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Background: Tear production increases ocular surface health and improves visual clarity. Which facilitates the physical activity comfortably. Different dosages of glucose intake had a significantly varying impact on tear production in euglycemic, initially decreasing followed by an increase. Objective: to compare the effect of 0.5% and 1% glucose intake on tear production in euglycemic. Methodology: A quasi-experimental study was conducted with n=200 participants at Irfan Eye Care Hospital Peshawar, from September 2022 to May 2023. The participants were euglycemic without any ocular and systemic pathology and determined its effect on tear production. The participants were divided into two groups equally for 0.5% and 1% glucose intake. Tear production was measured at baseline, after 60 minutes, 90 minutes, 120 minutes, and 150 minutes with the Schirmer test. Results: There was a significant reduction of tear production from baseline to 120 minutes (p

Overhead transmission lines produce significant Magnetic Fields (MF).MF impact is crucial for Overhead Transmission lines (OTL) design because of health concerns regarding radiation effects because they can induce electrical currents within the human body. This paper presents the MF measurement results underneath OTL in two different locations and periods in Malaysia. The first site consisted of two 132 kV double-circuit transmission lines, while the second site contained a 132 kV double-circuit line and a 132 kV quadruple-circuit system. The measurements are conducted in December 2023 and February 2024. The measured MF levels are presented via graphs to facilitate the localization of zones with high-intensity MF. The study found that areas beneath the transmission lines with the highest levels of MF intensities were identified by analyzing the measured results. In the first site, for both double and quadruple circuits, the maximum RMS magnetic flux density level is 2.81 μT, and in the second site, for double circuits is 3.5 μT. For validation of the measurement results, MF is simulated using ANSYS Electronics based on IEEE standards, CIGRE, and other researchers. The measurement outcomes closely matched the simulated MF with very few errors for both double-circuit and quadruple-circuit measurements, as well as for two double-circuit measurements. The simulated and measured MFs were compared with the International Commission on Non-Ionizing Radiation Protection (ICNIRP) limit in occupational and general exposure values. The study found that the measurement outcome closely matched the simulated MF under the ICNIRP limit.

Insulated cross-arms (ICA) allow for the compaction or enhancement of transmission lines. This study presents a comprehensive approach to designing and evaluating insulated cross-arm (ICA) grading devices to control electric fields for insulated cross-arms on a 132 kV lattice tower. A ring-shaped grading device is designed for the low voltage (LV) end of the insulator. A novel grading device is designed for the high voltage (HV) end—a single piece that controls the field for all four ICA members. Finite element analysis (FEA) simulations assess the electric field stress near the HV and LV ends of the ICAs, ensuring that it remains below the critical threshold of 18 kV/cm and effectively improves electric field stress at both ends of compression insulator by 70 % electric field stress at LV end and 80 % improved at HV end. The study outlines a thorough design methodology and provides valuable guidelines for utilising FEA in developing complex geometries. By adopting this approach, the researchers aim to enable the adequate compaction and upgrading of new and existing 132 kV overhead transmission lines, ultimately contributing to optimising power grid infrastructure. The findings of this study demonstrate the importance of integrating comprehensive design strategies and advanced simulation techniques to enhance the reliability and performance of ICA.

Insulated cross-arms for overhead transmission lines have become increasingly common in the past decade. The 3D finite element analysis (FEA) of the electric field distribution in insulated cross-arms is particularly intriguing due to the differences from conventional glass or ceramic insulators. The complex geometry of composite cross-arms, which feature four separate insulator strings and varying shed profiles, poses a challenge in modelling them using 3D FEA packages. The findings indicate that insulated cross-arms can operate within suitable parameters for traditional composite insulators. This paper presents and analyses the electric field distribution around an insulated cross-arm, which aims to replace existing high-voltage insulators and the steel cross-arms of transmission towers. The design of grading devices plays a crucial role in ensuring the safety of these structures. The use of grading ring devices at both ends of the insulator has proven effective in relieving stress on the insulator string under normal and abnormal conditions, enabling the insulated cross-arm to function effectively with conventional composite insulators. Significant reductions in electric field strength were observed, amounting to approximately 35.93 % inside the core, 31.14 % on the core surface, 35.64 % through the shed, and 16.67 % above the shed for compression members. For tension members, reductions from the low-voltage end to both ends were around 33.82 % inside the core, 38.55 % on the core surface, and 17.48 % through the shed. However, an 8.43 % increase was observed above the shed, indicating a deviation from the decreasing trend observed in other areas. These research findings provide valuable insights for designing and managing high-voltage systems, ensuring effective insulation and enhanced safety. It benefits electrical utilities and transmission line manufacturers by improving reliability and safety for overhead transmission lines.

Titanium dioxide (TiO2) has attracted much attention because of their desirable physicochemical properties especially in the water splitting process. In this work pure and Fe-doped TiO2 compounds are studies theoretically with the help of Generalized Gradient Approximation with the revised Pardew–Burke–Ernzerh (RPBE) exchange–correlation scheme. Total Density of States (TDOS) and Partial Density of States (DOS) were analyzed in detail which show that iron (Fe) and oxygen (O) orbitals hybridize, especially in the region of the doping system conduction band minima for both modes. Additionally, this interaction produces an energy level that effectively reduces the bandgap of the adsorbed system. Optical properties were elucidated which shows that Fe-doped TiO2 system results in high absorption and photoconductivity. Moreover, the results demonstrate low bandgap energy which is suitable for the reduction in water splitting without the need for external energy. Magnetic properties demonstrated that Fe-doped TiO2 systems show very low diamagnetic responses. The calculated elastic properties of Fe-doped TiO2 indicate ductile nature of the material with a strong average bond strength. Fe-doped TiO2 exhibited less microcracks with a mechanically stable composition.

This research delves into the primary cause of the ageing of insulated cross-arms in the field, which is attributed to the high electric stress experienced at the end fittings. To address this issue, a novel technique is introduced to meticulously analyse the influence of Grading rings on the electric field (E-field) stress, with the goal of regulating it within the prescribed limits on the surface of the insulated cross-arm. By employing advanced methodologies such as finite element analysis and design of experiment approaches, the impact of various geometrical characteristics of Grading rings on the E-field is comprehensively investigated. Through the application of the analysis of variance, the primary and interaction effects of these factors are carefully examined. Additionally, leveraging the power of the response surface technique, an optimal link between the E-field and the geometrical parameters is modelled and optimized. The results of this comprehensive study unequivocally reveal the profound influence of the geometrical parameters of Grading rings on the E-field. Furthermore, diligent efforts are made to estimate the Grading ring parameters that will effectively regulate the E-field within the suggested maximum threshold based on the derived model. The proposed technique not only significantly reduces the computational analysis time but also serves as an efficient and invaluable tool for investigating the intricate geometry of Grading rings without imposing any additional computing burden.According to the findings, the E-field is most impacted by the factors H, D, and T to optimise the shape of grading rings used in insulated cross-arms. The main objective was achieved by reducing the maximum E-field value by 65% compared to the E-field without a grading ring, which has been accomplished. The suggested technique provides a quick and easy way to analyse and improve the intricate geometry of grading rings. As a result, it lowers the cost and time related to computational analysis without needing an excessive amount of computing work to do this.

Abstract Introduction Cardiac blood cyst is a very rare benign tumor of the heart in adults. Though it is very common in the first half year of life, it regresses with time and its occurrence is very rare in children older than six months and in adults. Until now less than 100 valvular blood cyst cases have been reported in adults. Case presentation We present a case of a 66-year-old male who presented to us with exertional chest tightness, shortness of breath, and right leg weakness for two weeks. He was diagnosed with a cardiac mass two months ago in another hospital. The physical examination was unremarkable. Abdominal ultrasound showed a cyst in the liver and left kidney. Echocardiography showed a mass-occupying lesion of a cystic nature in the mitral valve with moderate mitral regurgitation. Based on echocardiography findings and computed tomography report, the preliminary diagnosis of mitral valve cystic tumor was made. The patient underwent minimally invasive resection of the cyst. The posterior mitral cusp was repaired and a mitral annuloplasty ring was placed. The postoperative recovery was uneventful. The histopathology report confirmed the diagnosis of a cardiac blood cyst. The patient was followed up for six months without any complications. This case is presented to enrich the medical literature on the cardiac blood cyst. Conclusion Although a cardiac blood cyst is a rare entity in adults, it still should be considered in the differential diagnosis of cardiac tumors. Because the natural history and hemodynamic effects are very diverse, large symptomatic cardiac blood cysts, especially in the left heart should be resected to avoid complications.

Abstract Background Intracardiac leiomyoma is a rare benign right heart tumor that usually extends from the intravenous system. The patient often has a history of uterine leiomyoma. Case presentation We report a 46-year-old female patient who presented to us with exertional dyspnea, chest tightness, and shortness of breath for two weeks and had a history of uterine leiomyoma resection. Echocardiography showed a pedunculated solid mass in the right heart with the pedicle attached to the inferior vena cava. The surgery was performed under cardiopulmonary bypass established through the femoral artery and vein with a probable diagnosis of leiomyoma. The tumor was removed by ingenious surgical technique: a snare made of silk suture in which the tumor’s pedicle was trapped, and the tumor with its pedicle was carefully removed with the help of a scalpel along the silk suture. The histopathology report confirmed the diagnosis of intravenous leiomyoma. The postoperative course was uneventful and the patient was discharged a week later. Conclusion Intracardiac leiomyoma is a rare benign smooth muscle tumor. Surgery is the mainstay of treatment with different surgical approaches available. It is possible to completely remove cardiac leiomyomas through sternotomy without the need for an abdominal incision if the leiomyoma is originated in the inferior vena cava not far from the right atrium.

Ischemic cardiomyopathy patients with severe left ventricular dysfunction are a specific group of patients with poor surgical outcomes. There are few surgical treatment options in practice for the treatment of these patients such as heart transplantation, coronary artery bypass surgery, surgical ventricular restoration, etc. Despite multiple treatment options, there are no explicit clinical guidelines available to guide surgeons in choosing the most appropriate option and ensuring that the specific patient can benefit from the selected surgical treatment. Heart transplantation is the gold standard treatment for ischemic cardiomyopathy patients with severe left ventricular dysfunction, but it is limited to very few highly equipped centers around the world due to donor shortages, complex perioperative and surgical management, and limited technological and human resources. It is evident from some studies that heart transplant-eligible candidates can benefit from alternative surgical options such as coronary artery bypass surgery alone or combined with surgical ventricular restoration. Therefore, alternative surgical options that are used for most of the population, especially in developing and underdeveloped countries, need to be discussed to improve their outcomes. A challenge in the recent era which has yet to find a solution is to determine which heart transplant candidate can benefit from simple revascularization compared to a complex heart transplantation procedure. Myocardial viability testing was one of the most important determinants in deciding whether a patient should undergo revascularization, but its role in guiding appropriate surgical options has been challenged. This review aims to discuss the available surgical management options and their long-term outcomes for patients with ischemic cardiomyopathy, which will eventually help surgeons when choosing a surgical procedure.

Abstract Background Cardiac hemangioma is a very rare benign tumor of the heart which accounts for 1–2% of all primary cardiac tumors. Multiple cardiac hemangiomas are even rarer with only three cases published in the literature. Pathologically it can be divided into cavernous hemangioma, capillary hemangioma, arteriovenous hemangioma, mixed-type hemangioma, and so on. At present, the etiology of cardiac hemangioma is not completely clear. In this study, we present multiple cardiac hemangiomas located in the right atrium and discuss the new unreported possible cause (rheumatism) of cardiac hemangioma. This is the fourth case of multiple cardiac hemangiomas in the medical literature and the first time to present rheumatism as the cause of cardiac hemangioma. Case presentation A 53-year-old man presented to the clinic with intermittent chest tightness and shortness of breath for 2 years. On echocardiography, multiple soft tissue masses in the right atrium were found. The patient had rheumatic heart disease with severe mitral stenosis and moderate tricuspid regurgitation. Two masses with a diameter of about 20 mm and 15 mm were seen in the right atrium. One mass was located on the inferior margin of the fossa ovalis and the other was adjacent to the inferior vena cava. Both masses were successfully removed surgically. The mitral valve replacement and tricuspid valve plasty were performed at the same time. The postoperative histopathology results confirmed the diagnosis of cavernous hemangioma. Conclusion The occurrence of multiple hemangiomas in the heart is possible, especially in the presence of rheumatism. Rheumatism is one of the possible etiologies of cardiac hemangioma. Cardiologists and cardiac surgeons should be aware of its occurrence and should consider cardiac hemangioma as a differential diagnosis especially in rheumatic heart disease patients when they present with soft tissue cardiac masses for accurate management.

BackgroundDonor/recipient size matching is paramount in heart transplantation. Body weight, height, body mass index, body surface area, and predicted heart mass (PHM) ratios are generally used in size matching. Precise size matching is important to achieve better clinical outcomes. This study aims to determine the donor/recipient ascending aortic diameter (AAoD) ratio as a metric for donor selection and its effect on postoperative clinical outcomes in heart transplant patients.MethodsWe retrospectively reviewed all consecutive patients who underwent heart transplantation from January 2015 to December 2018. A cutoff value of 0.8032 for the donor/recipient AAoD ratio (independent variable for the primary endpoint during unmatched cohort analysis) was determined for predicting in-hospital mortality. The patients were divided into two groups based on the cutoff value. Group A, AAoD < 0.8032 (n = 96), and Group B, AAoD > 0.8032 (n = 265). A propensity score-matched (PSM) study was performed to equalize the two groups comprising 77 patients each in terms of risk. A Cox regression model was developed to identify the independent preoperative variables affecting the primary end-point. The primary endpoint was all-cause in-hospital mortality.ResultsA total of 361 patients underwent heart transplantation during the given period. On the multivariate analysis, donor/recipient PHM ratio [HR 16.907, 95% confidence interval (CI) 1.535–186.246, P = 0.021], donor/recipient AAoD ratio 0.8032 could improve post-heart transplantation outcomes and donor heart utilization.

Abstract Background Internal thoracic arteries (ITAs) are considered to be the standard conduits used for coronary revascularization. Recently minimally invasive procedures are performed to harvest ITAs. The aim of this retrospective cohort study is to observe the effect and safety of less invasive LIMA harvesting approaches in the learning curve compared to conventional harvesting. Methods We retrospectively analyzed the data of 138 patients divided into three different groups based on the LIMA harvesting techniques: conventional sternotomy LIMA harvesting, CSLH (n: 64), minimally invasive direct LIMA harvesting, MIDLH (n: 42), and robotic-assisted LIMA harvesting, RALH (n: 32). The same 138 patients were also divided into sternotomy (n: 64), and non-sternotomy (n: 74) groups keeping both MIDLH and RALH in the non-sternotomy category. Parameters associated with LIMA’s quality and some other perioperative parameters such as harvesting time, LIMA damage, perioperative myocardial infarction, ventilation time, 24 h drainage, ICU stay, hospital mortality, computed tomographic angiography (CTA) LIMA patency on discharge, and after one year were recorded. Results The mean LIMA harvesting time was 36.9 ± 14.3, 74.4 ± 24.2, and 164.7 ± 51.9 min for CSLH, MIDLH, and RALH groups respectively (p

Excessive use of chemical fertilizers causing a serious threat to the agro-ecological system, developing resistance to pest and declining food safety. Under current scenario, the application of bio-organic nutrients sources become imperative to sustain the productivity of arable farming. Thus to study the possible use of bio-organic sources of nutrients in soil fertility, crop quality and saving the application cost of chemical fertilizer, a pot experiment was conducted in green-house at Land Resources Research Institute, NARC Islamabad. Integrated effects of bio-organic fertilizers such as phosphate solubilizing bacteria (PSB), vermicompost (VC) along with chemical fertilizer was investigated on soil-plant nutrients contents, growth and yield of tomato. Post-harvest results showed that the integrated use of bio-organic fertilizers with chemical fertilizer significantly increased the agronomic yield (Plant height and chlorophyll content) and fruit yield (Number of fruits, fruit weight, fruit diameter and yield) in tomato. The maximum plant height (161.24cm), chlorophyll contents (61.2), number of fruits (19), fruit weight (55g), fruit diameter (45.6a) and fruit yield (1.39 Kg/plant) were recorded in the treatment T5 where VC+PSB+75%RD were applied and minimum in treatment T1 (control). Treatment T5 has increased 117% fruit yield over control. The highest N (2.05% and 2.89%), P (0.33% and 0.50%) and K (2.32% and 6.67%) concentration in shoot and fruit of tomato respectively were found in treatment T5 (VC+PSB+75%RD). Similarly, in soil the highest N (4 mg Kg-1), P (0.66mg Kg-1) and K (3.53mg Kg-1) was recorded in treatment T6 (VC+PSB+100RD). Thus, study results recommend that the integrated use of bio-organic sources with appropriate proportion of chemical/synthetic fertilizers is best option of fertilizer savings and to achieve maximum benefits regarding quality and yield.

Abstract Internal thoracic arteries (ITAs) are the gold standard conduits for coronary revascularization because of their long-term patency and anti-atherosclerotic properties. Harvesting and preparation of ITAs for revascularization is a technically demanding procedure with multiple challenges. Over the last few decades, various methods and techniques for ITAs harvesting have been introduced by different surgeons and applied in clinical practice with different results. Harvesting of ITAs in pedicled or skeletonized fashion, with electrocautery or harmonic scalpel, with open or intact pleura, with clipping the end or keeping it perfused; papaverine delivery with intraluminal injection, perivascular injection, injecting into endothoracic fascia, and papaverine topical spray are the different techniques introduced by the number of researchers. At the same time, access to the ITAs for harvesting has also been studied. Access and harvesting through median sternotomy, mini anterolateral thoracotomy, thoracoscopic, and robotic-assisted harvesting of ITAs are the different techniques used in clinical practice. However, the single standard method for harvesting and preparation of ITAs has yet to be determined. In this review article, we aimed to discuss and analyze all these techniques of harvesting and preparing ITAs with the help of literature to find the best way for ITAs harvesting and preparation for myocardial revascularization.

Abstract Here, we investigated the relationship between Plant communities and the environment from the moist temperate vegetation of Lakoo mountainous forest District Swat. We sampled data from 162 sampling units (Quadrates) using 1x1m2 for herbs 5x5m2 and shrubs, while 10 x10m2 for trees, systematically considering six elevation gradients between the altitudinal from 1970m to 3095m. We performed statistical analysis like Canonical correspondence analysis (CCA) and TWINSPAN (two-way indicator species analysis) for ecological assessment and clustering of plant communities. To check upon the correlation of species (CR) with topographic and edaphic variables we used statistical software PC-ORD version 7. We recognized 264 species plants belonging to thirty families. We recorded key sampling measurements of density, frequency, and cover for all these species which are vital for community description. The results showed Shannon-Winner,s, and Simpson diversity values as 19.18 and 3.17 respectively. The importance value indexes (IVI) were used to identify the leading and rare species of plant in each community or cluster group. In total we recognized eleven different communities as: Berberis- Abies- Bergeni, Picea - Indigofera- Poa,Abies- Parrotiopsis- Poa, Quercus- Viburnum- Poa, Picea- Salix- Primula, Abies- Viburnum- Poa, Viburnum- Taxus- Poa, Pinus- Viburnum- Lithospermum, Abies-Berberis- carex, Pinus- Viburnum- Poa and Parrotiopsis- Picea- Poa through hierarchical cluster analysis (TWINSPAN). CCA analysis revealed that of all studied edaphic and topographic variables altitude, silt, calcium carbonate, and organic matter were the strongest factors determining plant community diversity and composition in each microclimate of the eleven communities. Visually the vegetation of the forest was dominated by small-sized trees followed by shrubs, and regenerates indicating the stage of secondary regeneration. We found severe human interference in disturbing the existing biodiversity, which requires immediate conservation to ensure sustainable management and utilization of natural resources of the Lalkoo moist temperate forest.

This paper introduces a multistep damage identification process that is both straightforward and useful for identifying damage in buildings with regular plan geometries. The algorithm proposed in this study combines the utilization of a multi-damage sensitivity feature and MATLAB programming, providing a comprehensive approach for the structural health monitoring (SHM) of different structures through vibration analysis. The system utilizes accelerometers attached to the structure to capture data, which is then subjected to a classical statistical subspace-based damage detection test. This test focuses on monitoring changes in the data by analyzing modal parameters and statistically comparing them to the structure’s baseline behavior. By detecting deviations from the expected behavior, the algorithm identifies potential damage in the structure. Additionally, the algorithm includes a step to localize damage at the story level, relying on the jerk energy of acceleration. To demonstrate its effectiveness, the algorithm was applied to a steel shear frame model in laboratory tests. The model utilized in this study comprised a total height of 900 mm and incorporated three lumped masses. The investigation encompassed a range of scenarios involving both single and multiple damages, and the algorithm proposed in this research demonstrated the successful detection of the induced damages. The results indicate that the proposed system is an effective solution for monitoring building structure condition and detecting damage.

Abstract Background Wandering spleen is a rare clinical entity with a less than 0.2% reporting incidence rate. In this case, the spleen is present abnormally in the abdominal or pelvic cavity instead of its normal anatomical location. The aetiology is either congenital or acquired. The condition is caused by the absence or maldevelopment of the spleen's suspensory ligaments, which holds the spleen static in the left hypochondrium. Case presentation A 27-year-old female patient presented to the emergency department with complaints of abdominal pain, fever, nausea, vomiting, and constipation for three days. A palpable movable mass was found during the physical examination, and torsion of the wandering spleen’s pedicle was confirmed by CT scan. Open splenectomy was performed, and the patient was recovered uneventfully. Conclusion Even though ectopic spleen is a rare disease, clinicians should be aware of its incidence. Early diagnosis in the case of an acute abdomen is vital for the preservation of the spleen. Patients presented with acute abdomen and absence of splenic shadow under left hemidiaphragm should be suspected, and further radiological investigation will confirm the diagnosis. Surgery is the gold standard for wandering spleen with either splenopexy or splenectomy, depending on the spleen's condition during surgery.

People have the right to live in a safe environment free from crime and fear of crime with the most basic social needs. Although the subject has many different dimensions, this study evaluates it from a spatial perspective. The main aim of the study is to determine whether urban design is effective in reducing crime and fear of crime in urban spaces. For this purpose, firstly, place-based theories were investigated and a total of 12 effective design factors in producing safer spaces were revealed. Secondly, these factors were tested by visual observations and a total of 109 surveys with the users of the Sahibata neighborhood which has the highest crime rate in the city. While the visual observations were interpreted by photographs, the derived survey data were interpreted by using frequency and crosstab analysis. In conclusion, besides producing some spatial strategies such as revitalizing the lost spaces, increasing the lighting level, providing activity generators, variety of functions, decreasing the acts of vandalism signs and providing legibility and belonging clues in the sample area, it was emphasized that urban design is effective in minimizing crime and fear of crime, but it cannot be a single tool and it is necessary to evaluate the issue in the long term in all its other dimensions.

Abstract Background Spontaneous biliary system perforation is a rare presentation in clinical practice especially in adults. It is rarely suspected and diagnosed preoperatively due to small number of cases, vague sign and symptoms, and ambiguous presentation. Case presentation We describe an interesting case of spontaneous perforation of the common bile duct in a 16 year-old female who presented a week after her first birth to the emergency department with complaints of diffuse abdominal pain, abdominal distention, fever, vomiting, and constipation. She was having generalized peritonitis but the etiology was unclear despite a thorough workup. She underwent exploratory laparotomy, and a perforation in the supra duodenal region of the common bile duct was found intraoperatively. The common bile duct was repaired over T-tube, and cholecystectomy was performed; the patient was recovered uneventfully. Conclusion Spontaneous biliary perforation is a rare cause of acute abdomen in adults and extremely rare in pregnancy. Its delayed diagnoses and management can lead to a high morbidity and mortality. All physicians, especially surgeons, should be aware of this possibility and consider it a cause of peritonitis on differential diagnosis particularly when there is no apparent etiology available for presentation.

Coronary artery bypass grafting (CABG) is the gold standard procedure for multi vessels and left main coronary artery disease. The prognosis and survival outcomes of CABG surgery are highly dependent on the patency of the bypass graft. Early graft failure which can occur during or soon after CABG remains a significant issue, with reported incidences of 3–10%. Graft failure can lead to refractory angina, myocardial ischemia, arrhythmias, low cardiac output, and fatal cardiac failure, emphasizing the importance of ensuring graft patency during and after surgery to prevent such complications. Technical errors during anastomosis are among the leading causes of early graft failure. To address this issue, various modalities and techniques have been developed to evaluate graft patency during and after CABG surgery. These modalities aim to assess the quality and integrity of the graft, thus enabling surgeons to identify and address any issues before they lead to significant complications. In this review article, we aim to discuss the strengths and limitations of all available techniques and modalities, with the goal to identify the best modality for evaluating graft patency during and after CABG surgery.

Abstract Background Acquired Hemophilia A (AHA) is a rare bleeding diathesis in patients with no previous personal or family bleeding history. The diagnosis of this disease often delays due to unfamiliarity of physicians with it, which leads to its high mortality rate. Case presentation Two cases (one 12 years old female and another 18 years old male) were admitted for right upper abdominal mass and right upper abdominal pain respectively at different times. Pre-operative diagnosis of both cases was congenital choledochal cyst. They suffered continuous gastrointestinal bleeding (hematemesis and melena) with reduced hemoglobin to 54 g/L and 60 g/L after Roux-en-Y anastomosis respectively. To investigate the exact bleeding site, Digital subtraction angiography (DSA) of case 1 showed contrast overflow at small branch of proper hepatic artery but had unremarkable result for case 2, whereas gastroscopy of both cases showed unremarkable results. Multiple surgeries were also performed for hemostatic purpose but each time no active bleeding site was found. Finally, hematologists consultation was mandated in both cases and they were diagnosed as acquired haemophilia A. However, unfortunately case 1 patient could not survive because of sever hemorrhage and infection while Case 2 of 18 years old male survived after proper haemophilia treatment catalog. Conclusion Awareness about surgery associated acquired haemophilia A (SAHA) can facilitate quick diagnosis and lifesaving management because the mortality rate in SAHA is high due to lake of knowledge or late recognition of the disease. Bleeding always occurs at surgical sites and it can occur immediately within few hours after surgery in some cases. Hemorrhage may be severe or even life threatening and it presents a special challenge for diagnosis and treatment in a patient who has just undergone a surgical procedure. The treatment strategies for AHA include resumption of hemostasis with either recombinant porcine factor VIII (rpFVIII) or bypassing agents and immunosuppressive therapy to suppress the production of the factor VIII inhibitor.

Hematological malignancies (HM) are a group of neoplastic diseases that are usually heterogenous in nature due to the complex underlying genetic aberrations in which collaborating mutations enable cells to evade checkpoints that normally safeguard it against DNA damage and other disruptions of healthy cell growth. Research regarding chromosomal structural rearrangements and alterations, gene mutations, and functionality are currently being carried out to understand the genomics of these abnormalities. It is also becoming more evident that cross talk between the functional changes in transcription and proteins gives the characteristics of the disease although specific mutations may induce unique phenotypes. Functional genomics is vital in this aspect as it measures the complete genetic change in cancerous cells and seeks to integrate the dynamic changes in these networks to elucidate various cancer phenotypes. The advent of CRISPR technology has indeed provided a superfluity of benefits to mankind, as this versatile technology enables DNA editing in the genome. The CRISPR-Cas9 system is a precise genome editing tool, and it has revolutionized methodologies in the field of hematology. Currently, there are various CRISPR systems that are used to perform robust site-specific gene editing to study HM. Furthermore, experimental approaches that are based on CRISPR technology have created promising tools for developing effective hematological therapeutics. Therefore, this review will focus on diverse applications of CRISPR-based gene-editing tools in HM and its potential future trajectory. Collectively, this review will demonstrate the key roles of different CRISPR systems that are being used in HM, and the literature will be a representation of a critical step toward further understanding the biology of HM and the development of potential therapeutic approaches.

Abstract Ninety days study was conducted in hapas installed in earthen ponds. Fish of an average initial weight (220g) were evenly distributed in triplicate groups within fifteen hapas. Five experimental diets labeled as T1 (25% CP and NRC recommended amino acid level) as control diet, T2 (with 2% low protein and 5% amino acid supplementation), T3 (with 2% low protein and 10% amino acid supplementation), T4 (with 4% low protein and 10% amino acid supplementation) and T5 (with 4% low protein and 20% amino acid supplementation) were prepared. Fish were fed with @3% of their body weight twice a day at 10.00 & 16:00 hour. Significantly higher percent weight gain (420.18 ± 66.84a) and specific growth rate (13499.33±1273.54a) along with improved feed conversion ratio (1.29 ± 0.09b) and hundred percent survivals were recorded during the trial. Furthermore proximate analysis of meat showed significant improvement in the crude protein level (81.77 ± 0.19a) served with diet containing 20% limiting amino acids mixture. Therefore, limiting amino acids can be a source of cost effective feed and use safely in L. rohita diet.

High-voltage transmission technology has advanced quickly with the overall development and increased use of renewable energy. More demands on the insulating system are made when high-voltage power systems evolve. One of the significant factors is the sharp rise in population density, which led to the high demand for electricity. Right-of-way infringement is a problem that frequently occurs these days. Transmission is done over a rated capacity; as a result, the transmission line heats up, the insulation ages, and the electric field becomes distorted. The insulating system is prone to fail too soon when the operating voltage inverses or when there is a significant temperature differential. Environmentally friendly insulating materials have received much attention recently. A synergistic optimisation of heat resistance properties, mechanical properties, and dielectric properties must be accomplished before these materials can be used in high-voltage transmission systems. They must also withstand harsh electrical and thermal shocks such as overvoltage and short-circuit faults. One of the developments that has become a popular research topic is the constantly evolving tower design. This review article presents advancements in cross-arm technology in high-voltage transmission systems to elaborate on the limitations and contributions of different research work.

Water scarcity has emerged as an intense global threat to humanity and needs prompt attention from the scientific community. Solar-driven interfacial evaporation and seawater desalination are promising strategies to resolve the primitive water shortage issue using renewable resources. However, the fragile solar thermal devices, complex fabricating techniques, and high cost greatly hinder extensive solar energy utilization in remote locations. Herein, we report the facile fabrication of a cost-effective solar-driven interfacial evaporator and seawater desalination system composed of carbon cloth (CC)-wrapped polyurethane foam (CC@PU). The developed solar evaporator had outstanding photo-thermal conversion efficiency (90%) with a high evaporation rate (1.71 kg m−2 h−1). The interfacial layer of black CC induced multiple incident rays on the surface allowing the excellent solar absorption (92%) and intensifying heat localization (67.37 °C) under 1 kW m−2 with spatially defined hydrophilicity to facilitate the easy vapor escape and validate the efficacious evaporation structure using extensive solar energy exploitation for practical application. More importantly, the long-term evaporation experiments with minimum discrepancy under seawater conditions endowed excellent mass change (15.24 kg m−2 in consecutive 8 h under 1 kW m−2 solar irradiations) and promoted its operational sustainability for multi-media rejection and self-dissolving potential (3.5 g NaCl rejected from CC@PU surface in 210 min). Hence, the low-cost and facile fabrication of CC@PU-based interfacial evaporation structure showcases the potential for enhanced solar-driven interfacial heat accumulation for freshwater production with simultaneous salt rejection.

Background: Chest x-ray is central in screening and diagnosis of tuberculosis. However, sputum culture remains gold standard for diagnosis. Aim: To establish the rate of normal chest x-rays in tuberculosis patients found by spot sputum culture screening, and compare them to a group identified through passive case finding. Method: Chest x-rays from 39 culture-positive patients, identified by spot sputum culture screening in Copenhagen from 2012 to 2014, were included in the study (spot sputum culture group(SSC)). 39 normal chest x-rays from persons screened by mobile x-ray, and 39 chest x-rays from tuberculosis-patients identified through passive case finding(PCF) were anonymised and randomised. Two respiratory physicians and two radiologists assessed the chest x-rays. Results: The normal chest x-ray rate was higher in the non-tuberculosis control group (median = 32 (82.1%), range = 74.4% – 100%), compared to the SSC group (median = 7 (17.9%), range = 10.3% – 33.3%), and the PCF controls (median = 3(7.7%), range = 2.6% – 15.4%). In the SSC group 14 (35.9%) were categorized as normal by at least one study participant. Conclusion: A substantial minority of patients diagnosed with tuberculosis by spot sputum culture screening, and through passive case finding would not have been identified with chest x-ray alone, highlighting that a normal chest x-ray does not exclude pulmonary tuberculosis. Keywords: Tuberculosis, Chest x-ray changes, Passive case finding, Active case finding, Chest x-ray assessment, Normal chest x-ray

Chronic inflammation such as asthma may lead to higher risks of malignancy, which may be inhibited by anti-inflammatory medicine such as inhaled corticosteroids (ICS). The aim of this study was to evaluate if patients with asthma-Chronic Obstructive Pulmonary Disease (COPD) overlap have a higher risk of malignancy than patients with COPD without asthma, and, secondarily, if inhaled corticosteroids modify such a risk in a nationwide multi-center retrospective cohort study of Danish COPD-outpatients with or without asthma. Patients with asthma-COPD overlap were propensity score matched (PSM) 1:2 to patients with COPD without asthma. The endpoint was cancer diagnosis within 2 years. Patients were stratified depending on prior malignancy within 5 years. ICS was explored as a possible risk modifier. We included 50,897 outpatients with COPD; 88% without prior malignancy and 20% with asthma. In the PSM cohorts, 26,003 patients without prior malignancy and 3331 patients with prior malignancy were analyzed. There was no association between asthma-COPD overlap and cancer with hazard ratio (HR) = 0.92, CI = 0.78–1.08, p = 0.31 (no prior malignancy) and HR = 1.04, CI = 0.85–1.26, and p = 0.74 (prior malignancy) as compared to patients with COPD without asthma. ICS did not seem to modify the risk of cancer. In conclusion, in our study, asthma-COPD overlap was not associated with an increased risk of cancer events.

Hepatitis B virus (HBV) is causally linked to hepatocellular injury and cell death, which are followed by hepatocellular carcinoma (HCC) after a long latent period. The HBV derived X protein (HBX) is the most potent carcinogenic factor for HCC, however, the molecular mechanism of HBX-induced transformation of hepatic cells in HCC is poorly understood. We have shown that nuclear receptor co-repressor (NCoR) is essential for the spatial repression of global transcription by the promyelocytic leukemia oncogenic domains (PODs), a frequent target of viral oncoproteins like HBX and that disintegration of PODs due to misfolded conformation dependent loss (MCDL) of NCoR is linked to promyelocytic and monocytic acute myeloid leukemia (AML). Given the key role of NCoR in cellular homeostasis across various tissue subtypes, we hypothesized that HBX-induced MCDL of NCoR might be linked to HCC through similar mechanism. Based on this hypothesis, the conformation of NCoR in HCC derived tumor cells and primary human tissue sections were analyzed and a selective MCDL of NCoR in HBX positive HCC cells was identified. HBX triggered the misfolding of NCoR through ubiquitination, followed by its degradation by autophagy, thus suggesting a cross talk between ubiquitin proteasome system (UPS) and autophagy lysosomal pathway (ALP) in MCDL of NCoR in HBX positive HCC cells. SiRNA-induced NCoR ablation selectively impaired the growth and survival of HBX positive HCC cells, suggesting a role of MCDL in the growth and survival of HBX positive HCC cells. These finding identify a possible crosstalk between UPS and ALP in the misfolding and loss of NCoR in HBX positive HCC cells and suggest a role of autophagic recycling of misfolded NCoR in the activation of oncogenic metabolic signaling in HCC. The misfolded NCoR reported in this study represents a novel conformation based molecular target which could be valuable in the design and development of tumor cell specific diagnostic and therapeutic approach for HBX positive HCC.

Abstract In this paper, we propose a new convex variational model for segmentation of vector valued images. The data term of the proposed model is based on the coefficient of variation, which works well in vector valued images having intensity inhomogeneity. Due to convexity of the model, it is independent of the placement of initial contour. Better performance of the proposed model can be seen from experimental results qualitatively and quantitatively. Images in practice are of large sizes, which makes numerical methods more important. In this paper, we also develop fast and stable numerical methods for solution of partial differential equation arisen from the minimization of the proposed model. We have developed a novel multigrid method based on a locally supported smoother. The proposed method is compared with the existing methods in terms of iterations and CPU time for vector valued images having large sizes.

Organic materials from various sources have been commonly adopted as soil amendments to improve crop productivity. Phosphorus deficiency and fixation in alkaline calcareous soils drives a reduction in crop production. A two-year field experiment was conducted to evaluate the impact of rock phosphate enriched composts and chemical fertilizers both individually and in combination with plant growth promoting rhizobacteria (PGPR) on wheat productivity and soil chemical and biological and biochemical properties. The present study demonstrates significant increments in crop agronomic and physiological parameters with Pseudomonas sp. inoculated RPEC1 (rock phosphate + poultry litter + Pseudomonas sp.) over the un-inoculated untreated control. However, among all other treatments i.e., RPEC2 (rock phosphate + poultry litter solubilized with Proteus sp.), RPC (rock phosphate + poultry litter), HDP (half dose inorganic P from Single Super Phosphate-SSP 18% P2O5) and SPLC (poultry litter only); RPEC1 remained the best by showing increases in soil chemical properties (available phosphorus, nitrate nitrogen, extractable potassium), biochemical properties (alkaline phosphatase activity) and biological properties (microbial biomass carbon and microbial biomass phosphorus). Economic analysis in terms of Value Cost Ratio (VCR) showed that the seed inoculation with Pseudomonas sp. in combination with RPEC1 gave maximum VCR (3.23:1) followed by RPEC2 (2.61:1), FDP (2.37:1), HDP (2.05:1) and SPLC (2.03:1). It is concluded that inoculated rock phosphate (RP) enriched compost (RPEC1) can be a substitute to costly chemical fertilizers and seed inoculation with Pseudomonas sp. may further increase the efficiency of composts.

The well-known solid-state reaction method is used for the synthesis of Tb doped LuGd2Ga2Al3O12 phosphor. XRD and SEM techniques are used for the phase and structural morphology of the synthesized phosphor. UV, X-ray and proton induced spectroscopy is used to study the luminescence properties. LuGd2Ga2Al3O12:Tb3+ phosphor shows its highest peak in green and blue region. The two major emission peaks correspond to 5D3→7FJ (at 480 to 510 nm, blue region) and 5D4→7FJ (at 535 to 565 nm, green region). Green emission is dominant; therefore, it may be used as an efficient green phosphor. The absorption spectra of the synthesized material matches well with the spectra of light emitting diodes (LEDs); therefore, it may have applications in LEDs. X-ray spectroscopic study suggests that this phosphor may have uses in medical applications, such as X-ray imaging. The synthesized phosphor exhibits 81% efficacy in comparison to the commercial plasma display panel material (Gd2O2S:Tb3+). The Commission Internationale de l’Eclairage (CIE) chromaticity diagram is obtained for this phosphor. The decay time of ms range is measured for the synthesized phosphor.

Wireless sensor network is a collection of small devices called sensors nodes, which are deployed in the sensing field to monitor physical and environmental information. Location information of sensor node is a critical issue for many applications in wireless sensor network. The main problem is to design a path for a mobile landmark to maximize the location accuracy as well as to reduce energy consumption. Different path planning schemes have been proposed for localization. Here, this study focused only on static path planning scheme. In this article, the performance of five static path planning schemes is evaluated, namely, random way point, Scan, D-Scan, Hilbert, and Circles based on three parameters such as location error ratio, energy consumption, and number of references. Network simulator-2 is used as a simulation tool. Simulation scenarios with three node densities are used in this research study such as sparse node density, medium node density, and dense node density. The analysis of simulation results concludes that random way point has higher performance efficiency compared to rest of the static path planning algorithms concerning location error ratio (accuracy), energy consumption, and number of references in medium and dense node density scenarios. Hilbert performance was found good only in sparse node density scenario.

Groundwater is considered to be the second largest contributor to the indoor radon concentration after soil. Therefore, measurement of waterborne radon has remained a point of interest for many researchers. The main objective of this study is to study waterborne radon activity in the city of Dera Ismail Khan. In this context, water samples were collected from different locations of the city and waterborne radon was measured using a pylon vacuum water degassing system and CR-39 based radon detectors. The pylon system measured waterborne radon activities in samples of hand pumps and motor driven pumps varying from 0.015 to 0.066 Bq/L and 0.021 to 0.145 Bq/L with average values of 0.041 ± 0.015 Bq/L and 0.076 ± 0.024 Bq/L, respectively. Whereas CR-39 based measured values ranged from 0.042 to 0.125 Bq/L and 0.075 to 0.158 Bq/L with average values of 0.081 ± 0.021 Bq/L and 0.120 ± 0.020 Bq/L, respectively. The estimated average annual effective dose due to ingestion of radon from drinking water using pylon and CR-39 based radon detectors for hand and motor pump samples was found to be 1.055×10-4 mSv and 1.947×10-4 mSv, and 2.067×10-4 mSv and 3.058×10-4 mSv, respectively. The waterborne radon concentrations and as a result the annual effective dose expected to be received from it are within the recommended safe limits.

To compare human observers to a mathematically derived computer model for differentiation between malignant and benign pulmonary nodules detected on baseline screening computed tomography (CT) scans.A case-cohort study design was chosen. The study group consisted of 300 chest CT scans from the Danish Lung Cancer Screening Trial (DLCST). It included all scans with proven malignancies (n = 62) and two subsets of randomly selected baseline scans with benign nodules of all sizes (n = 120) and matched in size to the cancers, respectively (n = 118). Eleven observers and the computer model (PanCan) assigned a malignancy probability score to each nodule. Performances were expressed by area under the ROC curve (AUC). Performance differences were tested using the Dorfman, Berbaum and Metz method. Seven observers assessed morphological nodule characteristics using a predefined list. Differences in morphological features between malignant and size-matched benign nodules were analyzed using chi-square analysis with Bonferroni correction. A significant difference was defined at p < 0.004.Performances of the model and observers were equivalent (AUC 0.932 versus 0.910, p = 0.184) for risk-assessment of malignant and benign nodules of all sizes. However, human readers performed superior to the computer model for differentiating malignant nodules from size-matched benign nodules (AUC 0.819 versus 0.706, p < 0.001). Large variations between observers were seen for ROC areas and ranges of risk scores. Morphological findings indicative of malignancy referred to border characteristics (spiculation, p < 0.001) and perinodular architectural deformation (distortion of surrounding lung parenchyma architecture, p < 0.001; pleural retraction, p = 0.002).Computer model and human observers perform equivalent for differentiating malignant from randomly selected benign nodules, confirming the high potential of computer models for nodule risk estimation in population based screening studies. However, computer models highly rely on size as discriminator. Incorporation of other morphological criteria used by human observers to superiorly discriminate size-matched malignant from benign nodules, will further improve computer performance.

Human beings are continuously exposed to the radiations coming from outside and inside their bodies. Outside and inside radiations are coming from ground, building materials, food, air, the universe and even elements within human own bodies. According to UNSCEAR 2000 report, background radiations deliver an average effective dose of 2.4 mSv per person worldwide. Sustained exposure from high background radiation levels may pose substantial health threats to general public. In the current study we are presenting the results of ambient outdoor gamma dose rates measured for Jhelum valley of the state of Azad Kashmir. This study has been carried out by using Ludlum micrometer-19 which is an active and portable detector. Effects of different parameters of interest on the measured values of gamma dose rates have been investigated. For the region under investigation, minimum and maximum indoor gamma dose rates were found as 610 ± 4.05 μGy·y−1 and 1372 ± 2.7 μGy·y−1, respectively, whilst minimum and maximum outdoor gamma dose rates were found as 495 ± 4.49 μGy·y−1 and 1296 ± 2.78 μGy·y−1, respectively. Overall arithmetic mean (A.M) and geometric mean (G.M) values of gamma dose rates for indoor and outdoor measurements were found as 940 ± 3.26 μGy·y−1, 892 ± 3.35 μGy·y−1 and 928 ± 3.28 μGy·y−1, 880 ± 3.37 μGy·y−1 respectively. Excess life time cancer risk (ELCR) for indoor exposure ranges from 1.057 × 10−3 to 2.377 × 10−3 with an average value of 1.629 × 10−3. For outdoor exposure, ELCR varies from 0.352 × 10−3 to 0.792 × 10−3 with mean value of 0.543 × 10−3. Average values of indoor gamma doses were found to be greater than the world population-weighted average for indoor gamma dose rates (780 μGy·y−1 or 89 nGy h−1).

We investigated S-RNase genotypes of nine useful Afghan apple cultivars including six original cultivars and one rootstock. We also determined S-RNase genotypes of 11 apple cultivars and lineages and seven rootstocks in Japan. We speculated regarding the unidentified parents of cultivars and lineages from the S-RNase genotypes and their fruit and branch characteristics and also identified mistaken parents. We compiled a database of the apple S-RNase genotypes of 622 apple cultivars investigated, which included a survey system of cultivar combinations showing those that were fully incompatible, semicompatible, and fully compatible, written in the Pashto language.

Phosphorus deficiency is wide spread in soils of Pakistan. It is imperative to explore the potential and economics of indigenous Hazara rock phosphate for preparation of single super phosphate fertilizer. For the subject study rock phosphate was collected from Hazara area ground at 160 mesh level with 26% total P2O5 content for manual preparation of single super phosphate fertilizer. The rock phosphate was treated with various concentrations of sulfuric acid (98.9%, diluted or pure) in the field. The treatments comprised of 20 and 35% pure acid and diluted with acid-water ratios of 1:5, 1:2, 1:1 and 2:1 v/v for acidulation at the rate of 60 liters 100 kg-1 rock phosphate. The amount was prior calculated in the laboratory for complete wetting of rock phosphate. A quantity of 150 kg rock phosphate was taken as treatment. The respective amount of acid was applied with the spray pump of stainless steel or poured with bucket. After proper processing, chemical analysis of the products showed a range of available P2O5 content from 9.56 to 19.24% depending upon the amount of acid and its dilution. The results reveal at that 1:1 dilutions gave the highest P2O5 content (19.24%), lowest free acid (6 %) and 32% weight increase. The application of acid beyond or below this combination either pure or diluted gave hygroscopic product and higher free acids. The cost incurred upon the manual processing was almost half the prevailing rates in the market. These results lead to conclude that application of sulfuric acid at the rate of 60 liters 100 kg-1 with the dilution of 50% (v/v) can yield better kind of SSP from Hazara rock phosphate at lower prices.

Results of indoor radon survey in the dwellings of district Bhimber are presented. Current study is continuation of our preceding studies aiming to setup baseline indoor radon data for the state of Azad Jammu & Kashmir, Pakistan. In this context, 60 representative houses were carefully selected and CN-85 based box type radon detectors were installed in bedrooms and living rooms of each house. The detectors were exposed to indoor radon for 90 days. After etching CN-85 detectors in 6M NaOH at 70°C for 3 hours, the observed track densities were related to the indoor radon concentration using calibration factor of 0.0092 tracks cm2/h per Bq/m3. The measured indoor radon concentration ranged from 29 ± 11 to 58 ± 8 Bq/m3, 40 ± 9 to 60 ± 7 Bq/m3, and 29 ± 12 to 66 ± 7 Bq/m3 in the regions of Bhimber, Samani, and Barnala, respectively. Excess relative risk factors were calculated using measured indoor radon concentrations, by using the risk model reported in the Biological Effects of Ionizing Radiation (BEIR VI, 1999) report. Excess relative risk was calculated for age groups of 35 and 55 years. Using local occupancy factor, average excess lung cancer risk for the population group of 35 and 55 years of age was found to be 0.42 ± 0.09 and 0.34 ± 0.08. The mean annual effective dose for Bhimber, Samani, and Barnala regions were found to be 1.05 ± 0.17 mSv, 1.09 ± 0.17 mSv, and 1.16 ± 0.17 mSv, respectively. These values are within in the safe limits recommended by the international organizations.

This study was designed to investigate variation in Varian′s Physical and Enhanced Dynamic Wedge Factors (WF) as a function of depth and field size. The profiles for physical wedges (PWs) and enhanced dynamic wedges (EDWs) were also measured using LDA-99 array and compared for confirmation of EDW angles at different depths and field sizes. WF measurements were performed in water phantom using cylindrical 0.66 cc ionization chamber. WF was measured by taking the ratio of wedge and open field ionization data. A normalized wedge factor (NWF) was introduced to circumvent large differences between wedge factors for different wedge angles. A strong linear dependence of PW Factor (PWF) with depth was observed. Maximum variation of 8.9% and 4.1% was observed for 60° PW with depth at 6 and 15 MV beams respectively. The variation in EDW Factor (EDWF) with depth was almost negligible and less than two per cent. The highest variation in PWF as a function of field size was 4.1% and 3.4% for thicker wedge (60°) at 6 and 15 MV beams respectively and decreases with decreasing wedge angle. EDWF shows strong field size dependence and significant variation was observed for all wedges at both photon energies. Differences in profiles between PW and EDW were observed on toe and heel sides. These differences were dominant for larger fields, shallow depths, thicker wedges and low energy beam. The study indicated that ignoring depth and field size dependence of WF may result in under/over dose to the patient especially doing manual point dose calculation.

Nuclear receptor co-repressor (N-CoR) is the key component of generic co-repressor complex essential for the transcriptional control of genes involved in cellular hemostasis. We have recently reported that N-CoR actively represses Flt3, a key factor of hematopoietic stem cells (HSC) self-renewal and growth; and that de-repression of Flt3 by the misfolded N-CoR plays important role in the pathogenesis of promyelocytic and monocytic acute myeloid leukemia (AML). The leukemic cells derived from the promyelocytic and monocytic AML are distinctly characterized by the ectopic reactivation of stem cell phenotypes in relatively committed myeloid compartment. However, the molecular mechanism underlying this phenomenon is not known. Here, we report that N-CoR function is essential for the commitment of primitive hematopoietic cells to the cells of myeloid lineage, and that loss of N-CoR function due to misfolding is linked to the ectopic reactivation of generic stem cell phenotypes in promyelocytic and monocytic AML. Analysis of N-CoR and Flt3 transcripts in mouse hematopoietic cells revealed a positive correlation between N-CoR level and the commitment of myeloid cells and an inverse correlation between N-CoR and Flt3 levels in primitive as well as committed myeloid cells. Enforced N-CoR expression in mouse HSCs inhibited their growth and self-renewal potentials and promoted maturation towards cells of myeloid lineage, suggesting a role of N-CoR in the commitment of cells of myeloid lineage. In contrast to AML cells with natively folded N-CoR, primary and secondary promyelocytic and monocytic AML cells harboring the misfolded N-CoR were highly positive for Flt3 and myeloid antigen based HSC marker CD34. Genetic and therapeutic restoration of N-CoR conformation significantly down-regulated the CD34 levels in monocytic AML cells, suggesting an important role of N-CoR in the suppression of CD34 based hematopoietic stem cell phenotypes. These finding collectively suggest that N-CoR is crucial for the commitment of primitive hematopoietic cells to cells of myeloid lineage and that misfolded N-CoR may contribute to transformation of committed myeloid cells through the ectopic reactivation of Flt3/CD34 based stem cell phenotypes in promyelocytic and monocytic AML. Moreover, these finding provide novel mechanistic insights into the formation of leukemic stem cells in a subsets

“M.9” rootstock is considered as one of the most useful apple (Malus x domestica Borkh.) rootstocks; it produces dwarfing trees efficiently. As “M.9” rootstock shows a poor, brittle, and shallow roots system, we grafted “M.9” rootstocks onto “Marubakaidou” (M. prunifolia Borkh. var. ringo Asami Mo 84-A). We then propagated them by mound layering to establish a high-density root system. It was found that covering the roots with rice seed coat (RSC), RSC + smoked rice seed coat (SRSC), and vermiculite during mound layering was effective for the initiation of rooting. Utilizing RSC and SRSC seemed especially effective for producing “M.9” roots efficiently.

The nuclear receptor co-repressor (N-CoR) is a key component of the generic co-repressor complex that plays an important role in the control of cellular growth and differentiation. As shown by us recently, the growth suppressive function of N-CoR largely relies on its capacity to repress Flt3, a key regulator of cellular gorwth during normal and malignant hematopoesis. We further demonstrated how de-repression of Flt3 due to the misfolded conformation dependent loss (MCDL) of N-CoR contributed to malignant growth in acute myeloid leukemia (AML). However, the molecular mechanism underlying the MCDL of N-CoR and its implication in AML pathogenesis is not fully understood. Here, we report that Akt-induced phosphorylation of N-CoR at the consensus Akt motif is crucial for its misfolding and subsequent loss in AML (AML-M5). N-CoR displayed significantly higher level of serine specific phosphorylation in almost all AML-M5 derived cells and was subjected to processing by AML-M5 specific aberrant protease activity. To identify the kinase linked to N-CoR phosphorylation, a library of activated kinases was screened with the extracts of AML cells; leading to the identification of Akt as the putative kinase linked to N-CoR phosphorylation. Consistent with this finding, a constitutively active Akt consistently phosphorylated N-CoR leading to its misfolding; while the therapeutic and genetic ablation of Akt largely abrogated the MCDL of N-CoR in AML-M5 cells. Site directed mutagenic analysis of N-CoR identified serine 1450 as the crucial residue whose phosphorylation by Akt was essential for the misfolding and loss of N-CoR protein. Moreover, Akt-induced phosphorylation of N-CoR contributed to the de-repression of Flt3, suggesting a cross talk between Akt signaling and N-CoR misfolding pathway in the pathogenesis of AML-M5. The N-CoR misfolding pathway could be the common downstream thread of pleiotropic Akt signaling activated by various oncogenic insults in some subtypes of leukemia and solid tumors.

The nuclear receptor co-repressor (N-CoR) is a key component of the generic multi-protein complex involved in transcriptional control. Flt3, a key regulator of hematopoietic cell growth, is frequently deregulated in AML (acute myeloid leukemia). Here, we report that loss of N-CoR-mediated transcriptional control of Flt3 due to misfolding, contributes to malignant growth in AML of the M5 subtype (AML-M5). An analysis of hematopoietic genes in AML cells led to the identification of Flt3 as a transcriptional target of N-CoR. Flt3 level was inversely related to N-CoR status in various leukemia cells. N-CoR was associated with the Flt3 promoter in-vivo, and a reporter driven by the Flt3 promoter was effectively repressed by N-CoR. Blocking N-CoR loss with Genistein; an inhibitor of N-CoR misfolding, significantly down-regulated Flt3 levels regardless of the Flt3 receptor mutational status and promoted the differentiation of AML-M5 cells. While stimulation of the Flt3 receptor with the Flt3 ligand triggered N-CoR loss, Flt3 antibody mediated blockade of Flt3 ligand-receptor binding led to N-CoR stabilization. Genetic ablation of N-CoR potentiated Flt3 ligand induced proliferation of BA/F3 cells. These findings suggest that N-CoR-induced repression of Flt3 might be crucial for limiting the contribution of the Flt3 signaling pathway on the growth potential of leukemic cells and its deregulation due to N-CoR loss in AML-M5, could contribute to malignant growth by conferring a proliferative advantage to the leukemic blasts. Therapeutic restoration of N-CoR function could thus be a useful approach in restricting the contribution of the Flt3 signaling pathway in AML-M5 pathogenesis.

Nuclear receptor co-repressor (N-CoR) plays important role in transcriptional control mediated by several tumor suppressor proteins. Recently, we reported a role of misfolded-conformation dependent loss (MCDL) of N-CoR in the activation of oncogenic survival pathway in acute promyelocytic leukemia (APL). Since N-CoR plays important role in cellular homeostasis in various tissues, therefore, we hypothesized that an APL like MCDL of N-CoR might also be involved in other malignancy. Indeed, our initial screening of N-CoR status in various leukemia and solid tumor cells revealed an APL like MCDL of N-CoR in primary and secondary tumor cells derived from non-small cell lung cancer (NSCLC). The NSCLC cell specific N-CoR loss could be blocked by Kaletra, a clinical grade protease inhibitor and by genistein, an inhibitor of N-CoR misfolding previously characterized by us. The misfolded N-CoR presented in NSCLC cells was linked to the amplification of ER stress and was subjected to degradation by NSCLC cell specific aberrant protease activity. In NSCLC cells, misfolded N-CoR was found to be associated with Hsc70, a molecular chaperone involved in chaperone mediated autophagy (CMA). Genetic and chemical inhibition of Lamp2A, a rate limiting factor of CMA, significantly blocked the loss of N-CoR in NSCLC cells, suggesting a crucial role of CMA in N-CoR degradation. These findings identify an important role of CMA-induced degradation of misfolded N-CoR in the neutralization of ER stress and suggest a possible role of misfolded N-CoR protein in the activation of oncogenic survival pathway in NSCLC cells.