. Further, the corrosion analysis of the finished samples specified that the resistance against corrosion is a direct function of the surface finish. The morphological analysis of the corroded morphologies indicated that the rough sites of the implant surface have provided the nuclei for corrosion mechanics that ultimately resulted in the shredding of the appetite layer. Overall results highlighted that the MRF-AF is a potential technique for obtaining nano-scale finishing of the high-strength β-phase Ti-Nb-Ta-Zr alloy.
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http://dx.doi.org/10.3390/ma13225156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698243PMC
November 2020

Calmodulin inhibitors improve erythropoiesis in Diamond-Blackfan anemia.

Sci Transl Med 2020 10;12(566)

Stem Cell Program, Boston Children's Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USA.

Diamond-Blackfan anemia (DBA) is a rare hematopoietic disease characterized by a block in red cell differentiation. Most DBA cases are caused by mutations in ribosomal proteins and characterized by higher than normal activity of the tumor suppressor p53. Higher p53 activity is thought to contribute to DBA phenotypes by inducing apoptosis during red blood cell differentiation. Currently, there are few therapies available for patients with DBA. We performed a chemical screen using zebrafish ribosomal small subunit protein 29 () mutant embryos that have a p53-dependent anemia and identified calmodulin inhibitors that rescued the phenotype. Our studies demonstrated that calmodulin inhibitors attenuated p53 protein amount and activity. Treatment with calmodulin inhibitors led to decreased p53 translation and accumulation but does not affect p53 stability. A U.S. Food and Drug Administration-approved calmodulin inhibitor, trifluoperazine, rescued hematopoietic phenotypes of DBA models in vivo in zebrafish and mouse models. In addition, trifluoperazine rescued these phenotypes in human CD34 hematopoietic stem and progenitor cells. Erythroid differentiation was also improved in CD34 cells isolated from a patient with DBA. This work uncovers a potential avenue of therapeutic development for patients with DBA.
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http://dx.doi.org/10.1126/scitranslmed.abb5831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709865PMC
October 2020

Effect of mesenchymal stem cells therapy in experimental kaolin induced syringomyelia model.

J Neurosurg Sci 2020 10 15. Epub 2020 Oct 15.

Department of Neurosurgery, Memorial Hospital, İstanbul, Turkey.

Background: Syringomyelia is a pathological cavitation of the spinal cord. In this study, we examined whether a syrinx cavity would limit itself with axonal regeneration and stem cell activity in the cavity, and we evaluated subjects on a functional basis.

Methods: Groups were designated as kaolin, trauma, kaolin-trauma, and saline groups. Also divided out of the syringomyelia treated groups were those given human mesenchymal stem cells (hMSCs). All groups were evaluated with immunohistochemistry, electron microscopy, confocal microscopy and functionally.

Results: The kaolin-trauma group had a significant correction of BBB score with hMSCs therapy. The syrinx cavity measurements showed significant improvement in groups treated with hMSCs. The tissue surrounding the syrinx cavity, however, appeared to be better organized in groups treated with hMSCs. The process of repair and regeneration of damaged axons in the lesion were more improved in groups treated with hMSCs. Using confocal microscopy, fluorescence of hMSCs was observed in the central canal, in the ependymal tissue, and around the lesion.

Conclusions: It was concluded that axonal repair accelerated in groups receiving stem cells, and thus, stem cells may be effective in recovery of neural tissue and myelin damage in syringomyelia.
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http://dx.doi.org/10.23736/S0390-5616.20.05026-2DOI Listing
October 2020

Tribological Properties of Chromium Nitride on the Cylinder Liner under the Influence of High Temperature.

Materials (Basel) 2020 Oct 11;13(20). Epub 2020 Oct 11.

Faculty of Mechanical Engineering, Lublin University of Technology, 20-618 Lublin, Poland.

The chromium nitride coating is a hard coating used to improve the sliding friction and wear behavior and is applied to engine components in various operating conditions even at an elevated temperature. In this study, chromium nitride was deposited by a physical vapor deposition process onto the cast iron substrate. All tribological tests were performed on linear reciprocating tribometer with a stroke length of 5 mm in a dry condition at variable temperature levels of 28 °C, 100 °C, 200 °C, and of 300 °C corresponding to loads of 10 N, 20 N, 30 N, and 40 N against the cylinder liner material. The worn surfaces of chromium nitride(CrN) coatings after friction tests were analyzed by scanning electron microscope (SEM) and energy-dispersive spectroscopy (EDS). The results showed that friction coefficients (COF) ranged from 0.93 to 0.34 from room temperature to 300 °C against the cylinder liner material as a counter-body of 6 mm in diameter; higher temperature results in the positive tribological performance of CrN, with at least 0.34 COF at 300 °C. The wear mechanisms of CrN and counter-body surfaces are abrasive wear accompanied by the slight oxidation. This study guides the wear behavior of cylinder liner coatings in an environment similar to the engine.
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http://dx.doi.org/10.3390/ma13204497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601342PMC
October 2020

An unusual familial dementia associated with G131V PRNP mutation.

Eur J Neurol 2021 Feb 18;28(2):377-380. Epub 2020 Oct 18.

Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

Background: Gerstmann-Struassler-Scheinker disease is one of the familial prion diseases secondary to mutations in the prion protein gene (PRNP). The clinical phenotype has a diverse spectrum and might show variation among cases with the same genotype. We report a patient with G131V mutation in the PRNP gene, who was initially considered to harbor familial Alzheimer's disease, based on the family history, clinical presentation and imaging findings.

Methods: A case with a G131V mutation in the PRNP gene is described, and the literature is reviewed.

Results: A 35-year-old man presented with personality changes, behavioral disturbances and cognitive complaints. A similar clinical phenotype was reported in the patient's father, a paternal uncle and a paternal aunt. In conjunction with the observation of mild cerebral atrophy on magnetic resonance imaging and hypometabolism in bilateral temporal and parietal lobes on positron-emission tomography studies, the diagnosis was initially considered as familial Alzheimer's disease. However, whole-exome sequencing of the index patient, confirmed with Sanger sequencing in his father and uncle, revealed the presence of a heterozygous G131V variant in the PRNP gene.

Conclusion: To the best of our knowledge, this is the third report of a G131V mutation in the PRNP gene in the literature. Although ataxia and extrapyramidal findings accompanied dementia in patients reported in the previous literature, the members of the family in the present case primarily reported cognitive impairment, underscoring the importance of genetic evaluation in familial early-onset dementia patients, regardless of clinical and imaging features suggestive of alternative pathologies.
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http://dx.doi.org/10.1111/ene.14559DOI Listing
February 2021

Structural Insights into N-terminal IgV Domain of BTNL2, a T Cell Inhibitory Molecule, Suggests a Non-canonical Binding Interface for Its Putative Receptors.

J Mol Biol 2020 11 5;432(22):5938-5950. Epub 2020 Oct 5.

School of Bioscience, Indian Institute of Technology Kharagpur, India. Electronic address:

T cell costimulation is mediated by the interaction of a number of receptors and ligands present on the surface of the T cell and antigen-presenting cell, respectively. Stimulatory or inhibitory signals from these receptor-ligand interactions work in tandem to preserve immune homeostasis. BTNL2 is a type-1 membrane protein that provides inhibitory signal to T cells and plays an important role in several inflammatory and autoimmune diseases. Therefore, manipulation of the molecular interaction of BTNL2 with its putative receptor could provide strategies to restore immune homeostasis in these diseases. Hence, it is imperative to study the structural characteristics of this molecule, which will provide important insights into its function as well. In this study, the membrane-distal ectodomain of murine BTNL2 was expressed in bacteria as inclusion bodies, refolded in vitro and purified for functional and structural characterization. The domain is monomeric in solution as demonstrated by size-exclusion chromatography and analytical ultracentrifugation, and also binds to its putative receptor on naïve B cells and activated T cell subsets. Importantly, for the first time, we report the structure of BTNL2 as determined by solution NMR spectroscopy and also the picosecond-nanosecond timescale backbone dynamics of this domain. The N-terminal ectodomain of BTNL2, which was able to inhibit T cell function as well, exhibits distinctive structural features. The N-terminal ectodomain of BTNL2 has a significantly reduced surface area in the front sheet due to the non-canonical conformation of the CC' loop, which provides important insights into the recognition of its presently unknown binding partner.
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http://dx.doi.org/10.1016/j.jmb.2020.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642044PMC
November 2020

KCO-Catalyzed Rapid Conversion of -Sulfonylhydrazones to Sulfinates.

ACS Omega 2020 Jul 8;5(28):17818-17827. Epub 2020 Jul 8.

Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India.

-Sulfonylhydrazones derived from alkyl, aryl, and heteroaryl aldehydes and ketones undergo rapid conversion into the corresponding sulfinates when heated with 10 mol % KCO in ,'-dimethylethylene urea (DMEU) at elevated temperature. The reaction conditions are amenable to several functional groups and suitable for gram-scale synthesis. Under these base-catalyzed conditions, -tosylhydrazones derived from -allylated and -propargylated 2-hydroxyarylaldehydes do not undergo the well-established intramolecular [3 + 2]-cycloaddition reactions and generate corresponding sulfinates in good yields. The base-catalyzed transformation proceeds via crucial rapid intermolecular protonation of the diazo intermediate to generate diazonium ion , which upon nucleophilic displacement by the sulfonyl ion provides the desired sulfinate selectively.
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http://dx.doi.org/10.1021/acsomega.0c02616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377682PMC
July 2020

Phenotypic and genotypic features of patients diagnosed with ALS in the city of Sakarya, Turkey.

Acta Neurol Belg 2020 Dec 15;120(6):1411-1418. Epub 2020 Jul 15.

Suna and İnan Kıraç Foundation, Neurodegeneration Research Laboratory (NDAL), KUTTAM, Koç University School of Medicine, İstanbul, Turkey.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease leading to motor neuron damage. In this study, the clinical, demographic, and genetic features of ALS patients in the city of Sakarya, Turkey, were investigated. Patients with an established diagnosis of ALS according to the Awaji criteria were included. Age, sex, age at onset of ALS, initial complaints, consanguineous marriage, and genetic features were retrospectively investigated. Conventional genetic analysis and NGS were used for molecular evaluation of patients. A total of 55 probands (10 familial, 45 sporadic) in whom ALS was suspected due to their phenotypic features were included. Thirty-two patients were male (58.2%), and 23 were female (41.8%); their mean ages were 62.65 ± 13 years. The mean age of onset for 37 familial patients from 10 families was 49.9 years. Two cases had juvenile-onset. Fourteen (25.5%) bulbar-onset versus 40 (72.7%) limb-onset patients were detected; one patient had both. Six (10.9%) patients showed marked frontotemporal dementia. Twenty-nine (52.7%) patients died during the follow-up period. Genetic analysis identified causative variants in eleven cases, carrying variants in six different ALS genes (C9orf72, SOD1, VCP, SPG11, TBK1, and SH3TC2). Genetic investigations have revealed more than 40 genes to be involved in the pathogenesis of ALS. Our relatively small study cohort restricted to one province of Turkey, however, prone to migration, consists of 10/55 familial ALS cases, which harbor two rare (SH3TC2-p.Met523Thr and TBK1-p.Glu643del) and two novel (SPG11-p.Lys656Valfs*11 and VCP-p.Arg191Pro) mutations contributing to the literature.
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http://dx.doi.org/10.1007/s13760-020-01441-zDOI Listing
December 2020

Natural products as inspiration for the development of bacterial antibiofilm agents.

Nat Prod Rep 2020 11 1;37(11):1454-1477. Epub 2020 Jul 1.

Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.

Natural products have historically been a rich source of diverse chemical matter with numerous biological activities, and have played an important role in drug discovery in many areas including infectious disease. Synthetic and medicinal chemistry have been, and continue to be, important tools to realize the potential of natural products as therapeutics and as chemical probes. The formation of biofilms by bacteria in an infection setting is a significant factor in the recalcitrance of many bacterial infections, conferring increased tolerance to many antibiotics and to the host immune response, and as yet there are no approved therapeutics for combatting biofilm-based bacterial infections. Small molecules that interfere with the ability of bacteria to form and maintain biofilms can overcome antibiotic tolerance conferred by the biofilm phenotype, and have the potential to form combination therapies with conventional antibiotics. Many natural products with anti-biofilm activity have been identified from plants, microbes, and marine life, including: elligic acid glycosides, hamamelitannin, carolacton, skyllamycins, promysalin, phenazines, bromoageliferin, flustramine C, meridianin D, and brominated furanones. Total synthesis and medicinal chemistry programs have facilitated structure confirmation, identification of critical structural motifs, better understanding of mechanistic pathways, and the development of more potent, more accessible, or more pharmacologically favorable derivatives of anti-biofilm natural products.
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http://dx.doi.org/10.1039/d0np00022aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677205PMC
November 2020

Revisiting the complex architecture of ALS in Turkey: Expanding genotypes, shared phenotypes, molecular networks, and a public variant database.

Hum Mutat 2020 08 24;41(8):e7-e45. Epub 2020 Jun 24.

Suna and İnan Kıraç Foundation, Neurodegeneration Research Laboratory (NDAL), Research Center for Translational Medicine (KUTTAM), Koç University School of Medicine, Istanbul, Turkey.

The last decade has proven that amyotrophic lateral sclerosis (ALS) is clinically and genetically heterogeneous, and that the genetic component in sporadic cases might be stronger than expected. This study investigates 1,200 patients to revisit ALS in the ethnically heterogeneous yet inbred Turkish population. Familial ALS (fALS) accounts for 20% of our cases. The rates of consanguinity are 30% in fALS and 23% in sporadic ALS (sALS). Major ALS genes explained the disease cause in only 35% of fALS, as compared with ~70% in Europe and North America. Whole exome sequencing resulted in a discovery rate of 42% (53/127). Whole genome analyses in 623 sALS cases and 142 population controls, sequenced within Project MinE, revealed well-established fALS gene variants, solidifying the concept of incomplete penetrance in ALS. Genome-wide association studies (GWAS) with whole genome sequencing data did not indicate a new risk locus. Coupling GWAS with a coexpression network of disease-associated candidates, points to a significant enrichment for cell cycle- and division-related genes. Within this network, literature text-mining highlights DECR1, ATL1, HDAC2, GEMIN4, and HNRNPA3 as important genes. Finally, information on ALS-related gene variants in the Turkish cohort sequenced within Project MinE was compiled in the GeNDAL variant browser (www.gendal.org).
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http://dx.doi.org/10.1002/humu.24055DOI Listing
August 2020

Human CRY1 variants associate with attention deficit/hyperactivity disorder.

J Clin Invest 2020 07;130(7):3885-3900

Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.

Attention deficit/hyperactivity disorder (ADHD) is a common and heritable phenotype frequently accompanied by insomnia, anxiety, and depression. Here, using a reverse phenotyping approach, we report heterozygous coding variations in the core circadian clock gene cryptochrome 1 in 15 unrelated multigenerational families with combined ADHD and insomnia. The variants led to functional alterations in the circadian molecular rhythms, providing a mechanistic link to the behavioral symptoms. One variant, CRY1Δ11 c.1657+3A>C, is present in approximately 1% of Europeans, therefore standing out as a diagnostic and therapeutic marker. We showed by exome sequencing in an independent cohort of patients with combined ADHD and insomnia that 8 of 62 patients and 0 of 369 controls carried CRY1Δ11. Also, we identified a variant, CRY1Δ6 c.825+1G>A, that shows reduced affinity for BMAL1/CLOCK and causes an arrhythmic phenotype. Genotype-phenotype correlation analysis revealed that this variant segregated with ADHD and delayed sleep phase disorder (DSPD) in the affected family. Finally, we found in a phenome-wide association study involving 9438 unrelated adult Europeans that CRY1Δ11 was associated with major depressive disorder, insomnia, and anxiety. These results defined a distinctive group of circadian psychiatric phenotypes that we propose to designate as "circiatric" disorders.
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http://dx.doi.org/10.1172/JCI135500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324179PMC
July 2020