Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality in the underdeveloped countries like Pakistan, leading to socioeconomic destabilization of the community. Among the different factors that play a role in the onset and progression of disease, raised plasma cholesterol levels is considered to be a major factor in the development of atherosclerosis, a typical character for the development of CVDs. Candidate gene screening of hypercholesterolemia families and sporadic individuals revealed two mutations in LDL-C binding domain (La) of LDLR (c.264G>C, p.R88S and c.887_889GCA>AGC, p.296*), four missense mutations in EGF like domain (c. 1019_1020delinsTG, p.C340L; c.1211C>T, p.T404I; c.1214 A>C, p.N405T; c.1634G>A, p.G545E and c.1916T>G, p.V639) and one premature terminating mutation (c.2416_2417 Ins G, p.V806GfsX11) in the transmembrane domain of LDLR. The La domain mutation has been shown to lead to inefficient binding of LDL-C with the receptor, while mutations in EGF like domain were found to cause decreased recycling of LDLR to the hepatocytes surface, which resulted in raised cholesterol levels in the patients. Two variants in PCSK9 i.e., c.314G>A, p.R105Q and c.464C>T, p.P155L, were also found in two different families with a history of CABG. The variant c.314G>A, p.R105Q resulted in 19% decrease in LDL-C levels in heterozygote carriers compared to homozygote normal individuals predicting it to be a “loss of function mutation”, while the second variant c.464C>T, p.P155L was located in the autocatalytic site of PCSK9 which may impact on LDL-C, but its exact effect could not be determined due to the small family size. In case control studies on MI cases in Pakistani population, the screening of selected panel of single nucleotide polymorphisms (SNPs) within five different genes was conducted. It was found that rs1333049 (ANRIL) was significantly associated with the onset of disease (p<0.001), while rs10920501 (FAM5C), rs1042579 (THBD), rs4646994 (ACE) and Intron 4 VNTR (eNOS) were not associated with the onset of MI (p>0.05). The stratification of data based on coronary artery disease (CAD) family history revealed significant association of the risk allele in ACE and eNOS polymorphisms with OR 1.83(95% CI=1.06-3.14) and 1.82(95% CI=1.03-3.22), respectively. This also indicates that the clustering of genetic factors within the ixfamilies are responsible for the onset of MI in Pakistani families. The relationship of rs1333049 risk allele “C” with phenotype impact on the lipid profile also showed a marked decrease in total cholesterol in individual homozygous for risk allele, which was observed in an independent cohort of hypercholesterolemia patients from the affected families as compared to their normolipidemic individuals. From this study, it is revealed that the Pakistani population has genetic heterogeneity, which predisposes the individuals to an increased risk of MI.
تخلیق‘تخلیق کار کی تخلیقی حِسیّت کی پہچان ہوتی ہے اور تخلیقی حِسیّت کی تشکیل میں عصری حِسیّت کا احساس بنیادی کردار ادا کرتا ہے۔ عصری حِسیّت کے شعور سے ہی نئی تخلیق میں تازگی نمو پاتی ہے۔اس تناظر میں جناب احمد رشید کی تصنیف”بائیں پہلو کی پسلی“کے افسانوں کی قرات کے بعد یہ ضرور محسوس ہوتا ہے کہ احمدرشید(علی گڑھ)ایک ایسے باشعور تخلیق کار ہیں‘جن کے بیشتر افسانوں میں تخلیقی حِسیّت کا احساس بھی موجود ہے اور عصری حِسیّت کا شعور بھی نظر آتاہے۔زیر نظر مجموعہ کا پہلا افسانہ”کہانی بن گئی“میں تخلیق کار کی تخلیقی فکر‘موضوعات کی فراوانی اور معاصر زندگی میں کہانی کی ضرورت اور قاری کے میلانات وغیرہ موضوعات کو موضوع گفتگو بنایا گیا ہے۔افسانے کی کہانی تجزیاتی فکرکے استفہامیہ بیانیہ پر تخلیق ہوئی ہے۔تجزیاتی فکر کا یہ استفہامیہ انداز مرکزی کردارکے لب و لہجہ سے صاف ظاہر ہوتا ہے۔ افسانے کی کہانی ریلوے اسٹیشن کے منظر سے شروع ہوتی ہے اور بعد میں استفہامیہ انداز سے ایک انٹرویوکی صورت اختیار کر جاتی ہے۔ اس طرح افسانے کے بیشتر پلاٹ میں انٹرویوکی تکنیک اپنائی گئی ہے۔ افسانے کے فرضی کردار بصورت راوی وغیرہ کے جذبات و احساسات کابیان دلچسپ فنی برتاؤکی عکاسی کررہے ہیں‘جس میں طنز ملیح بھی نظر آتا ہے اور تخلیقی سروکارکے اتار چڑھاؤکو بھی موضوع بحث بنایا گیا ہے۔ افسانے کی ابتدا ریلوے اسٹیشن کے سین سے ہوتی ہے جہاں پر مرکزی کردار بڑی بے چینی سے ٹرین کا انتظارکرتا ہے۔ٹرین کی آواز سنتے ہی لوگ اپنا سامان لیکر ادھر ادھردوڑنے میں لگ جاتے ہیں لیکن اس ہلچل میں مرکزی کردار کی مشاہداتی حِس بیدار ہوجاتی ہے اور وہ اسٹیشن پر موجود ایک کتّے کے شرم پسند فعل کا موازنہ اخلاقی طورپر مریض دماغوں کے ایک بے شرم قانون سے کرتے ہوئے تجزیاتی انداز سے طنز کرتاہے:
The paper deals with the different styles of iltifāt found in the Holy Qur’ān and coming out with a general scheme to account for its occurrence in order to enhance the understanding of the subtleties of this feature of Qur’ān ic style. To accomplish this, the research was carried out by way of an analytical study of the instances of iltifāt in the Holy Qur’ān. As a prelude to the discussion of this subject, the research provides the meaning of iltifāt among the Arab rhetoricians and the status of iltifāt as one of the rhetorical tropes. The paper also discussed the significations of iltifāt which have already been mentioned by previous scholars, and since those scholars touched on the significations only briefly, therefore, the research strived to explore further aspects of their interpretations making an effort to highlight new significations of iltifat and an attempt to introduce a new approach in looking at the iltifāt phenomenon, in different Sura’hs of Qur’ān, to demonstrate the application of this new perspective. Finally the research shows that the occurrence of iltifÉt in the Qur’ān follows certain patterns that are related to the intended significations at the various locations where they appear in the Qur’ān.
The present work deals with the synthesis of pyridine fused heterocyclic compounds, three condensed pyridine systems were selected for this project; Benzo[b]pyridine (Quinoline) (a), Pyrazolo[3,4-b]pyridine (b) and Pyrano[2,3-b]pyridine (c).Various strategies were utilized for introducing an ester functionality on the 4 position of (a) and (b) by utilizing Doebner-vonMiller reaction or additionally the use of Pfitzinger’s synthesis of quinolines. For (c) the ester group was introduced at the 3 position by applying a Knoevenagal condensation of ethyl acetoacetate and 2-hydoxypyridine-3- carbaldehyde. These ester groups in (a), (b) and (c) were converted to their respective carbohydrazides which were condensed with a number of arylcarbaldehydes to furnish their hydrazones. The final cyclization to the 1,3,4-oxadiazoles were effected by using various methods. POCl3 was very useful for this purpose. The products of the systems (a). (b) and (c) were thus synthesized and fully characterized by IR, 1HNMR, 13CNMR and MS and elemental (C,H andN) analyses.The results obtained confirmed the formation of the desired products. The final products were screened for their antioxidant and enzyme inhibition activities. viii Some azabicyclic compounds (I, II, III) were also prepared through ring closure metathesis by using Grubbs catalyst (Second Generation). These compounds were prepared through a multisetp strategy involving alkylation, RCM, decarboxylation, hydrolysis, Curtius reaction and finally cyclization to get the desired bicyclic compounds.These were characterized through 1HNMR, DEPT and HRMS.