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.
معروف محقق سید مظفر حسین برنی کی اقبال شناسی اقبال کے بارے میں بہت کچھ لکھا اورپڑھا جا چکا ہے مگر پھر بھی اقبالیات کے ماہرین اور اقبال شناس محققین کسی نہ کسی نئے موضوع کی تلاش میں سرگرداں رہتے ہیں۔ اقبال کے افکار کا مرکز و محور قرآن اور حدیث تھا۔ اقبال شناس اپنی دلچسپی کے مطابق موضوعات کی تفہیم و تفسیر میں سرگرداں رہتے ہیں۔سید مظفر حسین برنی نے بھی ایسا گوشہ ڈھونڈ نکالا جو مطالعہ اقبال میں بہت اہمیت کا حامل ہے۔ اس کے مطالعہ سے تحقیق و تنقید کے نئے گوشے کھلیں گے اور اقبالیات کے لیے مستند ماخذ کا اضافہ ہو گا۔سید مظفر حسین برنی کا تعلق”برن“ (بلند شہر) کے ایک ذی وقار خانو ادے سے تھا۔آپ نے جس گھرانے میں آنکھ کھولی تھی اس میں خدمتِ علم وادب کی ایک طویل اور مسلسل روایت رہی ہے۔آپ 14، اگست1923ء کو بلند شہر میں پیدا ہوئے۔آپ کا تعلیمی سلسلہ بہت عمدہ رہا۔ آپ نے بی۔اے میں انگریزی ادب میں ٹمپل گولڈ میڈل حاصل کیا۔پھر انگریزی ہی میں ایم۔اے بھی کیا۔1947ء میں انڈین ایڈمنسٹریٹو سروس”آئی اے ایس“ کے مقابلہ کے امتحان میں کامیاب ہوئے اور ریاست اڑیسہ میں تعینات ہوئے۔ مرکزی حکومت نے آپ کی صلاحیتوں سے بھر پور استفادہ کیا۔آپ جوائنٹ سیکرٹری کمیونٹی ڈویلپمنٹ رہے۔محکمہ زراعت میں جوائنٹ سیکرٹری رہے۔ایڈیشنل سیکریٹری وزارتِ پٹرولیم وکیمیکلزکاانتظامی عہدہ سنبھالے رکھا۔وزارتِ اطلاعات و نشریات کے اہم ترین ادارے میں سیکریٹری رہے۔بورڈ آف ریونیو میں رلیف کمشنر رہے۔چیف سیکرٹری اور ڈویلپمنٹ کمشنر کے اعلیٰ ترین عہدوں پر ذمہ داریاں سر انجام دیں۔وزارتِ داخلہ میں سیکریٹری جیسے عہدے پر کام کر کے نیک نامی حاصل کی۔ناگا لینڈ،منی پور،تری پورہ اور ہریانہ کے گورنر رہے۔مرکزی حکومت کے اقلیتی کمیشن کے چیرمین رہے۔پبلک سیکٹر کے تقریباً آٹھ اداروں میں ڈائریکٹر کی حیثیت سے ذمہ داریاں سرانجام دیں۔بہت سی بین الاقوامی...
Objectives: 1. To determine the impact of duration of exposure to industrial chemical fumes on Peak Expiratory Flow Rate (PEFR) and blood pressure of the industrial workers. 2. To find out the association between changes in blood pressure and PEFR due to exposure to industrial chemical fumes in these subjects. Methods: This cross-sectional study was performed at Aziz Fatimah Medical and Dental College, Faisalabad. The study participants were 151 males working in the chemical industries. The study was approved by institutional ethical committee and informed consent was taken from the participants. Free camp was arranged for three days in September 2020 in the industrial area of Faisalabad. Thorough history of exposure to chemicals was taken using structured proforma. PEFR values were recorded using Wrights handheld peak flow meter. Blood pressure was taken by auscultatory method using mercury sphygmomanometer. Data was analyzed using SPSS version 22. Results: Systolic and diastolic blood pressures were significantly raised with increase in duration of exposure. PEFR levels were significantly declined with increase in duration of exposure to chemicals. Significant negative association was noted between diastolic blood pressure and PEFR (p value = 0.003). Negative correlation was observed between PEFR and systolic Blood pressure, however it was not statistically significant (p value = 0.92). Conclusions: PEFR decreased while Systolic and diastolic blood pressures increased significantly with increase in the duration of exposure to chemicals. There was a significant negative correlation between PEFR and diastolic blood pressure while there was no association between PEFR and systolic blood pressure.
In the present study, we analyzed the prevalence of Hepatitis C virus (HCV) infection and its associated risk factors among pregnant women in five selected districts of Khyber Pakhtunkhwa (KP), Pakistan. The prevention of this highly infectious disease that largely remains asymptomatic, and leads to serious damage during pregnancy carries a substantial socio-economic benefit for the health and welfare of this region. The sensitivity and accuracy of the real-time polymerase chain reaction (qPCR) were also evaluated in comparison with the routine diagnostic methods: Immuno chromatographic technique (ICT), and enzyme-linked immunosorbent assay (ELISA). A total of 750 blood samples from five districts of Khyber Pakhtunkhwa namely, Mardan,Kohat, Peshawar, Nowshera, and Charsadda were screened for HCV infection using a combination of three diagnostic procedures: ELISA, ICT, and qPCR. The results showed that out of the 750 blood samples analyzed, the qPCR assay could confirm the presence of HCV RNA only in 10–30% of anti-HCV-positive samples in each district, with an average of 24% in all districts. ELISA was found to be the most sensitive method for detecting anti-HCV antibodies in 70–100% of HCV-positive blood samples in each district, with an average of 92% in all districts. ICT, which detected antibodies in 27–71% of HCV-positive blood samples from different districts with an average of 44%, is clearly less sensitive than ELISA. The overall prevalence rate in the KP, with 48 of the 750 blood samples tested positive for HCV among pregnant women, was estimated to be 6.4%, which falls within the HCV prevalence range of 4.5 to 8%, reported for Pakistan. However, there was a considerable variation in the rate of HCV prevalence at the district level, which are in order of Mardan (9.33%) >Kohat (7.33%) >Peshawar (6.00%) >Nowshera=Charsadda (4.33%). Logistic regression analysis was performed to determine the association of variables of HCV prevalence, like age, education, residential status, travel to abroad, gravidity, dilation and curettage (D&C), blood transfusion, abortion, general and dental surgery, etc., in participants found to be HCV-positive. The logistic regression model was found to be statistically insignificant (χ2 (8) = 8.785, p >0.05). The model explained 49.9% (Nagelkerke R2) of the variance in HCV-positive cases and correctly classified 95.6% of them. People with a marriage duration of 11–20 years were 17.228 times likely to exhibit HCV symptoms than people in other groups of marriage duration. Illiterates were 50.850 times more likely to acquire HCV infection than people with education. Respondents with urban residential status were 5.221 times more likely to be HCV-positive. Gravidity (primigravida) was also found to have a significant impact on HCV prevalence. A history of dental surgery is likely to increase the chances of HCV-positive status by 2.657 times, whereas the use of therapeutic injections is likely to increase the chances of HCV-positive status by 4.474 times. All other variables were found to be non-significant. District wise chi-square analysis showed age, marriage duration, education, residential status,HCV-positive husband, gravidity, dilation and curettage (D&C), blood transfusion, history of abortion, general and dental surgery, ear and nose piercing, awareness about HCV, history of accident, and use of therapeutic injections to be associated with HCV infection to variable extent in different districts. Our findings of a prevalence rate of 6.4% in KP have important health implications for a large number of pregnant women and their families as most of the infected women are ignorant of HCV infection. Since most of them are asymptomatic, they tend to have normal life implying that there exists a considerable potential for the transmission of HCV to the fetus.