Identification of Chromatin Regulators Perturbed in Hematopoietic Stem and Progenitor Cell Aging

As lifespan is increasing globally, there is a critical need to identify strategies to extend healthspan and prevent chronic diseases into older age. The long-term goal of my research is to identify novel strategies to ameliorate aging-induced decline in hematopoietic stem cell (HSC) function. HSCs give rise to all mature blood and immune cells. With age, HSCs undergo defects in their differentiation ability which correlates with a decline in immune function. Comprehensive knowledge of gene regulatory and epigenetic mechanisms underlying this defect is a barrier to developing therapies to ameliorate aging-associated decline in HSC function. Therefore, my project focuses on understanding the gene regulatory mechanisms underlying this decline in HSC function. Before delving into the gene regulatory mechanisms that go awry with age, it is important to identify which mechanisms are important for the differentiation of HSCs to mature cells. The majority of screening approaches for the identification of novel genes and gene regulatory elements rely on robust in vitro assays. In my thesis work, I have demonstrated in my thesis work that one such assay widely used in the field to differentiate hematopoietic stem and progenitor cells (HSPCs) to B-lymphoid cells performs in a qualitative rather than a quantitative manner which provides implications for interpretations of results this assay. Also, by mining publicly available gene expression data sets and data from an unpublished shRNA knockdown screen, I have identified that the epigenetic regulator lysine acetyltransferase 6b (Kat6b) is important for HSC function as well as demonstrated that KAT6B levels are significantly decreased in expression in aged long term-hematopoietic stem cells (LT-HSCs) at the transcript and protein levels, using qPCR and immunofluorescence. In addition, I have observed that knockdown of Kat6b leads to enhanced myeloid differentiation from LT-HSCs by using in vitro and in vivo assays which partially replicates aging-associated hematopoietic phenotypes. Transcriptome analysis suggests that Kat6b knockdown in LT-HSCs leads to dysregulation of differentiation signatures and an increase in inflammation. These data support increasing the levels of Kat6b as a novel therapeutic strategy for ameliorating aging-associated hematopoietic decline

Our experience of mega-prosthesis in bone tumours: A retrospective cross-sectional study in a tertiary care hospital

Objective: To evaluate the oncological and functional outcomes of bone tumour patients who underwent reconstruction with mega prosthesis.Methodology: A retrospective study was conducted in the department of Orthopaedics Aga Khan University Hospital, Karachi. All the paediatric and adult age group patients diagnosed with malignant, benign and metastatic bone tumours and meeting the inclusion criteria were selected and analysed. Retrospective data was collected from January 2008-January 2018.Results: Sixty-two patients, 30 (48.4%) females and 32 (51.6%) males. were included in the study. Of these 57 (92%) cases had involvement of the lower limb. The mean age was 36.95±19.1 years with a range of 9-81 years. The duration of patients follow up was from 1-124 months (mean 32.7±36.43 months). There were 29 (47%) malignant cases. The most commonly occurring tumour site was distal femur and proximal femur. There were 53 (85%) primary surgeries (first time conducted surgeries) while 9(15%) revision surgeries were done. Major complications were encountered in 19 (30.6%) patients and 13 (20.9%) had minor complications. Post-surgery local recurrence occurred in 2 (3.2%) patients while 7 (11.2%) had distant metastasis. In functional outcomes the mean MSTS score of our patients was 72.09±26.43. The survival rate was 69.8% with 45 patients recovered.Conclusions: With a good patient selection, adherence to the principles of tumour surgery and an adequate applied knowledge of mega prosthesis insertion, a good functional outcome was achieved

Crisis communication in the context of the Pakistan floods 2010

The report focuses on Crisis Communication during the most evastating floods of 2010 ever witnessed in the history of Pakistan in which the death toll of human beings exceeded 2,000. Millions of houses and other immovable properties were submerged, collapsed or totally destroyed. As per the estimates, about 21 million people have been rendered homeless and are constrained to take shelter in open areas under the scorching sun and bad weather. An estimate total number of people affected by the floods is around 21 million which has exceeded the combined total of the 2004 Indian Ocean tsunami, the 2005 Kashmir and the 2010 Haiti earthquakes. According to the views of various media reporters and natural calamity analysts, unfortunately crisis communication could not play any effective role in this most crucial time of Pakistan. Interviews carried out with the victims, studies, facts and figures indicate that international response to this natural calamity has been slow and inadequate. Pakistan government’s inability to sustain its grip in tackling this natural calamity is also responsible for the insufficient international reaction. The need of the time is to chalk out immediate rehabilitation programs and long-term planning in order to confront this crisis in the shortest possible time and to counter any similar calamity in future and to prevent it from turning into a long term mishap

Implementing cultural policies in universities of medical sciences: a model with mediating role of spirituality

Introduction: The aim of this study was to present a model for the implementation of cultural policies in relation to organizational culture with an emphasis on the mediating role of spirituality and mental health in universities of medical sciences. Methods: The present study was descriptive-correlational research. The data collection method was a combination of library and field studies and the data collection instruments included a review of documents, interviews and a researcher-made Cultural Policy Questionnaire, Workplace Spirituality Questionnaire, and Organizational Culture Questionnaire. The statistical population included 21496 hospital staffs and managers of medical sciences hospitals. Since structural equation modeling approach was used in this study, finally 472 people were statistically analyzed. The samples were determined using a stratified sampling method. In the present study, SPSS-23 and AMOS-24 software was used to analyze the data. Results: The research results confirmed the proposed research model and indicated a significant relationship between cultural policies and spirituality in university hospitals. Given the positive path coefficient, this relationship is direct. Based on the coefficient of determination (R2), 44% of spirituality changes in the hospital are explained by cultural policies. In addition to having a direct effect, cultural policies indirectly affect organizational culture through workplace spirituality. The level of direct impact was equal to 0.129 and the level of indirect impact through workplace spirituality was equal to 0.204. Conclusion: A direct relationship was between cultural policies and organizational culture and an indirect relationship between spirituality in university hospitals and organizational culture

Ethnic and Gender Diversity in Top Level Management and Firm Performance: Shareholder’s Perspectives

This study examines the relationship between demographic diversity in top management levels with a firms’ financial performance using 84 non-financial companies in Malaysia. Demographic diversity consists of ethnic diversity and gender diversity. The top management level includes both the top management team and the board of directors. This study uses data from 2008 to 2012. Return on assets measures the financial performance. Ethnic and gender diversity measured by the number of Non-Malays and the number of females in top management respectively. This study incorporates descriptive statistics, correlation testing, and regression analysis. The results show that ethnic diversity in the top management team as well as in a board of directors has no impact on firm performance (ROE). However, the results of gender diversity have a positive impact on performance (ROE) in both perspectives (TMTs and BODs)

Study of Production Performance and Economic of Broiler Farms in Parwan Afghanistan

Poultry industry is one of the main source of income in Afghanistan, where about 1.5 million people are engaged in this sector. In recent years, from 476 poultry farms only 165 farms are continuing their activities in Parwan province of Afghanistan, which means that most of previous farms are broken down. In this research, 30 broiler chicken farms were selected by random sampling method and to evaluate the production performance and economical status of broiler farms in Parwan, Afghanistan. Data were collected by using questionaries’ and personal interviews. Based on the results, it was found that the production performance of the chickens was such as the feed conversion ratio was 1.83, the livability percentage was 90.23%, the average market weight was 1.9 kg, and the mortality rate was 9.77%. The fixed costs included 5.64% worker\u27s salary, 0.79% farm rent and 0.32% electricity bill which are totally (6.75%). Variable costs include the cost of a day-old chicken 6.98%, feed cost 70.45%, veterinary service cost 3.44%, litter cost 1.41%, worker food cost 2.11%, fuel cost 7.05% and miscellaneous cost were 1.47%, which totally reached (93.25%). The total income which were earned 97.93% from live chickens as main product and 2.07% from manure as by product and the benefit cost ratio was 1.07%. To conclude this, as the broiler production is profitable, but the proportion of income is less than the investment. In order to improve the income, it is recommended to provide high-quality feed, prevent diseases, providing high-quality vaccines and medicines, and hiring experts in broiler farms

It\u27s a precious gift, not to waste : Is routine cross matching necessary in orthopedics surgery?: Retrospective study of 699 patients in 9 different procedures

Background: Orthopedic surgeries are usually associated with excessive blood loss which leads surgeons to overestimate need for blood transfusions and over ordering of blood. The cross matched blood, when not used, leads to the wastage of blood bank resources in terms of time, money and manpower. The objective of this study was to investigate the compliance to previously proposed MSBOS and to provide updated recommendations for all orthopedic procedures. Methods: A retrospective analysis was conducted between 1st June 2015 and 31st May 2016. Patients admitted to the orthopedic surgery service for whom blood products were requested were included. Cross Match/Transfusion (CT) Ratio, Transfusion Index and Transfusion Probability were calculated. Values of \u3c 2.5, \u3e 0.5 and \u3e 30% respectively, were taken as standards. Maximum Surgical Blood Ordering Schedule (MSBOS) was proposed based upon these calculations using Mead\u27s criteria. Results: Six hundred and ninety-nine patients were sampled after implementing exclusion criteria. The overall CT ratio was 4.87, transfusion index was 0.55 and transfusion probability was 25%. A compliance rate of 24.6% was observed with the reference CT ratio of 2.5. Highest CT ratio was calculated for arthroscopic procedures while tumor resection had the lowest ratio. Age, procedure performed, ASA status and use of tourniquet were found to be significantly associated with CT ratio being greater or less than 2.5. Conclusion: Results showed significant wastage of blood products and non-compliance with blood ordering guidelines. Hence there is need for large scale prospective studies to establish MSBOS and ensure its compliance

Evaluation of Morphological Characteristics and Fatty Acid Compositions of Some Local Varieties of Oil Flax

Oil flax (Linum usitatissimum L.) is a valuable agricultural crop with potential uses in industries including oil production, nutrition, and medicine. It has a good reputation in Afghanistan as an oil crop. The objective of the current research was to compare the most significant morphological parameters and fatty acid compositions of some local oilflax. The study used a randomized complete block design and was conducted on the research and experimental farm of Parwan University\u27s (REFPU) Faculty of Agriculture in Parwan, Afghanistan, during the 2022 growing season. In this experiment, four seed samples from various regions of Afghanistan [Parwan (V1), Badakhshan (V2), Baghlan (V3), and Kunduz (V4)] were used. The results showed no significant difference between the local varieties on all growth parameters except for the number of seeds per capsule (NSC) and the weight of a thousand seeds (WTS). The maximum NSC was significantly observed in the V1 (10.8), followed by the V3 (7.13) and the V4 (7.33), and the lowest was recorded in the V2 (6.7). The heaviest WTS were significantly produced by V1 (9 gr) compared to V2 (4.67 gr), V3 (5.67 gr), and V4 (4.67 gr). Also, there was not a noticeable difference in the concentration of linoleic acid (LA) and linolenic acid (LLA) between the varieties. Each of the studied local varieties can be used because of their similar performance

Precision Cas9 Genome Editing in vivo with All-in-one, Self-targeting AAV Vectors [preprint]

Adeno-associated virus (AAV) vectors are important delivery platforms for therapeutic genome editing but are severely constrained by cargo limits, especially for large effectors like Cas9s. Simultaneous delivery of multiple vectors can limit dose and efficacy and increase safety risks. The use of compact effectors has enabled single-AAV delivery of Cas9s with 1-3 guides for edits that use end-joining repair pathways, but many precise edits that correct disease-causing mutations in vivo require homology-directed repair (HDR) templates. Here, we describe single-vector, ~4.8-kb AAV platforms that express Nme2Cas9 and either two sgRNAs to produce segmental deletions, or a single sgRNA with an HDR template. We also examine the utility of Nme2Cas9 target sites in the vector for self-inactivation. We demonstrate that these platforms can effectively treat two disease models [type I hereditary tyrosinemia (HT-I) and mucopolysaccharidosis type I (MPS-I)] in mice. These results will enable single-vector AAVs to achieve diverse therapeutic genome editing outcomes