حاصل تحقیق
زبان اللہ تعالیٰ کی عطا کردہ نعمتوں میں سب سے بڑی اور عظیم نعمت ہے۔ اس پر سنجیدگی سے غورکرنے کا سلسلہ روزِ اول سے ہی جاری ہے۔ قبل مسیح کےمفکروں اور دانش وروں نے بھی اس پر بہت غور وخوض کیا اور اس کے متعلق مختلف نظریات قائم کیے، اس سلسلے میں مختلف کتب موجود ہیں جو زبان کے متعلق قبل مسیح کے نظریات سے بھری پڑی ہیں۔
اس کے بعد آنے والے مختلف مفکرین نے اس پر تحقیقی کام جاری رکھا۔ اور زبان کے متعلق اپنے نظریات پیش کرتے رہے۔ ان نظریات سے مختلف ماہرین لسانیات نے لسانیات کےمختلف شعبے تخلیق کیے اور ہر شعبے میں خاطر خواہ کام کیا۔
انیسویں صدی میں لسانیات پر باقاعدہ تحقیقی ادارے بننے شروع ہوئے،مغرب نے اس سلسلے میں بہت کام کیا، لیکن یہ بات عیاں ہے کہ بیسویں صدی میں ادب پر جتنا کام ہوا وہ گزشتہ ایک صدی تک نہ ہو سکا، بلاشبہ اس صدی کو ادب کی صدی کہا جاتا ہے اس میں باقی شعبوں کے ساتھ ساتھ لسانیات جیسے اہم مضمون پر بھی بہت زیادہ خامہ فرسائی کی گئی۔
زبان میں لسانیات کے موضوع کے حوالے سے اگر دیکھا جائے تو یہ مختلف عناوین اور اس کےمسائل ومباحث کو سمیٹے ہوئےہے۔ جہاں اس کا تعلق نطق انسانی سے ہے وہاں زبان کے قواعد اور لغتیات پر بھی بحث کرتی ہے۔ اگر لسانیات کی صرف نطق انسانی کے حوالے سے بات کی جائے تو یہ بات عیاں ہے کہ لسانیات کا کسی مخصوص گروہِ انسانی سے تعلق نہیں بلکہ یہ دنیا کی تمام زبانوں کے مسائل کو زیر بحث لاتی ہے۔ مختلف ماہرین لسانیات نے اس کی تعریف مختلف حوالوں سے کی ہے۔ ان میں چند ایک درج ذیل ہیں:
’’زبان کا سائنسی مطالعہ لسانیات کہلاتا ہے۔
This article describes the social problems face by the Egyptian people in the late nineteenth and beginning of twentieth century which are tackled by the writer Mu╖═afā Lu═fī Manfalū═ī in his articles and parables. In the mentioned period the Egyptian society was prone to immoralities carved by the English regime. Bad governance, deprivation of the Egyptian society from their basic rights, and negligence towards Islam were the major shortcomings on the part of the ruling elite. While poverty, problems of women, immorality, offence and other social evils were the main troubles on the part of Egyptian society. This article deals with the way the writer tackled those problems in his writings.
Embryonic stem cells are the pluripotent cells that act as a root of embryonic development to engender the specialized cells of the body. This property can be captured in vitro to cultivate indefinitely, providing a remarkable model to study early development and diseases. In vitro, mouse pluripotent embryonic stem cells (mESCs) exist in two different states, naïve and primed. The naïve state mimics in vivo inner cell mass of blastocyst with the pluripotency genes expressed more uniformly and have more developmental potential than the primed state. The primed state corresponds to a later embryonic developmental stage than the naïve state. Both states of cells express similar level of some key pluripotency genes but the signaling pathways that support their self-renewal and pluripotency are strikingly different. Mitochondrial metabolism, among others, is a major difference between the two states. The primed state has more mature mitochondria but doesn’t use them for ATP generation, which is generated solely through glycolysis. The naïve state however, has a bivalent metabolic state, i.e. uses both glycolysis and mitochondria to generate ATP. What role mitochondria play in these two states remains a very interesting and relevant question. Here in this study, we investigated the function of mitochondrial respiration in naïve mESCs by blocking the electron transport chain (ETC) with specific pharmacological inhibitors, Rotenone and Antimycin, and genetically with shRNAs against mitochondrial specific transcription factor A (TFAM) and a helicase, Twinkle. Both inhibitors and shRNAs resulted in blockade of cell proliferation and when released, the cells resumed self-renewal without affecting the pluripotency. The paused phenotype by ETC inhibition also appeared in the blastocysts cultured in vitro, which naturally die within 2-3 days of the development while Rotenone treatment extends survival of blastocysts for 3 more days. Moreover, the treated blastocysts were able to give live pups when injected back into surrogate mother, confirming a normal developmental potential. Upon ETC inhibition with either compounds or shTFAM, the mitochondrial mass and membrane potential increased and level of reactive oxygen species (ROS) decreased. The shRNAs against TFAM and Twinkle greatly reduced the mitochondrial DNA (mtDNA) copy number and expression of mtDNA encoded mRNA, leading to complete blockade of mitochondrial respiration. Paused mESCs stopped oxygen consumption and enhanced glycolysis instead to maintain a steady level of ATP generation, which is essential for the cells to be alive. Mechanistically, ETC inhibition induced pause is distinct from the pause induced through either mTOR or Myc inhibition. Neither pyruvate, aspartate nor nucleosides supplementation could rescue the self-renewal of mESCs which were shown to have the ability in other cell types upon ETC inhibition. The total non-targeted metabolomics showed that the ETC regulates the carbohydrates, proteins, lipid and nucleic acid metabolism. Specifically, lysosomal-related pathways are found to be significantly and commonly changed from both metabolomics and proteomic analyses. We could confirm the blockade of autophagy and lysosomal pathways in ETC inhibition-induced paused cells. These analyses suggest that an intimate link exists between mitochondria and lysosome in mESCs and highlights the potential important function of lysosomes for mESCs self-renewal. This work reported a new type of pause by ETC inhibition in mESCs and identified some unique metabolic roles of mitochondrial ETC for mESCs self-renewal. Furthermore this study first time shows the effect of Ursolic acid on mouse embryonic stem cells.