MECHANISM OF REGULATION OF KINESINS EG5 AND KIF15 BY TPX2

Cell division is the fundamental process by which the replicated genetic material is faithfully segregated to form two identical daughter cells. The mitotic spindle is the macromolecular cytoskeletal structure that is built during every round of cell division to successfully separate the duplicated genome equally into the daughter cells. Errors in spindle formation can thus causegenetic aberrations and can potentially lead to cancer. Understanding the mechanisms that govern proper spindle assembly and function is thus important. Eg5 and Kif15 are two important kinesins which play a major role in establishing and maintaining bipolarity of the mitotic spindle. Both Eg5 and Kif15 have been shown to be regulated by the spindle assembly factor Targeting Protein for Xklp2, or TPX2 the mechanistic details of which remains less clear. The studies presented in this dissertation are aimed at understanding how TPX2 regulates Eg5 and Kif15 using a combination of in vitro reconstitution experiments and live cell imaging. The microtubule co-sedimentation experiments show that removal of the Eg5 interaction domain located on the C-terminus of TPX2 does not abolish the microtubule binding ability of TPX2. My data show that the microtubule binding of TPX2 is vii electrostatic but does not involve the negatively charged tubulin E-hook region. In in vitro reconstitution Total Internal Reflection Fluorescence (TIRF) experiments, the Eg5-EGFP molecules derived from mammalian cells extracts display biophysical properties similar to the purified Eg5-EGFP molecules. In single molecule TIRF assays, full length TPX2 inhibited Eg5 motion on microtubules and removal of the Eg5 interaction domain from the C-terminus of TPX2 (TPX2-710) significantly reduced the inhibitory effect of TPX2 on Eg5. Data from microtubule surface gliding assays using monomeric and dimeric Eg5 molecules show that dimerization of Eg5 or the residues located in the neck and stalk region of Eg5 are important for the interaction of TPX2 with Eg5. These results suggest that both microtubule binding and ability of TPX2 to interact with Eg5 contribute to the regulation of Eg5 by TPX2. My data show that the presence of C-terminus of TPX2 enhances Kif15 recruitment of Kif15 onto spindle microtubules and is also required for Eg5 independent bipolar spindle assembly. Characterization of Kif15-GFP molecules from cell extracts suggest that the motor molecules exist as tetramers. In single molecule TIRF experiments, only full length TPX2 suppresses Kif15 motor walking but not the C-terminally truncated TPX2-710. In live cells, fluorescent Kif15-GFP puncta stream towards microtubule plus-ends at rates consistent with microtubule growth rates. Treatment with Paclitaxel suppresses the motility of Kif15 puncta suggesting that dynamic microtubules contribute to the Kif15 behavior in cells. These results offer some mechanistic insights into how TPX2 regulates both the motors Eg5 and Kif15 through its C-terminus

The effect of body mass index on blood pressure in adults with hypertension

Background: We investigated the association of body mass index (BMI) measurements in adult hypertensive patients with normal weight and overweight including obesity.Methods: This was a randomized study performed in Udaipur, India, on 200 hypertensive patients aged (32-90) years. Patients were divided according to their body weight (normal weight vs overweight and obesity) into two groups. Weight, height and BMI were measured to estimate the various categories of bodyweight.Results: We found significant relations between body weight and blood pressure. Patients with normal weight had a normal blood pressure. However, a significant increase in blood pressure was observed in patients with overweight and obesity.Conclusions: BMI is related with weight status in hypertensive overweight / obese patients. 

Lixisenatide: a once-daily glucagon-like peptide-1 receptor agonist

Lixisenatide (AVE0010) is a once-daily glucagon-like peptide-1 (GLP-1) receptor agonist used in the treatment of type 2 diabetes. Phase II dose-finding and pharmacodynamic studies identified the 20 µg once-daily dose as having the optimum combination of efficacy, convenience and tolerability. Lixisenatide was prospectively investigated in a series of 11 multinational, randomised, controlled phase III trials (GLP-1 agonist AVE0010 in patients with type 2 diabetes mellitus for Glycemic control and safety evaluation [Getgoal] programme) that included a direct head-to-head study with exenatide. The Getgoal programme established the efficacy and safety profile of lixisenatide 20 µg once daily across the spectrum of patients with type 2 diabetes, including patients not treated with anti-diabetic agents, those failing on oral agents and as an adjunct to basal insulin therapy. The main efficacy endpoints were met in all studies, with the baseline to endpoint reductions in HbA1c consistently ranging from 0.7% to 1.0%. In a head-to-head comparison with exenatide 10 µg twice daily, lixisenatide 20 µg once daily was non-inferior for HbA1c reduction, achieved with threefold fewer patients with symptomatic hypoglycemia events and better gastrointestinal tolerability. Three randomised trials of lixisenatide treatment added to basal insulin showed significantly improved glycemic control over placebo, with pronounced postprandial glucose reductions and good tolerability. Discontinuations for adverse events were consistently low, ranging from 2.5% to 10.4%. As the provision of individualized care moves center stage in diabetes management, lixisenatide with once-daily dosing, a single maintenance dose and fixed-dose pens offers an important treatment option for type 2 diabetes

Need of fostering academic research for bridging the gap of “science- commerce disconnect” in ‘non-profitable’ therapy areas

Pharmaceutical companies share the goal of patient benefit with healthcare professionals. However, they are commercial organizations and hence, sometimes, commercial interest may take over science, resulting in “science-commercial disconnect”. This can result in innovation-deficit and financial burden on the patients. Finding new indications for existing drugs and promoting academic research in ‘non-profitable areas’ are some measures to curtail pharmaceutical innovation-deficit. Greater involvement of academicians and non-government organizations in clinical research with government support/funding will help in providing best treatment options to the patients for better outcomes.

Sheppard's correction : moment relationships and correction terms

This thesis is concerned with the detailed derivation of Sheppard's Correction Formula relating the true to the raw moments by the use of Euler-MacLaurin formula. Special moment relationships have been derived using different special functions, whose application is made to derive correction formula for the semi-invariants. Special investigation is carried out on the error term resulting from the moment relationship mentioned above. Further, a moment relationship is established for a normal distribution function using a Taylor series approach

Digital model of a synchronous generator excitation system

This thesis develops a simplified and logical simulation model for an amplidyne excitation system for a synchronous generator with an automatic voltage regulator. The non-transfer function representation using field determined parameters including variable inductance and machine saturation was used to reduce the computing time for the stability analysis. The simulation of the above model was programmed in Fortran, The simulation results are compared with actual data taken in the laboratory. From the results it was observed that steady state voltage for the model and the actual system was within 3. 0%. But the transient response of the model and actual system did not agree

A study of the quantization procedure : higher order information and the conditions for minimum error

Quantization is a non-linear operation of converting a continuous signal into a discrete one, assuming a finite number of levels N. A study is made of the quantization procedure, starting from the year 1898 to the present time. Conditions for minimum error are derived with consideration of quantization in magnitude and time. An extension of the Mehler and Carlitz formulas involving Hermitian polynomials (quadrilinear case) has been created. Further, investigation is conducted toward obtaining an autocorrelation function of the output of the quantizer for Gaussian input. The method calls for the use of two different forms of the Euler-Maclaurin sum formulas and results are derived for a hard limiter, linear detector, clipper, and a smooth limiter. The method lends itself to the extension to the non-uniform case

Comparison of Seasonal Cycles of Phytoplankton Chlorophyll, Aerosols, Winds and Sea-Surface Temperature off Somalia

In climate research, an important task is to characterize the relationships between Essential Climate Variables (ECVs). Here, satellite-derived data sets have been used to examine the seasonal cycle of phytoplankton (chlorophyll concentration) in the waters off Somalia, and its relationship to aerosols, winds and Sea Surface Temperature (SST). Chlorophyll-a (Chl-a) concentration, Aerosol Optical Thickness (AOT), Ångström Exponent (AE), Dust Optical Thickness (DOT), SST and sea-surface wind data for a 16-year period were assembled from various sources. The data were used to explore whether there is evidence to show that dust aerosols enhance Chl-a concentration in the study area. The Cross Correlation Function (CCF) showed highest positive correlation (r2 = 0.3) in the western Arabian Sea when AOT led Chl-a by 1–2 time steps (here, 1 time step is 8 days). A 2 × 2◦ box off Somalia was selected for further investigations. The correlations of alongshore wind speed, Ekman Mass Transport (EMT) and SST with Chl-a were higher than that of AOT, for a lag of 8 days. When all four variables were considered together in a multiple linear regression, the increase in r2 associated with the AOT is only about 0.02, a consequence of covariance among AOT, SST, EMT and alongshore wind speed. The AOT data show presence of dust aerosols most frequently during the summer monsoon season (June–September). When the analyses were repeated for the dust aerosol events, the correlations were generally lower, but still significant. Again, the inclusion of DOT in the multiple linear regression increased the correlation coefficient by only 2%, indicating minor enhancement in Chl-a concentration. Interestingly, during summer monsoon season, there is a higher probability of finding more instances of positive changes in Chl-a after one time step, regardless of whether there is dust aerosol or not. On the other hand, during the winter monsoon season (November–December) and rest of the year, the probability of Chl-a enhancement is higher when dust aerosol is present than when it is absent. The phase relationship in the 8-day climatologies of Chl-a and AOT (derived from NASA’s SeaWiFS and MODIS-A ocean colour processing chain) showed that AOTled Chl-a for most of the summer monsoon season, except when Chl-a was very high, during which time, Chl-a led AOT. The phase shift in the Chl-a and AOT climatological relationship at the Chl-a peak was not observed when AOT from Aerosol Climate Change Initiative (Aerosol-CCI) was used

Fetomaternal outcome in pregnancies complicated by fibroid

Background: Fibromyoma (leiomyoma) is the most common benign tumour of the uterus. Approximately 10% to 30% of women with uterine fibroids developed complications during pregnancy. The aim of the study was planned to ascertain the fetomaternal outcome in pregnancies complicated by fibroid.Methods: A hospital based cross-sectional study was conducted among pregnant women with documented uterine fibroid who was admitted for any complication or delivered in the department of obstetrics and gynaecology, RIMS, Imphal from September 2017 to August, 2019 in the department of obstetrics and gynaecology in collaboration with department of paediatrics, Regional institute of Medical Sciences, Imphal. Detailed clinical history and socio-demographic profile were recorded in pre-designed proforma. General physical examination and systemic examination and obstetrical examination was carried out for the participants.Results: Major proportions was in the age group of 30-39 years (73.9%). Fibroids were more frequent in primigravida (76.1%) followed by P1 (15.2%) and ≥P2 (8.7%). Out of 46 patients 43 (93.5%) delivered by CS (69.76%), NVD (25.58%) and instrumental delivery (4.65%) while 3 patients (6.5%) undergo spontaneous abortions. Most common myoma found in this study was intramural (47.8%) followed by submucous (34.8%) and subserosal (17.4%). Out of 43 deliveries most common complications found was atonic PPH (6.97%) and placenta previa (6.97%) followed by degenerations (2.32%), abruptio placentae (2.32%), malpresentations (2.32%). Out of 43 deliveries 6.9% baby born with low birth weight, IUGR (6.9%), IUFD (4.6%), NICU admission (4.65%) and early neonatal death (2.32%).Conclusions: Pregnancies with fibroids are considered as high-risk pregnancy associated with complications during the antepartum, intrapartum, postpartum period. Pregnant women with myoma can be advised for regular ANC along with TAS for early diagnosis and management of complication

Discursos sagrados, seculares, y ecológicos: el Proyecto de Sethusamudram

The nature of discourse in public culture has changed significantly if not noticeably in just the past few decades. The Sethusamudram Shipping Canal Project (SSCP) intended to create a commercial shipping lane between India and Sri Lanka demonstrates the nature of this change in discourse, which seems focused around the convergence of traditional news media and public commentary through the medium of the Internet which increases the reach of news as well as the speed with which that news arrives to its audience. Just two decades earlier, at a time when the Internet was very young, many of the same political parties and government agencies involved with the SSCP were also involved in the Babri Mosque controversy which culminated in the deaths of perhaps 2000 people as well as the destruction of an historical site, the mosque itself. While many factors are likely to have contributed, the SSCP controversy, in which thousands of concerned Hindus mobilized in protests, resulted in little if no injury or damage to property. This was, perhaps, due in part to the nature of the public discourse.La naturaleza del discurso en la cultura pública ha experimentado cambios notables en el transcurso de unas décadas. El análisis del proyecto Sethusamudram Shipping Canal Project (SSCP) para la creación de una línea de navegación comercial entre la India y Sri Lanka muestra el efecto de este cambio en el que Internet ha sido decisivo debido a la mayor afluencia de noticias y a su rápida difusión respecto de los medios tradicionales de comunicación y de creación de opinión pública. Solo dos décadas atrás, cuando Internet iniciaba su andadura, muchos de los partidos políticos y agencias gubernamentales involucrados en el SSCP se vieron implicados en el polémico asunto de la Mezquita de Babri que culminó con la muerte de casi 2.000 personas así como con la destrucción del propio monumento. Aunque indudablemente hay que tener en cuenta otros factores, la controversia en torno al SSCP que ha seguido movilizando a miles de activistas hindúes, no ha producido daños personales ni materiales. Comportamientos tan distintos podrían explicarse, en parte, por los cambios habidos en las formas del discurso público