크기가 조절된 산화 그래핀 플레이크를 이용한 인간줄기세포의 세포 활성 및 분화 조절

학위논문(박사) -- 서울대학교대학원 : 공과대학 화학생물공학부, 2023. 2. 박태현.There is increasing interest in studying stem cell differentiation through cellular physical stimulation which can be translated into cell-recognized tension. It has been known that physical stimulation can direct human mesenchymal stem cell differentiation which called mechanotransduction. Recently, graphene oxide (GO), major derivative of graphene, has been synthesized as promising material which has suitable physico-chemical characteristics for stem cell lineage specification. GO can interact with integrin, the transmembrane receptor protein, through electrostatic, hydrophobic interactions. However, GO used in previous stem cell research has used GO with an irregular morphology and size. Such irregularity of GO causes diverse cellular responses according to lateral sizes of GO. In this study, we fabricated graphite mechanically with narrow size distribution by adjusting the ball-milling time. Then, size-controlled GO flakes were chemically synthesized from ball-milled graphite using modified Hummers method. Size distribution of GO were measured by hydrodynamic situations. Dose-dependent cytotoxicity of the size-controlled GO flakes on human stem cells was observed. The interaction between GO flakes and cells was analysed with electron microscopy. Also, effect of GO with osteogenic and neural differentiation of hMSCs were measured by staining and gene expression level. Also, by analyzing the shape and size of the cells through immunostaining, we confirmed that focal adhesion was key component involved in promoting stem cell differentiation and enhanced cell viability in apoptotic circumstances. We suggest that the size-controlled GO sheets would be efficient candidate for enhancement of lineage determination of human stem cells and therapeutic applications.세포 인식 장력으로 번역될 수 있는 세포 물리적 자극을 통한 줄기 세포 분화 연구에 대한 관심이 증가하고 있다. 물리적 자극은 기계적 형질도입(mechanotransduction)이라고 하는 인간 중간엽줄기세포 분화를 조절할 수 있는 것으로 알려져 있다. 최근 그래핀의 주요 유도체인 산화 그래핀이 줄기세포 계통 사양에 적합한 물리화학적 특성을 갖는 유망한 물질로 주목되고 있다. 산화 그래핀은 정전기적 소수성 상호작용을 통해 막횡단 수용체 단백질인 인테그린과 상호작용할 수 있다. 그러나 기존 줄기세포 연구에서 사용된 물질은 형태와 크기가 불규칙한 산화 그래핀을 사용하고 있다. 이러한 산화 그래핀 물성의 불규칙성은 산화 그래핀의 측면 크기에 따라 통제되기 어려운 다양한 세포 반응을 일으킨다. 이 연구에서는 볼 밀링 시간을 조정하여 좁은 크기 분포를 가진 흑연을 기계적으로 제작하였다. 그런 다음 수정된 Hummers의 방법을 사용하여 볼 밀링된 흑연에서 크기가 제어된 산화 그래핀 플레이크를 화학적으로 합성하였다. 합성된 산화 그래핀의 크기 분포는 수용액 환경에서 측정되었다. 인간 줄기 세포에서 크기 조절된 산화 그래핀 플레이크의 용량 의존적 세포독성이 관찰되었다. 산화 그래핀 플레이크와 세포 사이의 상호 작용은 전자현미경 분석되었고 인간 중간엽줄기세포의 골형성 및 신경 분화와 함께 산화 그래핀의 효과를 분석하기 위해 염색 및 유전자 발현을 측정하였다. 또한 면역염색을 통해 세포의 모양과 크기를 분석함으로써 국소적 접착이 줄기세포 분화 촉진과 세포자멸사 촉진 환경에서 세포 생존력 향상에 관여하는 핵심 요소이며 이는 세포 종류와 배양 환경에 따라 다른 크기의 산화 그래핀이 효율적임을 확인하였다. 이로서 크기 조절 산화 그래핀 플레이크가 인간 줄기 세포의 분화 계통 결정 및 치료적 응용을 위한 효율적인 후보가 될 것이라고 제안한다.Chapter 1. Research background and objectives 2 Chapter 2. Literature review 6 2.1. Human stem cells 6 2.1.1. Human mesenchymal stem cells 6 2.1.2. Human embryonic stem cells 6 2.2. Stem cell research utilizing graphene oxide 7 Chapter 3. Experimental procedures 11 3.1. Preparation of GO 11 3.1.1. Ball-milling of graphite 11 3.1.2. Preparation of GO by ball-milled graphite 11 3.2. Characterization of GO 11 3.3. Preparation of magnetic nanoparticles 12 3.4. Cultivation and differentiation of hMSCs 12 3.5. Cultivation of hESCs 13 3.6. Generation of hEBs and neural differentiation 14 3.7. Cell adhesion assay of GO 14 3.8. Cell viability assay 15 3.8.1. CCK8 assay 15 3.8.2 Fluorescence-based live and dead assay 15 3.9. qRT-PCR analysis 15 3.10. Alkaline phosphatase staining and Alizarin Red S staining 18 3.11. Immunocytochemistry 18 3.12. Western blotting 18 3.13. Statistical analysis 19 Chapter 4. Material characteristics and cellular interactions of size-controlled graphene oxide flakes 21 4.1. Introduction 21 4.2. Characterization of GO processed by ball-milling 21 4.3. Morphology and cytotoxic effect of GO attached to hMSCs 27 4.4. Conclusions 30 Chapter 5. Enhanced osteogenic differentiation of bone marrow-derived human mesenchymal stem cells using size-controlled graphene oxide flakes 31 5.1. Introduction 32 5.2. Enhancing effect of GO on osteogenic differentiation of hMSCs 35 5.3. Promotion of early cell spreading and focal adhesion complex formation of hMSCs by GO-1.7 39 5.4. Expression and localization of osteogenic marker proteins by GO-1.7 43 5.5. Proposed mechanism of osteogenic differentiation enhanced by GO 47 5.6. Conclusions 52 Chapter 6. Enhancing effect of graphene oxide flakes on stem cell viability in single-cell detachment and shear stress-caused apoptotic circumstances 53 6.1. Introduction 54 6.2. Viability of hMSCs treated with GO-1.7 in non-adhesive condition and shear stress 56 6.3. Viability of hESCs treated with size-controlled GO flakes in non-adhesive condition 60 6.4. Conclusions 62 Chapter 7. Enhanced neural differentiation of adipose-derived human mesenchymal stem cells using size-controlled graphene oxide flakes 64 7.1. Introduction 65 7.2. 3D culture of ADSCs 67 7.3. Gene expression of neural induction markers in ADSCs 69 7.4. Expression of neural induction markers in ADSCs 72 7.5. Conclusions 75 Chapter 8. Overall discussion and further suggestions 77 Appendix. Enhanced neural differentiation of 3D human embryonic stem cells via magnetic nanoparticle-based physical stimuli 80 A.1. Introduction 81 A.2. Improved neural induction of MNP-incorporated hEBs, manufactured through a concentrated magnetic force system 84 A.3. Morphological analysis of neurally induced hESCs 87 A.4. Genetical analysis of neural induction marker genes 91 A.5. Related mechanisms to accelerated neural induction of hEBs 94 A.6. Conclusions 96 Bibliography 97 국 문 초 록 109박

Relationship between serum sodium level and coronary artery abnormality in Kawasaki disease

PURPOSE: Kawasaki disease (KD) is an immune-related multisystemic vasculitis that occurs in children, especially ensuing from a coronary artery abnormality. Sodium level is known to be related to vascular injury, which could affect the progress of KD. The purpose of this study was to determine the serum sodium levels that could predict the occurrence of cardiac and coronary artery events in KD. METHODS: We conducted a retrospective review of medical records for 104 patients with KD from January 2015 to December 2015. Patients with serum Na levels of <135 mEq/L at the time of initial diagnosis were assigned to the hyponatremia group. Laboratory findings and echocardiographic data were analyzed for various aspects. RESULTS: Among the 104 patients with KD, 91 were included in the study, of whom 48 (52.7%) had hyponatremia. The degree of fever, white blood cell count, percentage of neutrophils, percentage of lymphocytes, total bilirubin level, brain natriuretic peptide level, erythrocyte sedimentation rate, and C-reactive protein level were higher in the patients with hyponatremia. They also demonstrated a trend of larger coronary artery diameters based on Z scores. CONCLUSION: The severity of vascular inflammation in acute KD with hyponatremia might worsen the prognosis of coronary vasculature. Although no statistically significant correlation was found between the initial serum sodium levels and coronary arteriopathy in the patients with KD in this study, a long-term follow-up study with a larger number of enrolled patients should be designed in the future to elucidate the relationship between serum sodium level and coronary arteriopathy in patients with KD.ope

Insulin resistance and bone age advancement in girls with central precocious puberty

PURPOSE: Precocious puberty has significantly increased recently. While obesity is associated with puberty timing, the relationship between obesity and central precocious puberty (CPP) remains controversial. The purpose of this study was to determine whether insulin resistance is associated with bone age (BA) advancement in girls with CPP. METHODS: We retrospectively analyzed the records of 804 girls referred for puberty evaluation. Anthropometric measurements, BA, sex hormone, sex hormone binding globulin (SHBG), and insulin levels, lipid profiles, and gonadotropin releasing hormone stimulation tests were assessed. Insulin resistance parameters were calculated using the homeostasis model assessment-insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) models. RESULTS: BA, BA advancement, free estradiol index, insulin, and HOMA-IR increased significantly in girls with high body mass index (BMI) compared with that of girls with low BMI in cases of CPP. HOMA-IR was positively correlated with BA advancement and BMI but negatively correlated with SHBG. QUICKI was negatively correlated with BA advancement and BMI and positively correlated with SHBG. When HOMA-IR increased by 1, the odds for BA advancement increased 120% after adjusting for age and BMI (P=0.033). CONCLUSIONS: Insulin resistance could be associated with BA advancement in girls with CPP.ope

Integration of enterprise risk management and management control system: Based on a case study

This paper aims to discuss the concepts and methodological issues of enterprise risk management (ERM). The case study of company A shows that ERM has been implemented and integrated with management control as a means of monitoring its subsidiaries. First, ERM system was implemented through comprehensive review of corporate risk policies, risk management processes, roles and responsibilities, and risk culture. Second, company A integrated ERM with the existing management control system in order to evaluate the risk underlying the current management activities. Finally, ERM implementation was expanded to all subsidiaries so that each business unit would be delegated for its own risk management. This paper provides insight on the process how group-level internal auditors can use ERM as a tool to manage risk of subsidiaries, thereby filling the gap between academic research and practice. This successful ERM adoption case can be used as a guideline for other organizations, which plan to adopt ERM with reduced costs and improved processes. © Ilhang Shin, Sorah Park, 2017

Comparative studies in 'Kim Yun-Deok's Gayageum Sanjo and Geomungo Sanjo

학위논문 (석사)-- 서울대학교 대학원 : 음악과, 2013. 8. 이지영.가야금산조는 19세기 말경에 가락이 형성된 이후, 여러 세대에 걸쳐 계승․확대 되었다. 가야금명인들은 스승에게 배운 가락에 자신의 가락을 추가하고 다듬어 음악적으로 완성도를 높여갔으며, 이렇게 완성된 각각의 가락에 그 명인의 이름을 붙여 ○○○류라 부르고 있다. 산조의 명인들은 보통 한 가지의 악기로 산조 가락을 구성하여 유파를 남기는 것이 일반적이나, 김윤덕은 자신의 이름으로 하나의 악기가 아닌 가야금과 거문고 두 악기로 각기 산조의 유파를 형성해 가락을 남겼다. 본 논문에서는 한 연주자가 각기 다른 악기로 산조를 형성할 경우 그 선율들이 서로 영향을 받았을 것이라는 전제하에 그 연계성을 살펴보고자 하였다. Ⅱ장에서는 김윤덕의 생애와 산조의 전승과정을 살펴 보았다. Ⅲ장에서 두 산조에 공통적으로 포함된 진양조․중모리․자진모리장단을 비교․분석하였다. Ⅳ장에서는 상이한 장단이지만 거문고산조의 자진모리와 같은 박자체계로 볼 수 있는 가야금산조의 중중모리와 휘모리를 비교․분석하였다. 그러나 가야금산조 단모리의 경우 박자체계가 달라 비교 가능한 장단이 없으므로, 연구의 범위에서 제외하였다. 김윤덕이 직접 남긴 음원을 기준으로 가야금산조와 거문고산조를 비교하여 공통선율과 유사선율을 살펴본 결과는 다음과 같다. 가야금산조와 거문고산조의 각 선율을 장단 단위로 비교한 결과 휘모리를 제외한 모든 장단에서 공통선율과 유사선율이 발견되었다. 휘모리에서는 단 하나의 공통선율만 발견되었으나 리듬을 제외한 음계의 조합이 반복․변형되는 부분들로 유사성을 찾아볼 수 있었다. 이는 상대적으로 느린 장단일수록 유사한 요소가 많이 발견되고, 장단이 빨라지면 각 악기의 특성에 맞추어 연주하는 선율이 많아지기 때문에 선율의 유사성이 적어지는 것으로 보인다. 이번 연구에서는 김윤덕류 가야금산조와 거문고산조 선율만을 범위로 하여 유사한 선율들을 찾아내었지만 추후 음계․리듬․형식․주법적 특징 등 각 음악적 요소별로 특징을 찾아 비교해 보는 연구를 진행한다면 더욱 심도 깊은 결과를 도출해 낼 수 있을 것으로 기대된다.I. 서론 1 1. 문제 제기 및 연구목적 1 2. 연구범위 및 연구방법 3 Ⅱ. 김윤덕의 생애와 산조의 전승과정 7 1. 김윤덕의 생애와 음악활동 7 2. 김윤덕류 산조의 전승과정 8 1) 김윤덕류 가야금산조 8 2) 김윤덕류 거문고 산조 10 Ⅲ. 동일 장단 간 선율비교 12 1. 진양조 12 1) 가야금산조 진양조와 거문고산조 진양조의 공통선율 13 2) 가야금산조 진양조와 거문고산조 진양조의 유사선율 22 2. 중모리 42 1) 가야금산조 중모리와 거문고산조 중모리의 공통선율 43 2) 가야금산조 중모리와 거문고산조 중모리의 유사선율 46 3. 자진모리 64 1) 가야금산조 자진모리와 거문고산조 자진모리의 공통선율 65 2) 가야금산조 자진모리와 거문고산조 자진모리의 유사선율 70 Ⅳ. 상이 장단 간 선율비교 78 1. 중중모리 78 1) 가야금산조 중중모리와 거문고산조 자진모리의 공통선율 79 2) 가야금산조 중중모리와 거문고산조 자진모리의 유사선율 83 2. 휘모리 87 1) 가야금산조 휘모리와 거문고산조 자진모리의 공통선율 88 2) 가야금산조 휘모리와 거문고산조 자진모리의 유사선율 89 Ⅴ. 결론 97 참고문헌 99 Abstract 101 첨부악보 104Maste

Audit quality and accrual quality: Do big 4 auditors indeed enhance accrual quality of ‘powerful’ clients?

External auditors are considered ‘watchdogs’ which closely monitor corporate financial reporting process and provide guidelines for investors and financial institutions. However, recent accounting scandals in Korea indicate that external auditors may cater their audit reports to their clients’ needs. Based on a sample of listed companies on the Korea Stock Exchange from 2001 to 2010, this study finds the evidence consistent with such conjecture. First, large business conglomerates in Korea (so called ‘chaebols’) audited by Big 4 have lower accrual quality than the others, indicating that Big 4 auditors may not serve as watchdogs to enhance accrual quality of ‘powerful’ clients. However, powerful clients who pay greater non-audit service fees to Big 4 auditors have higher accrual quality than the others. This result suggests that non-audit services provided by Big 4 may not necessarily harm the quality of accounting information, contrary to the traditional view in the literature. © by author(s); CC-BY

지방간 치료제로서 LXR 선택적 길항제의 개발

학위논문 (석사)-- 서울대학교 대학원 : 약학과, 2012. 2. 이병훈.The liver X receptors (LXRs) belong to the nuclear receptor superfamily and are comprised of two subtypes, LXRα and LXRβ. LXRα expression predominates in metabolically active tissues such as the liver, small intestine, kidney, macrophages, and adipose tissue, whereas LXRβ is more ubiquitously expressed. The LXRα agonists are well-documented to promote reverse cholesterol transport (RCT) in the blood macrophage to improve blood lipid profile, so there have been many recent studies in the development of the LXRα agonist as a therapeutic for atherosclerosis or cardiovascular diseases. There is, however, an adverse effect of increased hepatic lipid synthesis due to the increased activity of hepatic LXRα. As a result, much research has been done on finding a vascular selective LXRα agonist that does not activate LXRα in the liver. In this study, we proposed that a compound that selectively inhibits hepatic LXRα without vascular inhibition could be developed as a therapeutic for fatty liver disease, focusing on the mechanism for which an antagonist for LXRα can inhibit hepatic lipid synthesis. We commenced in vitro and in vivo screening to find a hepatic selective LXRα antagonist, revealed its mechanism, and confirmed its safety and efficacy via an animal test. In vitro, we found that promotor binding in LXRE decreased in human hepatoma cells, HepG2, through LXR luc-assay, and also found that lipid accumulation decreased as well in rat hepatoma cells, H4IIEC3, through Nilered assay with fluorescence intensity values and fluorescent images. The same was confirmed in HepG2 cells and primary cultured hepatocytes of rats. During in vivo screening, we verified the inhibition of fatty liver in mice with both non-alcoholic fatty liver induced by high fat diet, as well as alcoholic fatty liver through histopathologic images, clinical chemistry, lipid contents, and gene expressions. Furthermore, we also found that the DNA binding of LXR decreased in the liver of the mouse with alcoholic fatty liver via EMSA assay. We thus verified the findings from the in vitro screening through replication in vivo. In human monocytes, THP-1, and rat monocytes, RAW264.7, we found that the proposed compound does not inhibit ABCA1 and ABCG1, which are the main transporters in reverse cholesterol transport as downstream genes of LXRα by PCR. The expression levels were also checked in HepG2 cells. The same was confirmed in the mice orally administered with SPA019. To reveal the inhibitory mechanism of LXRα, we proceeded TR-FRET LXRα co-activator assay and found that the proposed compound inhibits the activation of LXRα by T0901317, an LXR activator, in a concentration-dependent manner. We performed co-immunoprecipitation using LXRα in HepG2 cells and among various co-activators, RIP140 decreased with increasing concentrations of the compound, leading us to conclude that one of the mechanisms of LXRα inhibition is the inhibition of RIP140. We also checked the lower signals from mTOR, S6K and JNK, which constitute the upper pathways from LXR, to see if they were affected by the compound. Our results showed no relationship or effect to the upper pathway. Finally, we wanted to verify the effects of long term treatment in fatty liver inhibition and its effects on reverse cholesterol transport. After we fed the mice with a high fat diet for 4 weeks, we orally administered the compound for the final two weeks continuing the diet. After 2 weeks of administration, steatosis and hepatitis induced by the high fat diet were recovered with improved blood lipid profile. In conclusion, it stands to reason that SPA019 can be considered as an effective therapeutic for fatty liver disease through selective inhibition of hepatic LXRα without inhibition of reverse cholesterol transport.Liver X receptor (LXR)은 지질 대사를 조절하는 nuclear receptor superfamily의 일종으로 LXRα와 LXRβ, 두 가지 subtype이 존재하는데, 그 중 전자는 주로 간, 소장, 신장, 대식 세포, 지방 조직 등에서 발현되며, 후자는 전신적으로 골고루 발현된다. LXRα의 효능제는 혈관 대식세포에서의 콜레스테롤 역전송 (reverse cholesterol transport, RCT)을 촉진시켜 혈중 지질 프로파일을 개선시킨다는 것이 알려져 있어, 최근 동맥 경화 및 관상동맥질환에 대한 치료제로서LXRα의 효능제에 대한 연구가 활발하게 진행되어 왔다. 하지만 간에서의 LXRα 활성이 증가함으로 인해 간 내에서 지방 합성이 증가하는 부작용이 있고, 이러한 간에서의 LXRα 촉진 작용이 없는 혈관 선택적인 LXRα 효능제를 찾는 데에 많은 노력이 이루어지고 있다. 본 연구에서는 반대로 LXRα의 길항제는 간에서 지방 합성을 억제할 수 있다는 사실에 초점을 맞추어, 혈관에서의 LXRα 활성은 억제하지 않으면서, 간에서만 선택적으로 LXRα 활성을 억제하는 물질을 지방간 치료제로 개발할 수 있을 것이라 가정하였다. 이에 in vitro, in vivo screening을 진행하여 간 선택적인 LXRα 길항제를 발견하였으며, 그 기전을 연구하였고 또한 동물실험으로 효능을 확인하였다. In vitro에서는 human hepatoma cell인 HepG2 cell에서 LXR luc-assay를 통해 LXRE에 대한 promotor binding이 감소함을 확인하였고, Nilered assay를 통해 Rat hepatoma cell, H4IIEC3에서의 지방 축적 억제를 수치와 형광 이미지로 확인하였다. In vivo screening으로는 알코올성 지방간을 유도시킨 마우스에서 추출한 간으로부터 EMSA assay를 통해 물질을 투여한 경우에 LXR의 DNA binding이 줄어드는 것을 확인하였다. 나아가 알코올성 지방간을 유도시킨 마우스와 고지방식이에 의한 지방간을 유도시킨 마우스에서 각기 지방간 억제 효과를 확인하였고, 이를 통해 in vitro에서의 screening결과가 in vivo에서도 재현됨을 보았다. 한편human monocyte인 THP-1 cell과 rat monocyte인 RAW264.7 cell에서 LXRα의 하위 유전자들로서 콜레스테롤 역전송에 있어 가장 중요한 transporter인 ABCA1, ABCG1을 억제하지 않음을 PCR로 확인하였으며, 또한 물질만을 단독 투여한 마우스에서 ABCA1의 발현이 억제되지 않음을 western blot으로 확인하였다. 이 물질의 이러한 LXRα 억제 기전을 알아보기 위하여 TR-FRET LXRα co-activator assay를 진행하였으며, 이를 통해 LXR activator인 T0901317이 LXR을 활성화시키는 것을 농도의존적으로 저해하는 것을 확인하였다. HepG2 cell에서 LXRα를 이용해 co-immunoprecipitation을 실시하였고, 여러 가지 co-activator 중 RIP140이 물질 처리에 따라 농도 의존적으로 감소함을 확인하여, 이를 통해 이 물질의 LXRα 활성 억제 기전 중 하나가 RIP140의 억제를 통한 것이라 결론지을 수 있었다. 한편, LXR의 상위 단계에 있는 mTOR로부터 이어지는 하위 신호인 S6K와 JNK에 의한 영향이 아닌지 또한 확인하였으며, 둘 모두 변화가 없음을 통해 상위 조절단계와는 무관함을 보였다. 마지막으로, 장기 투여에 따른 지방간 억제 효능과 콜레스테롤 역전송에는 영향이 없음을 확인하기 위해 6주간에 걸쳐 마우스에게 장기적으로 고지방식이를 투여하고 그 중 마지막 2주 동안 물질을 함께 투여하였다. 2주간의 투여를 통해 고지방식이로 인한 지방간이 억제되었으며, 혈중 지질 프로파일에는 영향이 없음을 확인하였다. 지방간뿐만 아니라 고지방식이에 의하여 유발되는 염증 인자들 또한 억제되는 것을 확인하였고, 이로서 지방간에서 더 나아가 간염으로까지 이어지는 발병과정을 모두 억제할 수 있는 효과적인 물질임을 보여주었다. 결론적으로 이 물질은 간에서의 선택적 LXRα 억제를 통해 혈관에서의 콜레스테롤 역전송은 억제하지 않는 지방간 치료제로서 가치가 있다고 사료된다.Maste

The internal control manager and operational efficiency: evidence from Korea

Purpose This study aims to examine the relationship between the internal control manager attributes and the firms&amp;amp;apos; operational efficiency. The internal control manager designs and maintains the firms&amp;amp;apos; policies and procedures to certify the effectiveness of its internal control system. Design/methodology/approach The study is an empirical research based on a sample of public companies listed on the Korean Stock Exchange from year 2011 to 2015. The authors derive measures of operational efficiency using the data envelopment analysis tool. Findings This study shows that the operational efficiency increases with internal control managers&amp;amp;apos; task-related knowledge and diverse firm knowledge, consistent with human capital theory. Also, the results reveal that internal control managers, equity ownership has a curvilinear relationship with the operational efficiency, indicating that excessive managerial ownership can deteriorate the firm value. Originality/value While many studies have examined the association between the internal control system and financial reporting quality, this paper is differentiated from prior studies by focussing on the internal control managers&amp;amp;apos; personal attributes. This is important, as the internal control system is essentially built by internal control managers who are in charge. This study contributes to accounting literature by shedding light on the role of internal control managers in enhancing the firms&amp;amp;apos; operational efficiency