Targeting phosphatidylinositol-3-kinase pathway for the treatment of Philadelphia-negative myeloproliferative neoplasms

Myeloproliferative neoplasms (MPN) are a diverse group of chronic hematological disorders that involve unregulated clonal proliferation of white blood cells. Sevearl of them are associated with mutations in receptor tyrosine kinases or cytokine receptor associated tyrosine kinases rendering them independent of cytokine-mediated regulation. Classically they have been broadly divided into BCR-ABL1 fusion + ve (Ph + ve) or -ve (Ph-ve) MPNs. Identification of BCR-ABL1 tyrosine kinase as a driver of chronic myeloid leukemia (CML) and successful application of small molecule inhibitors of the tyrosine kinases in the clinic have triggered the search for kinase dependent pathways in other Ph-ve MPNs. In the past few years, identification of mutations in JAK2 associated with a majority of MPNs raised the hopes for similar success with specific targeting of JAK2. However, targeting JAK2 kinase activity has met with limited success. Subsequently, mutations in genes other than JAK2 have been identified. These mutations specifically associate with certain MPNs and can drive cytokine independent growth. Therefore, targeting alternate molecules and pathways may be more successful in management of MPNs. Among other pathways, phosphatidylinositol -3 kinase (PI3K) has emerged as a promising target as different cell surface receptor induced signaling pathways converge on the PI3K signaling axis to regulate cell metabolism, growth, proliferation, and survival. Herein, we will review the clinically relevant inhibitors of the PI3K pathway that have been evaluated or hold promise for the treatment of Ph-ve MPNs

Localization of DOA trajectories -- Beyond the grid

The direction of arrival (DOA) estimation algorithms are crucial in localizing acoustic sources. Traditional localization methods rely on block-level processing to extract the directional information from multiple measurements processed together. However, these methods assume that DOA remains constant throughout the block, which may not be true in practical scenarios. Also, the performance of localization methods is limited when the true parameters do not lie on the parameter search grid. In this paper we propose two trajectory models, namely the polynomial and bandlimited trajectory models, to capture the DOA dynamics. To estimate trajectory parameters, we adopt two gridless algorithms: i) Sliding Frank-Wolfe (SFW), which solves the Beurling LASSO problem and ii) Newtonized Orthogonal Matching Pursuit (NOMP), which improves over OMP using cyclic refinement. Furthermore, we extend our analysis to include wideband processing. The simulation results indicate that the proposed trajectory localization algorithms exhibit improved performance compared to grid-based methods in terms of resolution, robustness to noise, and computational efficiency

Role of SHP2 in hematopoiesis and leukemogenesis

Purpose of review SH2 domain-containing tyrosine phosphatase 2 (SHP2), encoded by PTPN11 plays an important role in regulating signaling from cell surface receptor tyrosine kinases during normal development as well as oncogenesis. Herein we review recently discovered roles of SHP2 in normal and aberrant hematopoiesis along with novel strategies to target it. Recent findings Cell autonomous role of SHP2 in normal hematopoiesis and leukemogenesis has long been recognized. The review will discuss the newly discovered role of SHP2 in lineage specific differentiation. Recently, a noncell autonomous role of oncogenic SHP2 has been reported in which activated SHP2 was shown to alter the bone marrow microenvironment resulting in transformation of donor derived normal hematopoietic cells and development of myeloid malignancy. From being considered as an ‘undruggable’ target, recent development of allosteric inhibitor has made it possible to specifically target SHP2 in receptor tyrosine kinase driven malignancies. Summary SHP2 has emerged as an attractive target for therapeutic targeting in hematological malignancies for its cell autonomous and microenvironmental effects. However a better understanding of the role of SHP2 in different hematopoietic lineages and its crosstalk with signaling pathways activated by other genetic lesions is required before the promise is realized in the clinic

Sperm penetration assay and its correlation with semen analysis parameters

Background: Aim of current study was to determine whether the Sperm Penetration Assay (SPA) can be used as a test to discriminate the infertile male from fertile one. We have also correlated the SPA with semen analysis.Methods: Sperm characteristics namely Semen analysis and the sperm penetration assay were tested in 44 infertile and 10 fertile men. Sperm penetration assay was determined by using zona free hamster eggs.Results: With decreasing spermatozoa concentration in the semen there was significant decrease in percentage penetration of zona free Hamster eggs (p0.05).  Conclusions: The Sperm penetration assay could discriminate the infertile group from fertile group significantly (p<0.001). The test appeared to be highly reproducible and probably identifies a truly infertile male.

Improving trajectory localization accuracy via direction-of-arrival derivative estimation

Sound source localization is crucial in acoustic sensing and monitoring-related applications. In this paper, we do a comprehensive analysis of improvement in sound source localization by combining the direction of arrivals (DOAs) with their derivatives which quantify the changes in the positions of sources over time. This study uses the SALSA-Lite feature with a convolutional recurrent neural network (CRNN) model for predicting DOAs and their first-order derivatives. An update rule is introduced to combine the predicted DOAs with the estimated derivatives to obtain the final DOAs. The experimental validation is done using TAU-NIGENS Spatial Sound Events (TNSSE) 2021 dataset. We compare the performance of the networks predicting DOAs with derivative vs. the one predicting only the DOAs at low SNR levels. The results show that combining the derivatives with the DOAs improves the localization accuracy of moving sources

Tunable Visible Emission of Ag-Doped CdZnS Alloy Quantum Dots

Highly luminescent Ag-ion-doped Cd1−xZnxS (0 ≤ x ≤ 1) alloy nanocrystals were successfully synthesized by a novel wet chemical precipitation method. Influence of dopant concentration and the Zn/Cd stoichiometric variations in doped alloy nanocrystals have been investigated. The samples were characterized by X-ray diffraction (XRD) and high resolution transmission electron microscope (HRTEM) to investigate the size and structure of the as prepared nanocrystals. A shift in LO phonon modes from micro-Raman investigations and the elemental analysis from the energy dispersive X-ray analysis (EDAX) confirms the stoichiometry of the final product. The average crystallite size was found increasing from 1.0 to 1.4 nm with gradual increase in Ag doping. It was observed that photoluminescence (PL) intensity corresponding to Ag impurity (570 nm), relative to the other two bands 480 and 520 nm that originates due to native defects, enhanced and showed slight red shift with increasing silver doping. In addition, decrease in the band gap energy of the doped nanocrystals indicates that the introduction of dopant ion in the host material influence the particle size of the nanocrystals. The composition dependent bandgap engineering in CdZnS:Ag was achieved to attain the deliberate color tunability and demonstrated successfully, which are potentially important for white light generation