Background: As with many chronic infections, the initiation and progression of periodontal diseas... more Background: As with many chronic infections, the initiation and progression of periodontal diseases are modified by local and systemic host conditions, or risk factors, that markedly affect the resistance of the host to infecting periodontal pathogens. There are large number of factors including genetic, environmental, and psychosocial which constitute a substantial risk in the development of periodontal destructive diseases. Aim: The aim of present study was to scrutinize the relationship between clinical depression, sleep quality and severity of periodontitis using clinical parameters and a depression and sleep quality rating scale. Materials and Methods: Hundred patients were enrolled in this case-control study, of which 50 patients diagnosed with chronic periodontitis were categorized into cases and 50 patients who were systemically and periodontally healthy were designated as controls. The periodontal parameters recorded included probing depth and simplified oral hygiene index (OHI-S). Depression was determined using Beck’s depression scale. Pittsburgh Sleep Quality Index (PSQI) was used for scrutinizing sleep quality. Results: Self‑reported scoring of depression and sleep quality by using Beck’s depression inventory and Pittsburgh Sleep Quality Index questionnaire has revealed that patients diagnosed with chronic periodontitis had an appreciable elevated score of depression and poor sleep quality than normal controls. Conclusion: Findings of this case-control study revealed a statistically significant relationship between depression, its associated oral health behavior, sleep deprivation experienced and severity of destructive periodontal diseases.
Journal of the Indian Dental Association, Aug 24, 2021
Introduction:Anemia of chronic disease is defined as anemia occurring in chronic infections, infl... more Introduction:Anemia of chronic disease is defined as anemia occurring in chronic infections, inflammatory conditions or neoplastic disorders that are not due to marrow deficiencies or other diseases, and occurring despite presence of adequate iron stores and vitamins. Methods: A total of 40 patients were selected for the study. Participants were divided into two groups viz group A (test group; n=20) with moderate to severe periodontitis and group B (control group; n=20) with periodontally healthy subjects. The patients chosen for the study had at least 30% or more of teeth having greater than or equal to 4 mm probing depth. Clinical parameters like gingival index (GI), Sulcus Bleeding Index (SBI), plaque index (PI),probing pocket depth (PD) and clinical attachment levels (CAL) were recorded for all the patients and blood parameters (hemoglobin and red blood cell count) were determined from peripheralblood samples. The results were analyzed statistically. Results: The mean values of hemoglobin (Hb) and red blood cell (RBC) count were significantly reduced in test group as compared to control group. Conclusion: A positive relationship was observed between the blood parameters viz. Hb, RBC count, and the severity of the chronic periodontal disease. Like other chronic conditions, periodontitis can tend towards anemia showing their association. Keywords: Anemia, Chronic Periodontitis, Hemoglobin (Hb), Red Blood Cell Count (RBC Count).
This is a critical introduction to the special issue on the fundamental rights of states. Whether... more This is a critical introduction to the special issue on the fundamental rights of states. Whether such rights exist, the bounds of their existence, or whether they ought to be striven towards are questions of considerable import in the wake of the Greek sovereign debt crisis, or even given the ongoing Palestinian struggle for permanent sovereignty over their natural resources. I briefly outline how we might consider the question: is there any progressive political value in buttressing the state and its autonomy, through the doctrine of fundamental rights, in today's neoliberal world? First, I examine how we may progressively look at fundamental rights-as doctrine, narrative, memory or discourse. Second, I question the extent to which it is useful to see competing subjectivities, ie the maligned state against technocratic institutions, in a time where neoliberal logic has come to structure the workings of the state. It becomes quickly apparent that the discourse of fundamental rights may be used to both resist neoliberalism and enable it.
C-terminal Binding Proteins (CtBP) 1 and 2 constitute a family of oncogenic transcriptional co-re... more C-terminal Binding Proteins (CtBP) 1 and 2 constitute a family of oncogenic transcriptional co-regulators overexpressed in tumor tissues that are associated with worse prognostic outcome and aggressive tumor characteristics in multiple cancer types. Specifically, CtBP has been found to repress expression of genes responsible for apoptosis and EMT (eg. BIK and CDH1) and promote expression of genes that partake in the migration of cancer cells and those that are responsible for enhanced drug resistance (eg. TIAM1 and MDR1). CtBP2 is also critically required for colon cancer stem cell self-renewal. CtBP is unique among transcription co-regulators in harboring a conserved D-isomer specific 2-hydroxyacid dehydrogenase (D2DH) domain, which reduces an alpha-keto acid substrate to an alpha-hydroxy acid in the presence of NADH. The presence of NADH also facilities oligomerization of CtBP, leading to assembly of higher order complexes of CtBP with both DNA binding transcription factors and histone modifying enzymes that then leads to modulation target genes. We have identified hydroxyimino-3-phenylpropanoic acid and its 4-chloro derivative (HIPP; 4-Cl-HIPP) as potent substrate competitive inhibitors of the CtBP dehydrogenase (IC50’s=240nM, 180 nM), which also disrupt CtBP oligomerization, promoter localization, and transcriptional regulation. Co-crystallization of HIPP and CtBP1/2 indicated a strong π-π interaction between the HIPP phenyl ring and the indolyl ring in tryptophan W318/324 of CtBP1/2, indicating that this tryptophan is critical to CtBP interaction with HIPP inhibitors, dehydrogenase function, and quaternary structure. Of note W318/324, though conserved in CtBP1/2, is unique among D2DH, suggesting that a better understanding of W318/324 role and function in CtBP structure and function is critical to optimizing design of inhibitors that targeting this evolutionary unique residue among dehydrogenases. To further elucidate the mechanism of action in catalysis and oligomerization, as well as functional importance for transcription of CtBP2 W324, we analyzed enzyme kinetics, oligomerization, transcriptional co-regulatory activity and cell migration in a series of CtBP2 W324 mutants overexpressed in breast and colon cancer cell lines with concomitant knockdown (siRNA) or knockout (CRISPR/Cas9) of CtBP2. Our data demonstrates that mutation of W324 abrogated dehydrogenase activity, oligomerization, transactivation of the validated CtBP target gene TIAM1 and induction of migration. In summary, our findings suggest that the W324 residue is critical for CtBP2’s function and its unique conservation in CtBP1/2 vs. other dehydrogenases will allow the development of high specificity CtBP W318/324 inhibitors to limit potential toxicity due to off target inhibition of related metabolic dehydrogenases. Citation Format: Martin M. Dcona, Benjamin L. Morris, Priyadarshan K. Damle, Zaid Nawaz, Francisco Zarate Perez, Michael J. Dennis, Sahib J. Singh, William E. Royer, Keith C. Ellis, Steven R. Grossman. Tryptophan 318/324, the target of C-terminal binding protein (CtBP) inhibitors, plays a critical role in CtBP enzymatic activity, oligomerization and transcriptional coregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3204. doi:10.1158/1538-7445.AM2017-3204
Recent advances in differentially private deep learning have demonstrated that application of dif... more Recent advances in differentially private deep learning have demonstrated that application of differential privacy-specifically the DP-SGD algorithm-has a disparate impact on different subgroups in the population, which leads to a significantly high drop-in model utility for subpopulations that are under-represented (minorities), compared to well-represented ones. In this work, we aim to compare PATE, another mechanism for training deep learning models using differential privacy, with DP-SGD in terms of fairness. We show that PATE does have a disparate impact too, however, it is much less severe than DP-SGD. We draw insights from this observation on what might be promising directions in achieving better fairness-privacy trade-offs.
Natural Language Processing (NLP) techniques can be applied to help with the diagnosis of medical... more Natural Language Processing (NLP) techniques can be applied to help with the diagnosis of medical conditions such as depression, using a collection of a person's utterances. Due to the sensitive nature of such data, privacy measures need to be taken for handling and training models with such data. In this work we study the effects that the application of Differential Privacy (DP) has, in both a centralized and a Federated Learning (FL) setup, on training contextualized language models (BERT, ALBERT, RoBERTa and DistilBERT). We offer insights on how to privately train NLP models and what architectures and setups provide more desirable privacy utility trade-offs. We envisage this work to be used in future healthcare and mental health studies to keep medical history private. Therefore, we provide an open-source implementation of this work 1 .
The paper follows an analytic-deductive approach to realize the issues related to present power c... more The paper follows an analytic-deductive approach to realize the issues related to present power crisis and growing demand of backup power systems (BPSs), especially in India. It not only explores the need of high cost BPSs in current scenario but also put emphasis to reduce the running cost through parametric optimizations. Different improvement initiatives being used to improve efficiency of BPS have been studied but found quite rare application of Six Sigma in BPS sector, in actual. A Define-Measure-Analyse-Improve-Control (DMAIC) model of Six Sigma is being suggested and practiced for bringing breakthrough in efficiency or mileage of a Diesel Genset (used as a BPS). The diversified methodology of Six Sigma has been successfully implemented through a case study discussed and further validates the approach adopted to tackle the problem formulated in paper, ahead. Use of Six Sigma in BPS sector which is a major part of the energy sector in all is too infrequent and next, motivates t...
Concepts shape how we understand and participate in international legal affairs. They are an impo... more Concepts shape how we understand and participate in international legal affairs. They are an important site for order, struggle and change. This comprehensive and authoritative volume introduces a large number of concepts that have shaped, at various points in history, international legal practice and thought; intimates at how the many projects of international law have grappled with, and influenced, the world through certain concepts; and introduces new concepts into the discipline.
In this modern world, Information Technology gives impacts on society, countries, economy, and en... more In this modern world, Information Technology gives impacts on society, countries, economy, and environment. This paper discusses the positive, negative, direct and indirect impacts of IT on environmental issues. Information technology is playing a vital role in saving the environment. Everyday lacks of trees are saved from being cut. Information technology have also reduces the transportation traffic and wastage of natural resources like petrol and diesel. But as there is rose there are thrones. Information technology has also some negative impacts on environment like radiations, e-wastes and so on. This paper throws light on various impacts of Information technology on environment.
This paper constitutes the introduction of the volume 'Concepts for International Law'. I... more This paper constitutes the introduction of the volume 'Concepts for International Law'. It is accompanied by the table of contents as well as the chapter abstracts. This introduction - a standalone piece - grapples with the relation between legal concepts, life and living in international law. First, we briefly explore the contemporary malaise in international law’s disciplinary life, in and for which this book emerges. We urge a sensibility that sees working on international law’s concepts as opening up a range of possibilities in how we may act, live, know, see and understand within and towards the discipline. Second, we offer an overview into how legal thought has, in its diversity, approached legal concepts. We aim to draw out those sensibilities that remain prevalent in today’s legal writings on concepts, whilst also pointing to the limits, nuances and fractures of these sensibilities. In this regard we offer detailed readings, criticisms and extensions of texts by Jhering, Hohfeld, Ross, Cohen, Kennedy, Koskenniemi, and Marks to name but a few. These readings primarily point to the intricate and intractable difficulties of reconciling concepts with social life. They also point to a series of shifting and entwined aesthetic, ethical and political presuppositions that dominate the various ways in which we approach legal concepts today. In showing the diversity of legal sensibilities towards legal concepts, we hope to not only open up the various possibilities and limits of these sensibilities, but to point towards the intellectual cultural resources at the modern scholar’s disposal. Third, and finally, we offer an introduction to the volume itself. Here we outline how we chose its concepts, the types of concepts contained therein, and how we see the complex relations between different concepts.
C-terminal binding proteins (CtBP1/2) are oncogenic transcriptional coregulators and dehydrogenas... more C-terminal binding proteins (CtBP1/2) are oncogenic transcriptional coregulators and dehydrogenases often overexpressed in multiple solid tumors, including breast, colon, and ovarian cancer, and associated with poor survival. CtBPs act by repressing expression of genes responsible for apoptosis (e.g., PUMA, BIK) and metastasis-associated epithelial-mesenchymal transition (e.g., CDH1), and by activating expression of genes that promote migratory and invasive properties of cancer cells (e.g., TIAM1) and genes responsible for enhanced drug resistance (e.g., MDR1). CtBP's transcriptional functions are also critically dependent on oligomerization and nucleation of transcriptional complexes. Recently, we have developed a family of CtBP dehydrogenase inhibitors, based on the parent 2-hydroxyimino-3-phenylpropanoic acid (HIPP), that specifically disrupt cancer cell viability, abrogate CtBP's transcriptional function, and block polyp formation in a mouse model of intestinal polyposis that depends on CtBP's oncogenic functions. Crystallographic analysis revealed that HIPP interacts with CtBP1/2 at a conserved active site tryptophan (W318/324; CtBP1/2) that is unique among eukaryotic D2-dehydrogenases. To better understand the mechanism of action of HIPP-class inhibitors, we investigated the contribution of W324 to CtBP2's biochemical and physiologic activities utilizing mutational analysis. Indeed, W324 was necessary for CtBP2 self-association, as shown by analytical ultracentrifugation and in vivo cross-linking. Additionally, W324 supported CtBP's association with the transcriptional corepressor CoREST, and was critical for CtBP2 induction of cell motility. Notably, the HIPP derivative 4-chloro-HIPP biochemically and biologically phenocopied mutational inactivation of CtBP2 W324. Our data support further optimization of W318/W324-interacting CtBP dehydrogenase inhibitors that are emerging as a novel class of cancer cell-specific therapeutic.
C-terminal Binding Proteins (CtBP) 1 and 2 constitute a family of oncogenic transcriptional co-re... more C-terminal Binding Proteins (CtBP) 1 and 2 constitute a family of oncogenic transcriptional co-regulators overexpressed in tumor tissues that are associated with worse prognostic outcome and aggressive tumor characteristics in multiple cancer types. Specifically, CtBP has been found to repress expression of genes responsible for apoptosis and EMT (eg. BIK and CDH1) and promote expression of genes that partake in the migration of cancer cells and those that are responsible for enhanced drug resistance (eg. TIAM1 and MDR1). CtBP2 is also critically required for colon cancer stem cell self-renewal. CtBP is unique among transcription co-regulators in harboring a conserved D-isomer specific 2-hydroxyacid dehydrogenase (D2DH) domain, which reduces an alpha-keto acid substrate to an alpha-hydroxy acid in the presence of NADH. The presence of NADH also facilities oligomerization of CtBP, leading to assembly of higher order complexes of CtBP with both DNA binding transcription factors and hi...
Background: As with many chronic infections, the initiation and progression of periodontal diseas... more Background: As with many chronic infections, the initiation and progression of periodontal diseases are modified by local and systemic host conditions, or risk factors, that markedly affect the resistance of the host to infecting periodontal pathogens. There are large number of factors including genetic, environmental, and psychosocial which constitute a substantial risk in the development of periodontal destructive diseases. Aim: The aim of present study was to scrutinize the relationship between clinical depression, sleep quality and severity of periodontitis using clinical parameters and a depression and sleep quality rating scale. Materials and Methods: Hundred patients were enrolled in this case-control study, of which 50 patients diagnosed with chronic periodontitis were categorized into cases and 50 patients who were systemically and periodontally healthy were designated as controls. The periodontal parameters recorded included probing depth and simplified oral hygiene index (OHI-S). Depression was determined using Beck’s depression scale. Pittsburgh Sleep Quality Index (PSQI) was used for scrutinizing sleep quality. Results: Self‑reported scoring of depression and sleep quality by using Beck’s depression inventory and Pittsburgh Sleep Quality Index questionnaire has revealed that patients diagnosed with chronic periodontitis had an appreciable elevated score of depression and poor sleep quality than normal controls. Conclusion: Findings of this case-control study revealed a statistically significant relationship between depression, its associated oral health behavior, sleep deprivation experienced and severity of destructive periodontal diseases.
Journal of the Indian Dental Association, Aug 24, 2021
Introduction:Anemia of chronic disease is defined as anemia occurring in chronic infections, infl... more Introduction:Anemia of chronic disease is defined as anemia occurring in chronic infections, inflammatory conditions or neoplastic disorders that are not due to marrow deficiencies or other diseases, and occurring despite presence of adequate iron stores and vitamins. Methods: A total of 40 patients were selected for the study. Participants were divided into two groups viz group A (test group; n=20) with moderate to severe periodontitis and group B (control group; n=20) with periodontally healthy subjects. The patients chosen for the study had at least 30% or more of teeth having greater than or equal to 4 mm probing depth. Clinical parameters like gingival index (GI), Sulcus Bleeding Index (SBI), plaque index (PI),probing pocket depth (PD) and clinical attachment levels (CAL) were recorded for all the patients and blood parameters (hemoglobin and red blood cell count) were determined from peripheralblood samples. The results were analyzed statistically. Results: The mean values of hemoglobin (Hb) and red blood cell (RBC) count were significantly reduced in test group as compared to control group. Conclusion: A positive relationship was observed between the blood parameters viz. Hb, RBC count, and the severity of the chronic periodontal disease. Like other chronic conditions, periodontitis can tend towards anemia showing their association. Keywords: Anemia, Chronic Periodontitis, Hemoglobin (Hb), Red Blood Cell Count (RBC Count).
This is a critical introduction to the special issue on the fundamental rights of states. Whether... more This is a critical introduction to the special issue on the fundamental rights of states. Whether such rights exist, the bounds of their existence, or whether they ought to be striven towards are questions of considerable import in the wake of the Greek sovereign debt crisis, or even given the ongoing Palestinian struggle for permanent sovereignty over their natural resources. I briefly outline how we might consider the question: is there any progressive political value in buttressing the state and its autonomy, through the doctrine of fundamental rights, in today's neoliberal world? First, I examine how we may progressively look at fundamental rights-as doctrine, narrative, memory or discourse. Second, I question the extent to which it is useful to see competing subjectivities, ie the maligned state against technocratic institutions, in a time where neoliberal logic has come to structure the workings of the state. It becomes quickly apparent that the discourse of fundamental rights may be used to both resist neoliberalism and enable it.
C-terminal Binding Proteins (CtBP) 1 and 2 constitute a family of oncogenic transcriptional co-re... more C-terminal Binding Proteins (CtBP) 1 and 2 constitute a family of oncogenic transcriptional co-regulators overexpressed in tumor tissues that are associated with worse prognostic outcome and aggressive tumor characteristics in multiple cancer types. Specifically, CtBP has been found to repress expression of genes responsible for apoptosis and EMT (eg. BIK and CDH1) and promote expression of genes that partake in the migration of cancer cells and those that are responsible for enhanced drug resistance (eg. TIAM1 and MDR1). CtBP2 is also critically required for colon cancer stem cell self-renewal. CtBP is unique among transcription co-regulators in harboring a conserved D-isomer specific 2-hydroxyacid dehydrogenase (D2DH) domain, which reduces an alpha-keto acid substrate to an alpha-hydroxy acid in the presence of NADH. The presence of NADH also facilities oligomerization of CtBP, leading to assembly of higher order complexes of CtBP with both DNA binding transcription factors and histone modifying enzymes that then leads to modulation target genes. We have identified hydroxyimino-3-phenylpropanoic acid and its 4-chloro derivative (HIPP; 4-Cl-HIPP) as potent substrate competitive inhibitors of the CtBP dehydrogenase (IC50’s=240nM, 180 nM), which also disrupt CtBP oligomerization, promoter localization, and transcriptional regulation. Co-crystallization of HIPP and CtBP1/2 indicated a strong π-π interaction between the HIPP phenyl ring and the indolyl ring in tryptophan W318/324 of CtBP1/2, indicating that this tryptophan is critical to CtBP interaction with HIPP inhibitors, dehydrogenase function, and quaternary structure. Of note W318/324, though conserved in CtBP1/2, is unique among D2DH, suggesting that a better understanding of W318/324 role and function in CtBP structure and function is critical to optimizing design of inhibitors that targeting this evolutionary unique residue among dehydrogenases. To further elucidate the mechanism of action in catalysis and oligomerization, as well as functional importance for transcription of CtBP2 W324, we analyzed enzyme kinetics, oligomerization, transcriptional co-regulatory activity and cell migration in a series of CtBP2 W324 mutants overexpressed in breast and colon cancer cell lines with concomitant knockdown (siRNA) or knockout (CRISPR/Cas9) of CtBP2. Our data demonstrates that mutation of W324 abrogated dehydrogenase activity, oligomerization, transactivation of the validated CtBP target gene TIAM1 and induction of migration. In summary, our findings suggest that the W324 residue is critical for CtBP2’s function and its unique conservation in CtBP1/2 vs. other dehydrogenases will allow the development of high specificity CtBP W318/324 inhibitors to limit potential toxicity due to off target inhibition of related metabolic dehydrogenases. Citation Format: Martin M. Dcona, Benjamin L. Morris, Priyadarshan K. Damle, Zaid Nawaz, Francisco Zarate Perez, Michael J. Dennis, Sahib J. Singh, William E. Royer, Keith C. Ellis, Steven R. Grossman. Tryptophan 318/324, the target of C-terminal binding protein (CtBP) inhibitors, plays a critical role in CtBP enzymatic activity, oligomerization and transcriptional coregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3204. doi:10.1158/1538-7445.AM2017-3204
Recent advances in differentially private deep learning have demonstrated that application of dif... more Recent advances in differentially private deep learning have demonstrated that application of differential privacy-specifically the DP-SGD algorithm-has a disparate impact on different subgroups in the population, which leads to a significantly high drop-in model utility for subpopulations that are under-represented (minorities), compared to well-represented ones. In this work, we aim to compare PATE, another mechanism for training deep learning models using differential privacy, with DP-SGD in terms of fairness. We show that PATE does have a disparate impact too, however, it is much less severe than DP-SGD. We draw insights from this observation on what might be promising directions in achieving better fairness-privacy trade-offs.
Natural Language Processing (NLP) techniques can be applied to help with the diagnosis of medical... more Natural Language Processing (NLP) techniques can be applied to help with the diagnosis of medical conditions such as depression, using a collection of a person's utterances. Due to the sensitive nature of such data, privacy measures need to be taken for handling and training models with such data. In this work we study the effects that the application of Differential Privacy (DP) has, in both a centralized and a Federated Learning (FL) setup, on training contextualized language models (BERT, ALBERT, RoBERTa and DistilBERT). We offer insights on how to privately train NLP models and what architectures and setups provide more desirable privacy utility trade-offs. We envisage this work to be used in future healthcare and mental health studies to keep medical history private. Therefore, we provide an open-source implementation of this work 1 .
The paper follows an analytic-deductive approach to realize the issues related to present power c... more The paper follows an analytic-deductive approach to realize the issues related to present power crisis and growing demand of backup power systems (BPSs), especially in India. It not only explores the need of high cost BPSs in current scenario but also put emphasis to reduce the running cost through parametric optimizations. Different improvement initiatives being used to improve efficiency of BPS have been studied but found quite rare application of Six Sigma in BPS sector, in actual. A Define-Measure-Analyse-Improve-Control (DMAIC) model of Six Sigma is being suggested and practiced for bringing breakthrough in efficiency or mileage of a Diesel Genset (used as a BPS). The diversified methodology of Six Sigma has been successfully implemented through a case study discussed and further validates the approach adopted to tackle the problem formulated in paper, ahead. Use of Six Sigma in BPS sector which is a major part of the energy sector in all is too infrequent and next, motivates t...
Concepts shape how we understand and participate in international legal affairs. They are an impo... more Concepts shape how we understand and participate in international legal affairs. They are an important site for order, struggle and change. This comprehensive and authoritative volume introduces a large number of concepts that have shaped, at various points in history, international legal practice and thought; intimates at how the many projects of international law have grappled with, and influenced, the world through certain concepts; and introduces new concepts into the discipline.
In this modern world, Information Technology gives impacts on society, countries, economy, and en... more In this modern world, Information Technology gives impacts on society, countries, economy, and environment. This paper discusses the positive, negative, direct and indirect impacts of IT on environmental issues. Information technology is playing a vital role in saving the environment. Everyday lacks of trees are saved from being cut. Information technology have also reduces the transportation traffic and wastage of natural resources like petrol and diesel. But as there is rose there are thrones. Information technology has also some negative impacts on environment like radiations, e-wastes and so on. This paper throws light on various impacts of Information technology on environment.
This paper constitutes the introduction of the volume 'Concepts for International Law'. I... more This paper constitutes the introduction of the volume 'Concepts for International Law'. It is accompanied by the table of contents as well as the chapter abstracts. This introduction - a standalone piece - grapples with the relation between legal concepts, life and living in international law. First, we briefly explore the contemporary malaise in international law’s disciplinary life, in and for which this book emerges. We urge a sensibility that sees working on international law’s concepts as opening up a range of possibilities in how we may act, live, know, see and understand within and towards the discipline. Second, we offer an overview into how legal thought has, in its diversity, approached legal concepts. We aim to draw out those sensibilities that remain prevalent in today’s legal writings on concepts, whilst also pointing to the limits, nuances and fractures of these sensibilities. In this regard we offer detailed readings, criticisms and extensions of texts by Jhering, Hohfeld, Ross, Cohen, Kennedy, Koskenniemi, and Marks to name but a few. These readings primarily point to the intricate and intractable difficulties of reconciling concepts with social life. They also point to a series of shifting and entwined aesthetic, ethical and political presuppositions that dominate the various ways in which we approach legal concepts today. In showing the diversity of legal sensibilities towards legal concepts, we hope to not only open up the various possibilities and limits of these sensibilities, but to point towards the intellectual cultural resources at the modern scholar’s disposal. Third, and finally, we offer an introduction to the volume itself. Here we outline how we chose its concepts, the types of concepts contained therein, and how we see the complex relations between different concepts.
C-terminal binding proteins (CtBP1/2) are oncogenic transcriptional coregulators and dehydrogenas... more C-terminal binding proteins (CtBP1/2) are oncogenic transcriptional coregulators and dehydrogenases often overexpressed in multiple solid tumors, including breast, colon, and ovarian cancer, and associated with poor survival. CtBPs act by repressing expression of genes responsible for apoptosis (e.g., PUMA, BIK) and metastasis-associated epithelial-mesenchymal transition (e.g., CDH1), and by activating expression of genes that promote migratory and invasive properties of cancer cells (e.g., TIAM1) and genes responsible for enhanced drug resistance (e.g., MDR1). CtBP's transcriptional functions are also critically dependent on oligomerization and nucleation of transcriptional complexes. Recently, we have developed a family of CtBP dehydrogenase inhibitors, based on the parent 2-hydroxyimino-3-phenylpropanoic acid (HIPP), that specifically disrupt cancer cell viability, abrogate CtBP's transcriptional function, and block polyp formation in a mouse model of intestinal polyposis that depends on CtBP's oncogenic functions. Crystallographic analysis revealed that HIPP interacts with CtBP1/2 at a conserved active site tryptophan (W318/324; CtBP1/2) that is unique among eukaryotic D2-dehydrogenases. To better understand the mechanism of action of HIPP-class inhibitors, we investigated the contribution of W324 to CtBP2's biochemical and physiologic activities utilizing mutational analysis. Indeed, W324 was necessary for CtBP2 self-association, as shown by analytical ultracentrifugation and in vivo cross-linking. Additionally, W324 supported CtBP's association with the transcriptional corepressor CoREST, and was critical for CtBP2 induction of cell motility. Notably, the HIPP derivative 4-chloro-HIPP biochemically and biologically phenocopied mutational inactivation of CtBP2 W324. Our data support further optimization of W318/W324-interacting CtBP dehydrogenase inhibitors that are emerging as a novel class of cancer cell-specific therapeutic.
C-terminal Binding Proteins (CtBP) 1 and 2 constitute a family of oncogenic transcriptional co-re... more C-terminal Binding Proteins (CtBP) 1 and 2 constitute a family of oncogenic transcriptional co-regulators overexpressed in tumor tissues that are associated with worse prognostic outcome and aggressive tumor characteristics in multiple cancer types. Specifically, CtBP has been found to repress expression of genes responsible for apoptosis and EMT (eg. BIK and CDH1) and promote expression of genes that partake in the migration of cancer cells and those that are responsible for enhanced drug resistance (eg. TIAM1 and MDR1). CtBP2 is also critically required for colon cancer stem cell self-renewal. CtBP is unique among transcription co-regulators in harboring a conserved D-isomer specific 2-hydroxyacid dehydrogenase (D2DH) domain, which reduces an alpha-keto acid substrate to an alpha-hydroxy acid in the presence of NADH. The presence of NADH also facilities oligomerization of CtBP, leading to assembly of higher order complexes of CtBP with both DNA binding transcription factors and hi...
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