Ayla Arslan | Üsküdar University, İstanbul, TURKEY (original) (raw)
Featured Papers by Ayla Arslan
This chapter primarily focuses on the progress in depression precision medicine with specific emp... more This chapter primarily focuses on the progress in depression precision medicine with specific emphasis on the integrative approaches that include artificial intelligence and other data, tools, and technologies. After the description of the concept of precision medicine and a comparative introduction to depression precision medicine with cancer and epilepsy, new avenues of depression precision medicine derived from integrated artificial intelligence and other sources will be presented. Additionally, less advanced areas, such as comorbidity between depression and cancer, will be examined.
International Journal of Neuroscience , 2024
The γ-Aminobutyric acid type A receptors (GABAARs) function as heteropentameric chloride channels... more The γ-Aminobutyric acid type A receptors (GABAARs) function as heteropentameric chloride channels, crucial for primary inhibition in the mammalian brain. The GABRD gene encodes the δ subunit of GABAARs and is implicated in various disorders, including schizophrenia, epilepsy, and insomnia. However, the increasing number of variants of unknown clinical significance (VUS) within the GABRD gene poses a challenge to precision medicine and our understanding of relevant pathophysiology. The primary aim of this study is to address this challenge by predicting the most pathogenic GABRD VUS. Employing a combination of in silico algorithms, the study analyzes 82 GABRD gene VUS sourced from the ClinVar database. Initially, separate algorithms based on sequence homology were used to assess this VUS set. Subsequently, consensus variants predicted as pathogenic underwent further evaluation through a web server utilizing the algorithm based on structural homology. The resulting 11 VUS were then validated using in silico tools, assessing variant effects based on genetic and molecular data. This led to the determination of pathogenicity probability considering disease association and protein stability due to amino acid substitutions. The identification of specific variants (L111R, R114C, D123N, G150S, L243P) in the coding region of the GABRD gene, predicted as deleterious by multiple algorithms, suggests structural or functional consequences for pathogenicity. These evolutionarily conserved variants, mapped onto the extracellular domain of the δ subunit, were linked to idiopathic generalized epilepsy. These findings guide wet-lab experimentation and contribute to validating clinically significant genetic variants in the GABRD gene crucial for personalized and pharmacogenetic interventions.
Journal of Community Genetics, Dec 21, 2023
Wikipedia, the open crowdsourced encyclopedia that anyone can edit, ranks among the top ten most-... more Wikipedia, the open crowdsourced encyclopedia that anyone can edit, ranks among the top ten most-visited websites globally. Its integration into university curriculum as an innovative educational tool is a slowly growing trend; however, many higher education institutions have yet to fully grasp its potential. In response, a specific optional module for Wikipedia editing, designed for the selected undergraduate science courses at the School of Advanced Studies, Russia, was implemented as an optional extra credit service-learning activity, a teaching methodology combining meaningful service to the community with curriculum-based learning. Students who chose to participate and those who preferred not to participate in the activity were invited to participate in a research project to explore their perspectives and experiences. In total, five sessions of focus group discussions were conducted with participants (12 females and 2 males) in one set and non-participants (5 females and 4 males) in another to identify students' perspectives on themes such as their interest in science, reasons for their choices, and their expectations before the activity while post-experience focus group discussions were used to identify the perspectives of participant students on themes, encompassing contribution of the service-learning activity, acquisition of new skills, and the development of prosocial behaviors. Students' opinions on integrating social responsibility topics into the curriculum were also explored. The results extracted from these focus group discussions, analyzed through consensual coding, revealed factors promoting student participation, like interest in the subject, novelty of the activity, and grade improvement opportunities, as well as factors deterring participation, such as concerns about academic benefits, workload, and time constraints. Furthermore, the results demonstrated that Wikipedia editing serves as a novel teaching methodology, promoting student learning and development in digital literacy and information literacy, which are among the twenty-first-century skills. Interestingly, at the same time, not all students could address the value of contributing to open, crowdsourced knowledge for public service or interpret this activity as an academic service-learning. These suggest that Wikipedia editing is an innovative teaching approach, fostering students' learning and development while also indicating its potential to enhance students' understanding of responsible citizenship and public service in the digital age.
Heliyon, 2023
Critical for brain development, neurodevelopmental and network disorders, the GABRA1 gene encodes... more Critical for brain development, neurodevelopmental and network disorders, the GABRA1 gene encodes for the α1 subunit, an abundantly and developmentally expressed subunit of heteropentameric gamma-aminobutyric acid A receptors (GABAARs) mediating primary inhibition in the brain. Mutations of the GABAAR subunit genes including GABRA1 gene are associated with epilepsy, a group of syndromes, characterized by unprovoked seizures and diagnosed by integrative approach, that involves genetic testing. Despite the diagnostic use of genetic testing, a large fraction of the GABAAR subunit gene variants including the variants of GABRA1 gene is not known in terms of their molecular consequence, a challenge for precision and personalized medicine. Addressing this, one hundred thirty-seven GABRA1 gene variants of unknown clinical significance have been extracted from the ClinVar database and computationally analyzed for pathogenicity. Eight variants (L49H, P59L, W97R, D99G, G152S, V270G, T294R, P305L) are predicted as pathogenic and mapped to the α1 subunit's extracellular domain (ECD), transmembrane domains (TMDs) and extracellular linker. This is followed by the integration with relevant data for cellular pathology and severity of the epilepsy syndromes retrieved from the literature. Our results suggest that the pathogenic variants in the ECD of GABRA1 (L49H, P59L, W97R, D99G, G152S) will probably manifest decreased surface expression and reduced current with mild epilepsy phenotypes while V270G, T294R in the TMDs and P305L in the linker between the second and the third TMDs will likely cause reduced cell current with severe epilepsy phenotypes. The results presented in this study provides insights for clinical genetics and wet lab experimentation.
Frontiers in Psychiatry Schizophrenia, 2023
J Neuropsychiatry Clin Neurosci., 2015
The majority of neuropsychiatric disorders show a strong degree of heritability, yet little is kn... more The majority of neuropsychiatric disorders show a strong degree of heritability, yet little is known about molecular factors involved in the pathophysiology of diseases like schizophrenia. After a brief historical introduction into the current understanding of neuropsychiatric disorders, the aim of this study is to discuss imaging genetics as a strategy to explore the pathophysiology of neuropsychiatric disorders. The candidate gene approach of imaging genetics is used for validation/ replication studies of genes, whereas the hypothesis-free, noncandidate gene approach appears to be a tool for gene discovery. Besides, integration of environmental factors into neuroimaging begins to converge on neuroimaging studies of genetic variation. In the light of data from other avenues such as animal experimentation, these developments show a model of interdisciplinary research, which may lead to identifying markers for neuropsychiatric disorders.
Journal of Integrative Neuroscience, 2021
Translational Research Methods for Major Depressive Disorder. Neuromethods, , 2022
Optogenetics, the light-induced reversible control of specific neuronal ensembles, has revolution... more Optogenetics, the light-induced reversible control of specific neuronal ensembles, has revolutionized the circuit level analysis of depression, leading to the identification of relevant circuitries in several brain regions including—but not limited to—medial prefrontal cortex, ventral tegmental area, and nucleus accumbens in rodents. While it is still early to observe a direct translational utility, the continuous progress in optogenetic interrogation of specific neural populations has great potential for untangling the complex pathophysiology of depression.
J o u r n a l o f I n t e g r a t i v e N e u r o s c i e n c e , 2019
The γ-Aminobutyric acid type A receptors (GABA A Rs) are heteropentameric chloride channels respo... more The γ-Aminobutyric acid type A receptors (GABA A Rs) are heteropentameric chloride channels responsible for primary inhibition in the mammalian brain. Studies have shown the expression of recombinant GABA A R subunits tagged with the green fluorescent protein (GFP), a 26.9 kDa protein that exhibits bright green fluorescence when exposed to light in the blue to ultraviolet range. This allows the formation of recombinant proteins essential for the development of relevant in-vitro and in-vivo method-ologies. Among the GABA A R subunits, the δ subunit was never tagged in its cytoplasmic domain, an evolutionary conserved domain found in between the third and the fourth transmembrane domains. In this study, first, we have cloned the mouse cDNAs encoding for the δ, α1, β2 subunits of GABA A Rs, and then developed two fusion proteins of δ subunit each tagged with the GFP variant, EGFP (enhanced GFP) at unique sites in the cytoplasmic domain. The recombinant proteins were expressed alone or in combination with α1 and/or β2 subunits in neurob-lastoma 2a cells. Live cell confocal microscopy indicated that the cytoplasmically tagged δ subunits were targeted to the cell membrane when expressed in the presence of α1 and β2 subunits in neuroblastoma 2a cells. However, this was not observed when they were expressed alone or only with α1 or β2 subunits in the same cell line. These results confirm the general oligomerization and targeting pattern of GABA A R subtypes described in the other in-vitro studies in the literature. Thus, our results suggest that the EGFP tagging in the ctoplasmic domain did not interfere with the oligomerization and cell surface expression of recombinant δ subunits. To our knowledge, this is the first study showing the generation, expression and preliminary analysis of the δ-GABA A Rs tagged in the cytoplasmic domain of the δ subunit which can be further elaborated to probe intracellular protein interactions of GABA A Rs via the δ subunit.
Advances in experimental medicine and biology, 2021
The research of depression genetics has been occupied by historical candidate genes which were te... more The research of depression genetics has been occupied by historical candidate genes which were tested by candidate gene association studies. However, these studies were mostly not replicable. Thus, genetics of depression have remained elusive for a long time. As research moves from candidate gene association studies to GWAS, the hypothesis-free non-candidate gene association studies in genome-wide level, this trend will likely change. Despite the fact that the earlier GWAS of depression were not successful, the recent GWAS suggest robust findings for depression genetics. These altogether will catalyze a new wave of multidisciplinary research to pin down the neurobiology of depression.
CLEAN Soil Air Water, 2022
Antidepressants accumulate in the aquatic environment due to human wastes. Harmful effects of the... more Antidepressants accumulate in the aquatic environment due to human wastes. Harmful effects of these antidepressants on the non-target species will likely increase in the future, a problem that requires urgent attention. To contribute, we explored the possibility of microbial fuel cells (MFCs), an environmentally benign energy source to eliminate antidepressants introduced with human urine while producing electricity as an added value. Human urine containing selective serotonin reuptake inhibitors (paroxetine) and serotonin-norepinephrine reuptake inhibitors (venlafaxine, O-desmethylvenlafaxine (ODV)) were used as substrates in MFCs. Electricity production by the MFCs was monitored while simultaneous drug degradation was analyzed using liquid chromatography-tandem mass spectrometry. When the human urine samples containing drugs (10 or 50 ng drug/mL) were treated in MFCs, electricity production decreased in response to increasing drug concentrations. Maximum momentary electricity production was 188 mV. Upon addition of drugs-containing urine, chemical oxygen demand removal capacity of MFCs decreased from 54 to 37%. Mass spectrometry results showed that drugs were degraded at a rate of 10 ng/mL per hour for paroxetine, 11 ng/mL per hour for venlafaxine and 16 ng/mL per hour for ODV, i.e., 94% of paroxetine, 66% of venlafaxine and 48% of ODV was cleared in 9 h of treatment. Thus, it could be stated that MFC exhibits great potential in elimination of paroxetine, venlafaxine and ODV from wastewater. Our results will help to develop sustainable strategies to combat antidepressant pollution.
This article is protected by copyright. All rights reserved
IFMBE Proceedings, 2021
Chemical methods are commonly used for the induction of Escherichia coli (E. coli) competency to ... more Chemical methods are commonly used for the induction of Escherichia coli (E. coli) competency to allow transformation mediated by heat shock, an essential procedure for gene cloning. Being the most labor and resource efficient chemical method, the 'calcium chloride' (CaCl 2) method involves a brief heat shock of bacteria in the presence of Ca 2+ ions. Several optimizations were made on this original protocol but the effect of vibration or rotational shaking (revolution per minute) accompanied by the heat shock has not been studied. This paper reports the effect of shaking during or after the heat shock of competent DH5-Alpha strain of E. coli, induced by CaCl 2. Our results show that shaking during heat shock does not have any positive impact on the transformation efficiency. On the other hand, after the heat shock, 180 rpm shaking at 37°C for 1 h has increased transformation efficiency significantly (P < 0.05). Thus, a post-heat shock incubation with a rotational shaking attains higher yield of transformed cells affecting overall efficiency of transformation of E. coli DH5-Alpha.
Journal of Integrative Neuroscience, 2014
GABA A receptors (GABA A Rs) are hetero-pentameric chloride channels and the primary sites for fa... more GABA A receptors (GABA A Rs) are hetero-pentameric chloride channels and the primary sites for fast synaptic inhibition. We have expressed recombinant 2 and subunits of GABA A Rs in cultured hippocampal neurons to analyze the membrane targeting of synaptic and extrasynaptic GABA A Rs, a phenomenon not well understood. Our data demonstrate that the synaptic targeting of 2-containing GABA A Rs (2-GABA A Rs) does not depend on the cytoplasmic loop of 2 subunit, in parallel with previous¯ndings, showing that the synaptic localization of 2-GABA A Rs requires the TM4 domain of 2 rather than the large cytoplasmic loop. On the other hand, we showed here that the extrasynaptic targeting of the-containing GABA A Rs (-GABA A Rs) depends on the cytoplasmic loop of subunit via an active or a passive mechanism. We also show that the amino acid sequences of loop is highly conserved across the whole span of vertebrate evolution suggesting an active role of loop in extrasynaptic targeting of corresponding receptor subtypes.
International Journal of Molecular Sciences, 2018
Schizophrenia (SZ) is a heritable brain disease originating from a complex interaction of genetic... more Schizophrenia (SZ) is a heritable brain disease originating from a complex interaction of genetic and environmental factors. The genes underpinning the neurobiology of SZ are largely unknown but recent data suggest strong evidence for genetic variations, such as single nucleotide polymorphisms, making the brain vulnerable to the risk of SZ. Structural and functional brain mapping of these genetic variations are essential for the development of agents and tools for better diagnosis, treatment and prevention of SZ. Addressing this, neuroimaging methods in combination with genetic analysis have been increasingly used for almost 20 years. So-called imaging genetics, the opportunities of this approach along with its limitations for SZ research will be outlined in this invited paper. While the problems such as reproducibility, genetic effect size, specificity and sensitivity exist, opportunities such as multivariate analysis, development of multisite consortia for large-scale data collection, emergence of non-candidate gene (hypothesis-free) approach of neuroimaging genetics are likely to contribute to a rapid progress for gene discovery besides to gene validation studies that are related to SZ.
GABA(A) receptors (GABA(A)Rs) are hetero-pentameric chloride channels and the primary sites for f... more GABA(A) receptors (GABA(A)Rs) are hetero-pentameric chloride channels and the primary sites for fast synaptic inhibition. We have expressed recombinant γ2 and δ subunits of GABA(A)Rs in cultured hippocampal neurons to analyze the membrane targeting of synaptic and extra-synaptic GABA(A)Rs, a phenomenon not well understood. Our data demonstrate that the synaptic targeting of γ2-containing GABA(A)Rs (γ2-GABA(A)Rs) does not depend on the cytoplasmic loop of γ2 subunit, in parallel with previous findings, showing that the synaptic localization of γ2-GABA(A)Rs requires the TM4 domain of γ2 rather than the large cytoplasmic loop. On the other hand, we showed here that the extrasynaptic targeting of the δ-containing GABA(A)Rs (δ-GABA(A)Rs) depends on the cytoplasmic loop of δ subunit via an active or a passive mechanism. We also show that the amino acid sequences of δ loop is highly conserved across the whole span of vertebrate evolution suggesting an active role of δ loop in extra-synaptic targeting of corresponding receptor subtypes.
Frontiers in Psychiatry. Advances in Experimental Medicine and Biology, 2019
This chapter presents an overview of accumulating neuroimaging data with emphasis on translationa... more This chapter presents an overview of accumulating neuroimaging data with emphasis on translational potential. The subject will be described in the context of three disease states, i.e., schizophrenia, bipolar disorder, and major depressive disorder, and for three clinical goals, i.e., disease risk assessment, subtyping, and treatment decision.
Prog Neuropsychopharmacol Biol Psychiatry. , 2018
Imaging genetics is a research methodology studying the effect of genetic variation on brain stru... more Imaging genetics is a research methodology studying the effect of genetic variation on brain structure, function, behavior, and risk for psychopathology. Since the early 2000s, imaging genetics has been increasingly used in the research of schizophrenia (SZ). SZ is a severe mental disorder with no precise knowledge of its underlying neurobiology, however, new genetic and neurobiological data generate a climate for new avenues. The accumulating data of genome wide association studies (GWAS) continuously decode SZ risk genes. Global neuroi-maging consortia produce collections of brain phenotypes from tens of thousands of people. In this context, imaging genetics will be strategically important both for the validation and discovery of SZ related findings. Thus, the study of GWAS supported risk variants as candidate genes to validate by neuroimaging is one trend. The study of epigenetic differences in relation to variations of brain phenotypes and the study of large scale multivariate analysis of genome wide and brain wide associations are other trends. While these studies hold a big potential for understanding the neurobiology of SZ, the problem of reproducibility appears as a major challenge, which requires standardizations in study designs and compensations of methodological limitations such as sensitivity and specificity. On the other hand, advancements of neuroimaging, optical and electron microscopy along with the use of genetically encoded fluorescent probes and robust statistical approaches will not only catalyze integrative methodologies but also will help better design the imaging genetics studies. In this invited paper, I will discuss the current perspective of imaging genetics and emerging opportunities of SZ research.
Adv Exp Med Biol.
This chapter presents an overview of accumulating neuroimaging data with emphasis on translationa... more This chapter presents an overview of accumulating neuroimaging data with emphasis on translational potential. The subject will be described in the context of three disease states, i.e., schizophrenia, bipolar disorder, and major depressive disorder, and for three clinical goals, i.e., disease risk assessment, subtyping, and treatment decision.
This chapter primarily focuses on the progress in depression precision medicine with specific emp... more This chapter primarily focuses on the progress in depression precision medicine with specific emphasis on the integrative approaches that include artificial intelligence and other data, tools, and technologies. After the description of the concept of precision medicine and a comparative introduction to depression precision medicine with cancer and epilepsy, new avenues of depression precision medicine derived from integrated artificial intelligence and other sources will be presented. Additionally, less advanced areas, such as comorbidity between depression and cancer, will be examined.
International Journal of Neuroscience , 2024
The γ-Aminobutyric acid type A receptors (GABAARs) function as heteropentameric chloride channels... more The γ-Aminobutyric acid type A receptors (GABAARs) function as heteropentameric chloride channels, crucial for primary inhibition in the mammalian brain. The GABRD gene encodes the δ subunit of GABAARs and is implicated in various disorders, including schizophrenia, epilepsy, and insomnia. However, the increasing number of variants of unknown clinical significance (VUS) within the GABRD gene poses a challenge to precision medicine and our understanding of relevant pathophysiology. The primary aim of this study is to address this challenge by predicting the most pathogenic GABRD VUS. Employing a combination of in silico algorithms, the study analyzes 82 GABRD gene VUS sourced from the ClinVar database. Initially, separate algorithms based on sequence homology were used to assess this VUS set. Subsequently, consensus variants predicted as pathogenic underwent further evaluation through a web server utilizing the algorithm based on structural homology. The resulting 11 VUS were then validated using in silico tools, assessing variant effects based on genetic and molecular data. This led to the determination of pathogenicity probability considering disease association and protein stability due to amino acid substitutions. The identification of specific variants (L111R, R114C, D123N, G150S, L243P) in the coding region of the GABRD gene, predicted as deleterious by multiple algorithms, suggests structural or functional consequences for pathogenicity. These evolutionarily conserved variants, mapped onto the extracellular domain of the δ subunit, were linked to idiopathic generalized epilepsy. These findings guide wet-lab experimentation and contribute to validating clinically significant genetic variants in the GABRD gene crucial for personalized and pharmacogenetic interventions.
Journal of Community Genetics, Dec 21, 2023
Wikipedia, the open crowdsourced encyclopedia that anyone can edit, ranks among the top ten most-... more Wikipedia, the open crowdsourced encyclopedia that anyone can edit, ranks among the top ten most-visited websites globally. Its integration into university curriculum as an innovative educational tool is a slowly growing trend; however, many higher education institutions have yet to fully grasp its potential. In response, a specific optional module for Wikipedia editing, designed for the selected undergraduate science courses at the School of Advanced Studies, Russia, was implemented as an optional extra credit service-learning activity, a teaching methodology combining meaningful service to the community with curriculum-based learning. Students who chose to participate and those who preferred not to participate in the activity were invited to participate in a research project to explore their perspectives and experiences. In total, five sessions of focus group discussions were conducted with participants (12 females and 2 males) in one set and non-participants (5 females and 4 males) in another to identify students' perspectives on themes such as their interest in science, reasons for their choices, and their expectations before the activity while post-experience focus group discussions were used to identify the perspectives of participant students on themes, encompassing contribution of the service-learning activity, acquisition of new skills, and the development of prosocial behaviors. Students' opinions on integrating social responsibility topics into the curriculum were also explored. The results extracted from these focus group discussions, analyzed through consensual coding, revealed factors promoting student participation, like interest in the subject, novelty of the activity, and grade improvement opportunities, as well as factors deterring participation, such as concerns about academic benefits, workload, and time constraints. Furthermore, the results demonstrated that Wikipedia editing serves as a novel teaching methodology, promoting student learning and development in digital literacy and information literacy, which are among the twenty-first-century skills. Interestingly, at the same time, not all students could address the value of contributing to open, crowdsourced knowledge for public service or interpret this activity as an academic service-learning. These suggest that Wikipedia editing is an innovative teaching approach, fostering students' learning and development while also indicating its potential to enhance students' understanding of responsible citizenship and public service in the digital age.
Heliyon, 2023
Critical for brain development, neurodevelopmental and network disorders, the GABRA1 gene encodes... more Critical for brain development, neurodevelopmental and network disorders, the GABRA1 gene encodes for the α1 subunit, an abundantly and developmentally expressed subunit of heteropentameric gamma-aminobutyric acid A receptors (GABAARs) mediating primary inhibition in the brain. Mutations of the GABAAR subunit genes including GABRA1 gene are associated with epilepsy, a group of syndromes, characterized by unprovoked seizures and diagnosed by integrative approach, that involves genetic testing. Despite the diagnostic use of genetic testing, a large fraction of the GABAAR subunit gene variants including the variants of GABRA1 gene is not known in terms of their molecular consequence, a challenge for precision and personalized medicine. Addressing this, one hundred thirty-seven GABRA1 gene variants of unknown clinical significance have been extracted from the ClinVar database and computationally analyzed for pathogenicity. Eight variants (L49H, P59L, W97R, D99G, G152S, V270G, T294R, P305L) are predicted as pathogenic and mapped to the α1 subunit's extracellular domain (ECD), transmembrane domains (TMDs) and extracellular linker. This is followed by the integration with relevant data for cellular pathology and severity of the epilepsy syndromes retrieved from the literature. Our results suggest that the pathogenic variants in the ECD of GABRA1 (L49H, P59L, W97R, D99G, G152S) will probably manifest decreased surface expression and reduced current with mild epilepsy phenotypes while V270G, T294R in the TMDs and P305L in the linker between the second and the third TMDs will likely cause reduced cell current with severe epilepsy phenotypes. The results presented in this study provides insights for clinical genetics and wet lab experimentation.
Frontiers in Psychiatry Schizophrenia, 2023
J Neuropsychiatry Clin Neurosci., 2015
The majority of neuropsychiatric disorders show a strong degree of heritability, yet little is kn... more The majority of neuropsychiatric disorders show a strong degree of heritability, yet little is known about molecular factors involved in the pathophysiology of diseases like schizophrenia. After a brief historical introduction into the current understanding of neuropsychiatric disorders, the aim of this study is to discuss imaging genetics as a strategy to explore the pathophysiology of neuropsychiatric disorders. The candidate gene approach of imaging genetics is used for validation/ replication studies of genes, whereas the hypothesis-free, noncandidate gene approach appears to be a tool for gene discovery. Besides, integration of environmental factors into neuroimaging begins to converge on neuroimaging studies of genetic variation. In the light of data from other avenues such as animal experimentation, these developments show a model of interdisciplinary research, which may lead to identifying markers for neuropsychiatric disorders.
Journal of Integrative Neuroscience, 2021
Translational Research Methods for Major Depressive Disorder. Neuromethods, , 2022
Optogenetics, the light-induced reversible control of specific neuronal ensembles, has revolution... more Optogenetics, the light-induced reversible control of specific neuronal ensembles, has revolutionized the circuit level analysis of depression, leading to the identification of relevant circuitries in several brain regions including—but not limited to—medial prefrontal cortex, ventral tegmental area, and nucleus accumbens in rodents. While it is still early to observe a direct translational utility, the continuous progress in optogenetic interrogation of specific neural populations has great potential for untangling the complex pathophysiology of depression.
J o u r n a l o f I n t e g r a t i v e N e u r o s c i e n c e , 2019
The γ-Aminobutyric acid type A receptors (GABA A Rs) are heteropentameric chloride channels respo... more The γ-Aminobutyric acid type A receptors (GABA A Rs) are heteropentameric chloride channels responsible for primary inhibition in the mammalian brain. Studies have shown the expression of recombinant GABA A R subunits tagged with the green fluorescent protein (GFP), a 26.9 kDa protein that exhibits bright green fluorescence when exposed to light in the blue to ultraviolet range. This allows the formation of recombinant proteins essential for the development of relevant in-vitro and in-vivo method-ologies. Among the GABA A R subunits, the δ subunit was never tagged in its cytoplasmic domain, an evolutionary conserved domain found in between the third and the fourth transmembrane domains. In this study, first, we have cloned the mouse cDNAs encoding for the δ, α1, β2 subunits of GABA A Rs, and then developed two fusion proteins of δ subunit each tagged with the GFP variant, EGFP (enhanced GFP) at unique sites in the cytoplasmic domain. The recombinant proteins were expressed alone or in combination with α1 and/or β2 subunits in neurob-lastoma 2a cells. Live cell confocal microscopy indicated that the cytoplasmically tagged δ subunits were targeted to the cell membrane when expressed in the presence of α1 and β2 subunits in neuroblastoma 2a cells. However, this was not observed when they were expressed alone or only with α1 or β2 subunits in the same cell line. These results confirm the general oligomerization and targeting pattern of GABA A R subtypes described in the other in-vitro studies in the literature. Thus, our results suggest that the EGFP tagging in the ctoplasmic domain did not interfere with the oligomerization and cell surface expression of recombinant δ subunits. To our knowledge, this is the first study showing the generation, expression and preliminary analysis of the δ-GABA A Rs tagged in the cytoplasmic domain of the δ subunit which can be further elaborated to probe intracellular protein interactions of GABA A Rs via the δ subunit.
Advances in experimental medicine and biology, 2021
The research of depression genetics has been occupied by historical candidate genes which were te... more The research of depression genetics has been occupied by historical candidate genes which were tested by candidate gene association studies. However, these studies were mostly not replicable. Thus, genetics of depression have remained elusive for a long time. As research moves from candidate gene association studies to GWAS, the hypothesis-free non-candidate gene association studies in genome-wide level, this trend will likely change. Despite the fact that the earlier GWAS of depression were not successful, the recent GWAS suggest robust findings for depression genetics. These altogether will catalyze a new wave of multidisciplinary research to pin down the neurobiology of depression.
CLEAN Soil Air Water, 2022
Antidepressants accumulate in the aquatic environment due to human wastes. Harmful effects of the... more Antidepressants accumulate in the aquatic environment due to human wastes. Harmful effects of these antidepressants on the non-target species will likely increase in the future, a problem that requires urgent attention. To contribute, we explored the possibility of microbial fuel cells (MFCs), an environmentally benign energy source to eliminate antidepressants introduced with human urine while producing electricity as an added value. Human urine containing selective serotonin reuptake inhibitors (paroxetine) and serotonin-norepinephrine reuptake inhibitors (venlafaxine, O-desmethylvenlafaxine (ODV)) were used as substrates in MFCs. Electricity production by the MFCs was monitored while simultaneous drug degradation was analyzed using liquid chromatography-tandem mass spectrometry. When the human urine samples containing drugs (10 or 50 ng drug/mL) were treated in MFCs, electricity production decreased in response to increasing drug concentrations. Maximum momentary electricity production was 188 mV. Upon addition of drugs-containing urine, chemical oxygen demand removal capacity of MFCs decreased from 54 to 37%. Mass spectrometry results showed that drugs were degraded at a rate of 10 ng/mL per hour for paroxetine, 11 ng/mL per hour for venlafaxine and 16 ng/mL per hour for ODV, i.e., 94% of paroxetine, 66% of venlafaxine and 48% of ODV was cleared in 9 h of treatment. Thus, it could be stated that MFC exhibits great potential in elimination of paroxetine, venlafaxine and ODV from wastewater. Our results will help to develop sustainable strategies to combat antidepressant pollution.
This article is protected by copyright. All rights reserved
IFMBE Proceedings, 2021
Chemical methods are commonly used for the induction of Escherichia coli (E. coli) competency to ... more Chemical methods are commonly used for the induction of Escherichia coli (E. coli) competency to allow transformation mediated by heat shock, an essential procedure for gene cloning. Being the most labor and resource efficient chemical method, the 'calcium chloride' (CaCl 2) method involves a brief heat shock of bacteria in the presence of Ca 2+ ions. Several optimizations were made on this original protocol but the effect of vibration or rotational shaking (revolution per minute) accompanied by the heat shock has not been studied. This paper reports the effect of shaking during or after the heat shock of competent DH5-Alpha strain of E. coli, induced by CaCl 2. Our results show that shaking during heat shock does not have any positive impact on the transformation efficiency. On the other hand, after the heat shock, 180 rpm shaking at 37°C for 1 h has increased transformation efficiency significantly (P < 0.05). Thus, a post-heat shock incubation with a rotational shaking attains higher yield of transformed cells affecting overall efficiency of transformation of E. coli DH5-Alpha.
Journal of Integrative Neuroscience, 2014
GABA A receptors (GABA A Rs) are hetero-pentameric chloride channels and the primary sites for fa... more GABA A receptors (GABA A Rs) are hetero-pentameric chloride channels and the primary sites for fast synaptic inhibition. We have expressed recombinant 2 and subunits of GABA A Rs in cultured hippocampal neurons to analyze the membrane targeting of synaptic and extrasynaptic GABA A Rs, a phenomenon not well understood. Our data demonstrate that the synaptic targeting of 2-containing GABA A Rs (2-GABA A Rs) does not depend on the cytoplasmic loop of 2 subunit, in parallel with previous¯ndings, showing that the synaptic localization of 2-GABA A Rs requires the TM4 domain of 2 rather than the large cytoplasmic loop. On the other hand, we showed here that the extrasynaptic targeting of the-containing GABA A Rs (-GABA A Rs) depends on the cytoplasmic loop of subunit via an active or a passive mechanism. We also show that the amino acid sequences of loop is highly conserved across the whole span of vertebrate evolution suggesting an active role of loop in extrasynaptic targeting of corresponding receptor subtypes.
International Journal of Molecular Sciences, 2018
Schizophrenia (SZ) is a heritable brain disease originating from a complex interaction of genetic... more Schizophrenia (SZ) is a heritable brain disease originating from a complex interaction of genetic and environmental factors. The genes underpinning the neurobiology of SZ are largely unknown but recent data suggest strong evidence for genetic variations, such as single nucleotide polymorphisms, making the brain vulnerable to the risk of SZ. Structural and functional brain mapping of these genetic variations are essential for the development of agents and tools for better diagnosis, treatment and prevention of SZ. Addressing this, neuroimaging methods in combination with genetic analysis have been increasingly used for almost 20 years. So-called imaging genetics, the opportunities of this approach along with its limitations for SZ research will be outlined in this invited paper. While the problems such as reproducibility, genetic effect size, specificity and sensitivity exist, opportunities such as multivariate analysis, development of multisite consortia for large-scale data collection, emergence of non-candidate gene (hypothesis-free) approach of neuroimaging genetics are likely to contribute to a rapid progress for gene discovery besides to gene validation studies that are related to SZ.
GABA(A) receptors (GABA(A)Rs) are hetero-pentameric chloride channels and the primary sites for f... more GABA(A) receptors (GABA(A)Rs) are hetero-pentameric chloride channels and the primary sites for fast synaptic inhibition. We have expressed recombinant γ2 and δ subunits of GABA(A)Rs in cultured hippocampal neurons to analyze the membrane targeting of synaptic and extra-synaptic GABA(A)Rs, a phenomenon not well understood. Our data demonstrate that the synaptic targeting of γ2-containing GABA(A)Rs (γ2-GABA(A)Rs) does not depend on the cytoplasmic loop of γ2 subunit, in parallel with previous findings, showing that the synaptic localization of γ2-GABA(A)Rs requires the TM4 domain of γ2 rather than the large cytoplasmic loop. On the other hand, we showed here that the extrasynaptic targeting of the δ-containing GABA(A)Rs (δ-GABA(A)Rs) depends on the cytoplasmic loop of δ subunit via an active or a passive mechanism. We also show that the amino acid sequences of δ loop is highly conserved across the whole span of vertebrate evolution suggesting an active role of δ loop in extra-synaptic targeting of corresponding receptor subtypes.
Frontiers in Psychiatry. Advances in Experimental Medicine and Biology, 2019
This chapter presents an overview of accumulating neuroimaging data with emphasis on translationa... more This chapter presents an overview of accumulating neuroimaging data with emphasis on translational potential. The subject will be described in the context of three disease states, i.e., schizophrenia, bipolar disorder, and major depressive disorder, and for three clinical goals, i.e., disease risk assessment, subtyping, and treatment decision.
Prog Neuropsychopharmacol Biol Psychiatry. , 2018
Imaging genetics is a research methodology studying the effect of genetic variation on brain stru... more Imaging genetics is a research methodology studying the effect of genetic variation on brain structure, function, behavior, and risk for psychopathology. Since the early 2000s, imaging genetics has been increasingly used in the research of schizophrenia (SZ). SZ is a severe mental disorder with no precise knowledge of its underlying neurobiology, however, new genetic and neurobiological data generate a climate for new avenues. The accumulating data of genome wide association studies (GWAS) continuously decode SZ risk genes. Global neuroi-maging consortia produce collections of brain phenotypes from tens of thousands of people. In this context, imaging genetics will be strategically important both for the validation and discovery of SZ related findings. Thus, the study of GWAS supported risk variants as candidate genes to validate by neuroimaging is one trend. The study of epigenetic differences in relation to variations of brain phenotypes and the study of large scale multivariate analysis of genome wide and brain wide associations are other trends. While these studies hold a big potential for understanding the neurobiology of SZ, the problem of reproducibility appears as a major challenge, which requires standardizations in study designs and compensations of methodological limitations such as sensitivity and specificity. On the other hand, advancements of neuroimaging, optical and electron microscopy along with the use of genetically encoded fluorescent probes and robust statistical approaches will not only catalyze integrative methodologies but also will help better design the imaging genetics studies. In this invited paper, I will discuss the current perspective of imaging genetics and emerging opportunities of SZ research.
Adv Exp Med Biol.
This chapter presents an overview of accumulating neuroimaging data with emphasis on translationa... more This chapter presents an overview of accumulating neuroimaging data with emphasis on translational potential. The subject will be described in the context of three disease states, i.e., schizophrenia, bipolar disorder, and major depressive disorder, and for three clinical goals, i.e., disease risk assessment, subtyping, and treatment decision.
Diagnosis of depression is based on clinical parameters which may be clinically reliable but lack... more Diagnosis of depression is based on clinical parameters which may be clinically reliable but lack biological validity leading to problems of differential diagnosis or treatment. Thus, there is a need for biologically relevant criteria for better diagnosis and treatment of depression. Accumulating neuroimaging studies suggest potential biomarkers such as metabolic activity and structural or functional connectivity within the limbic-cortical circuitries that may serve for this purpose. However, employment of such neuroimaging measures as biomarkers in a clinical setting still requires further investigation. While there are some converging results, a major challenge in the field is the inconsistencies across multiple studies. This is probably due to the heterogeneous patient groups used in these studies, the variety of tasks or methodologies used during neuroimaging, and the different types of treatments or problems associated with poor data quality, which require better statistical approaches. As these problems are likely addressed, neuroimaging biomarkers can be established in the future to facilitate significant improvements in the diagnosis and treatment of depression.
Journal of Community Genetics, Dec 20, 2023
Wikipedia, the open crowdsourced encyclopedia that anyone can edit, ranks among the top ten most-... more Wikipedia, the open crowdsourced encyclopedia that anyone can edit, ranks among the top ten most-visited websites globally. Its integration into university curriculum as an innovative educational tool is a slowly growing trend; however, many higher education institutions have yet to fully grasp its potential. In response, a specific optional module for Wikipedia editing, designed for the selected undergraduate science courses at the School of Advanced Studies, Russia, was implemented as an optional extra credit service-learning activity, a teaching methodology combining meaningful service to the community with curriculum-based learning. Students who chose to participate and those who preferred not to participate in the activity were invited to participate in a research project to explore their perspectives and experiences. In total, five sessions of focus group discussions were conducted with participants (12 females and 2 males) in one set and non-participants (5 females and 4 males) in another to identify students' perspectives on themes such as their interest in science, reasons for their choices, and their expectations before the activity while post-experience focus group discussions were used to identify the perspectives of participant students on themes, encompassing contribution of the service-learning activity, acquisition of new skills, and the development of prosocial behaviors. Students' opinions on integrating social responsibility topics into the curriculum were also explored. The results extracted from these focus group discussions, analyzed through consensual coding, revealed factors promoting student participation, like interest in the subject, novelty of the activity, and grade improvement opportunities, as well as factors deterring participation, such as concerns about academic benefits, workload, and time constraints. Furthermore, the results demonstrated that Wikipedia editing serves as a novel teaching methodology, promoting student learning and development in digital literacy and information literacy, which are among the twenty-first-century skills. Interestingly, at the same time, not all students could address the value of contributing to open, crowdsourced knowledge for public service or interpret this activity as an academic service-learning. These suggest that Wikipedia editing is an innovative teaching approach, fostering students' learning and development while also indicating its potential to enhance students' understanding of responsible citizenship and public service in the digital age.
Heliyon
Critical for brain development, neurodevelopmental and network disorders, the GABRA1 gene encodes... more Critical for brain development, neurodevelopmental and network disorders, the GABRA1 gene encodes for the α1 subunit, an abundantly and developmentally expressed subunit of heteropentameric gamma-aminobutyric acid A receptors (GABAARs) mediating primary inhibition in the brain. Mutations of the GABAAR subunit genes including GABRA1 gene are associated with epilepsy, a group of syndromes, characterized by unprovoked seizures and diagnosed by integrative approach, that involves genetic testing. Despite the diagnostic use of genetic testing, a large fraction of the GABAAR subunit gene variants including the variants of GABRA1 gene is not known in terms of their molecular consequence, a challenge for precision and personalized medicine. Addressing this, one hundred thirty-seven GABRA1 gene variants of unknown clinical significance have been extracted from the ClinVar database and computationally analyzed for pathogenicity. Eight variants (L49H, P59L, W97R, D99G, G152S, V270G, T294R, P305L) are predicted as pathogenic and mapped to the α1 subunit's extracellular domain (ECD), transmembrane domains (TMDs) and extracellular linker. This is followed by the integration with relevant data for cellular pathology and severity of the epilepsy syndromes retrieved from the literature. Our results suggest that the pathogenic variants in the ECD of GABRA1 (L49H, P59L, W97R, D99G, G152S) will probably manifest decreased surface expression and reduced current with mild epilepsy phenotypes while V270G, T294R in the TMDs and P305L in the linker between the second and the third TMDs will likely cause reduced cell current with severe epilepsy phenotypes. The results presented in this study provides insights for clinical genetics and wet lab experimentation.
Frontiers in Psychiatry, 2023
Neuromethods, 2022
Optogenetics, the light-induced reversible control of specific neuronal ensembles, has revolution... more Optogenetics, the light-induced reversible control of specific neuronal ensembles, has revolutionized the circuit level analysis of depression, leading to the identification of relevant circuitries in several brain regions including—but not limited to—medial prefrontal cortex, ventral tegmental area, and nucleus accumbens in rodents. While it is still early to observe a direct translational utility, the continuous progress in optogenetic interrogation of specific neural populations has great potential for untangling the complex pathophysiology of depression.
CLEAN – Soil, Air, Water, 2022
Antidepressants accumulate in the aquatic environment due to human wastes. Harmful effects of the... more Antidepressants accumulate in the aquatic environment due to human wastes. Harmful effects of these antidepressants on the non-target species will likely increase in the future, a problem that requires urgent attention. To contribute, we explored the possibility of microbial fuel cells (MFCs), an environmentally benign energy source to eliminate antidepressants introduced with human urine while producing electricity as an added value. Human urine containing selective serotonin reuptake inhibitors (paroxetine) and serotonin-norepinephrine reuptake inhibitors (venlafaxine, O-desmethylvenlafaxine (ODV)) were used as substrates in MFCs. Electricity production by the MFCs was monitored while simultaneous drug degradation was analyzed using liquid chromatography-tandem mass spectrometry. When the human urine samples containing drugs (10 or 50 ng drug/mL) were treated in MFCs, electricity production decreased in response to increasing drug concentrations. Maximum momentary electricity production was 188 mV. Upon addition of drugs-containing urine, chemical oxygen demand removal capacity of MFCs decreased from 54 to 37%. Mass spectrometry results showed that drugs were degraded at a rate of 10 ng/mL per hour for paroxetine, 11 ng/mL per hour for venlafaxine and 16 ng/mL per hour for ODV, i.e., 94% of paroxetine, 66% of venlafaxine and 48% of ODV was cleared in 9 h of treatment. Thus, it could be stated that MFC exhibits great potential in elimination of paroxetine, venlafaxine and ODV from wastewater. Our results will help to develop sustainable strategies to combat antidepressant pollution. This article is protected by copyright. All rights reserved
Journal of integrative neuroscience, 2021
γ-Aminobutyric acid type A receptors (GABAARs) are GABA gated heteropentameric chloride channels ... more γ-Aminobutyric acid type A receptors (GABAARs) are GABA gated heteropentameric chloride channels responsible for the adult brain's primary inhibition. In specific brain cells, such as in the hippocampus, one of the subtypes of GABAARs, the δ subunit containing GABAARs (δ-GABAARs), is predominantly expressed and located in extrasynaptic or perisynaptic positions. δ-GABAARs mediate a slow constant inhibitory current called tonic inhibition. While δ-GABAARs and tonic inhibition is critical for the excitability of single neurons, accumulating data suggest that the function of δ-GABAARs are broader and includes an integrative role in the network oscillations. While these open new horizons on the neurobiology of δ-GABAARs, the complexity continues to challenge the analysis of GABAARs and their subtypes. This review will summarize the current knowledge of molecular, cellular and physiological characteristics of δ-GABAARs during health and disease.
IFMBE Proceedings, 2021
Chemical methods are commonly used for the induction of Escherichia coli (E. coli) competency to ... more Chemical methods are commonly used for the induction of Escherichia coli (E. coli) competency to allow transformation mediated by heat shock, an essential procedure for gene cloning. Being the most labor and resource efficient chemical method, the ‘calcium chloride’ (CaCl2) method involves a brief heat shock of bacteria in the presence of Ca2+ ions. Several optimizations were made on this original protocol but the effect of vibration or rotational shaking (revolution per minute) accompanied by the heat shock has not been studied. This paper reports the effect of shaking during or after the heat shock of competent DH5-Alpha strain of E. coli, induced by CaCl2. Our results show that shaking during heat shock does not have any positive impact on the transformation efficiency. On the other hand, after the heat shock, 180 rpm shaking at 37 °C for 1 h has increased transformation efficiency significantly (P < 0.05).
Journal of Integrative Neuroscience, 2019
Understanding Depression, 2017
Diagnosis of depression is based on clinical parameters which may be clinically reliable but lack... more Diagnosis of depression is based on clinical parameters which may be clinically reliable but lack biological validity leading to problems of differential diagnosis or treatment. Thus, there is a need for biologically relevant criteria for better diagnosis and treatment of depression. Accumulating neuroimaging studies suggest potential biomarkers such as metabolic activity and structural or functional connectivity within the limbic-cortical circuitries that may serve for this purpose. However, employment of such neuroimaging measures as biomarkers in a clinical setting still requires further investigation. While there are some converging results, a major challenge in the field is the inconsistencies across multiple studies. This is probably due to the heterogeneous patient groups used in these studies, the variety of tasks or methodologies used during neuroimaging, and the different types of treatments or problems associated with poor data quality, which require better statistical approaches. As these problems are likely addressed, neuroimaging biomarkers can be established in the future to facilitate significant improvements in the diagnosis and treatment of depression.
International journal of molecular sciences, Jan 11, 2018
Schizophrenia (SZ) is a heritable brain disease originating from a complex interaction of genetic... more Schizophrenia (SZ) is a heritable brain disease originating from a complex interaction of genetic and environmental factors. The genes underpinning the neurobiology of SZ are largely unknown but recent data suggest strong evidence for genetic variations, such as single nucleotide polymorphisms, making the brain vulnerable to the risk of SZ. Structural and functional brain mapping of these genetic variations are essential for the development of agents and tools for better diagnosis, treatment and prevention of SZ. Addressing this, neuroimaging methods in combination with genetic analysis have been increasingly used for almost 20 years. So-called imaging genetics, the opportunities of this approach along with its limitations for SZ research will be outlined in this invited paper. While the problems such as reproducibility, genetic effect size, specificity and sensitivity exist, opportunities such as multivariate analysis, development of multisite consortia for large-scale data collect...
Frontiers in Psychiatry, 2019
This chapter presents an overview of accumulating neuroimaging data with emphasis on translationa... more This chapter presents an overview of accumulating neuroimaging data with emphasis on translational potential. The subject will be described in the context of three disease states, i.e., schizophrenia, bipolar disorder, and major depressive disorder, and for three clinical goals, i.e., disease risk assessment, subtyping, and treatment decision.
The Journal of neuropsychiatry and clinical neurosciences, Jan 9, 2015
The majority of neuropsychiatric disorders show a strong degree of heritability, yet little is kn... more The majority of neuropsychiatric disorders show a strong degree of heritability, yet little is known about molecular factors involved in the pathophysiology of diseases like schizophrenia. After a brief historical introduction into the current understanding of neuropsychiatric disorders, the aim of this study is to discuss imaging genetics as a strategy to explore the pathophysiology of neuropsychiatric disorders. The candidate gene approach of imaging genetics is used for validation/replication studies of genes, whereas the hypothesis-free, noncandidate gene approach appears to be a tool for gene discovery. Besides, integration of environmental factors into neuroimaging begins to converge on neuroimaging studies of genetic variation. In the light of data from other avenues such as animal experimentation, these developments show a model of interdisciplinary research, which may lead to identifying markers for neuropsychiatric disorders.
Major Depressive Disorder, 2021
GABA(A) receptors (GABA(A)Rs) are hetero-pentameric chloride channels and the primary sites for f... more GABA(A) receptors (GABA(A)Rs) are hetero-pentameric chloride channels and the primary sites for fast synaptic inhibition. We have expressed recombinant γ2 and δ subunits of GABA(A)Rs in cultured hippocampal neurons to analyze the membrane targeting of synaptic and extra-synaptic GABA(A)Rs, a phenomenon not well understood. Our data demonstrate that the synaptic targeting of γ2-containing GABA(A)Rs (γ2-GABA(A)Rs) does not depend on the cytoplasmic loop of γ2 subunit, in parallel with previous findings, showing that the synaptic localization of γ2-GABA(A)Rs requires the TM4 domain of γ2 rather than the large cytoplasmic loop. On the other hand, we showed here that the extrasynaptic targeting of the δ-containing GABA(A)Rs (δ-GABA(A)Rs) depends on the cytoplasmic loop of δ subunit via an active or a passive mechanism. We also show that the amino acid sequences of δ loop is highly conserved across the whole span of vertebrate evolution suggesting an active role of δ loop in extra-synapti...
Periodicals of Engineering and Natural Sciences (PEN)
The Journal of Neurobehavioral Sciences, 2014
The Journal of Neurobehavioral Sciences, 2015