Cytotoxic activity of the novel heterocyclic compound G-11 is primarily mediated through intrinsic apoptotic pathway

Natural and chemically synthesized heterocyclic compounds have been explored for their potential use as anticancer agents. We had synthesized non-natural heterocyclic analogs and evaluated their anti-tumor activity by measuring effect on cell proliferation and induction of apoptosis in different cell lines. Previously, we identified a pyrazole-containing compound (G-11) showing cytotoxic effect towards leukemia and lymphoma cell lines. In this study, we further investigated the mechanistic aspects of anticancer properties of G-11 in HL-60 cell line. We demonstrated that cytotoxic effect of G-11 is mediated by caspase-dependent apoptosis. However, the involvement of mitochondrial dysfunction induced by G-11 was independent of caspases. G-11 triggered generation of ROS, caused disruption of mitochondrial transmembrane potential, increased release of cytochrome c to the cytosol, and altered the expression of Bcl-2 and Bax proteins. These results suggest significant involvement of intrinsic apoptotic pathway. This study comprehensively details the possible mechanisms of action of a novel heterocyclic compound which could find its potential use as an anticancer agent.     

Maastrichtian-early Paleocene foraminiferal palaeobathymetry and depositional sequences at Gebel El Sharawna,south Luxor,Egypt

Maastrichtian-early Paleocene foraminiferal palaeobathymetry, palaeodiversity and vertical facies changes of Gebel El Sharawna, south Luxor, Egypt have been studied to determine the depositional sequences, their relationships to global records and/or tectonic signatures. Five benthonic assemblages are recorded and replicated in the present study reflect fluctuation in palaeo-water depth from restricted marginal marine to outer shelf palaeoenvironments. Four sequence boundaries that coincide with the Campanian/Maastrichtian, intra-early Maastrichtian, Early/Late Maastrichtian, Cretaceous/Palaeogene (K/Pg) and intra-Danian were recognized based upon sharp vertical facies changes, foraminiferal assemblage changes, hiatuses, mineral hard ground and reworking. The K/Pg unconformity reveals an unexpected ca. 4.2 Myr time gap as indicated by the absence of the CF2 Zone through lower part of the P1c Zone. It is easily distinguished in the field by conglomeration and winnowing of phosphate and glauconite in the lower Paleocene. These sequence boundaries defined five third-order depositional sequences mainly developed as the result of the eustatic sea-level changes, coupled with the Arabian–Nubian shield tectonic uplift at the southern edge of the Tethys Ocean.     

Greater epithelial ridge cells are the principal organoid-forming progenitors of the mouse cochlea

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The rejuvenating influence of young plasma on aged intestine

This study aims to investigate the effects of plasma exchange on the biomolecular profiles and histology of ileum and colon tissues in young and aged Sprague–Dawley male rats. Fourier transform infrared (FTIR) spectroscopy, linear discriminant analysis and support vector machine (SVM) techniques were employed to analyse the lipid, protein, and nucleic acid indices in young and aged rats. Following the application of young plasma, aged rats demonstrated biomolecular profiles similar to those of their younger counterparts. Histopathological and immunohistochemical assessments showed that young plasma had a protective effect on the intestinal tissues of aged rats, increasing cell density and reducing inflammation. Additionally, the expression levels of key inflammatory mediators tumour necrosis factor-alpha and cyclooxygenase-2 significantly decreased after young plasma administration. These findings underscore the therapeutic potential of young plasma for mitigating age-related changes and inflammation in the intestinal tract. They highlight the critical role of plasma composition in the ageing process and suggest the need for further research to explore how different regions of the intestines respond to plasma exchange. Such understanding could facilitate the development of innovative therapies targeting the gastrointestinal system, enhancing overall health during ageing.     

Heterogeneous mechanics of the mouse pulmonary arterial network

Individualized modeling and simulation of blood flow mechanics find applications in both animal research and patient care. Individual animal or patient models for blood vessel mechanics are based on combining measured vascular geometry with a fluid structure model coupling formulations describing dynamics of the fluid and mechanics of the wall. For example, one-dimensional fluid flow modeling requires a constitutive law relating vessel cross-sectional deformation to pressure in the lumen. To investigate means of identifying appropriate constitutive relationships, an automated segmentation algorithm was applied to micro-computerized tomography images from a mouse lung obtained at four different static pressures to identify the static pressure–radius relationship for four generations of vessels in the pulmonary arterial network. A shape-fitting function was parameterized for each vessel in the network to characterize the nonlinear and heterogeneous nature of vessel distensibility in the pulmonary arteries. These data on morphometric and mechanical properties were used to simulate pressure and flow velocity propagation in the network using one-dimensional representations of fluid and vessel wall mechanics. Moreover, wave intensity analysis was used to study effects of wall mechanics on generation and propagation of pressure wave reflections. Simulations were conducted to investigate the role of linear versus nonlinear formulations of wall elasticity and homogeneous versus heterogeneous treatments of vessel wall properties. Accounting for heterogeneity, by parameterizing the pressure/distention equation of state individually for each vessel segment, was found to have little effect on the predicted pressure profiles and wave propagation compared to a homogeneous parameterization based on average behavior. However, substantially different results were obtained using a linear elastic thin-shell model than were obtained using a nonlinear model that has a more physiologically realistic pressure versus radius relationship.     

Next Generation Sequencing of Acute Myeloid Leukemia: Influencing Prognosis

Background

Epilepsy is genetically complex neurological disorder affecting millions of people of different age groups varying in its type and severity. Copy number variants (CNVs) are key players in the genetic etiology of numerous neurodevelopmental disorders and prior findings also revealed that chromosomal aberrations are more susceptible against the pathogenesis of epilepsy. Novel technologies, such as array comparative genomic hybridization (array-CGH), may help to uncover the pathogenic CNVs in patients with epilepsy.

Results

This study was carried out by high density whole genome array-CGH analysis with blood DNA samples from a cohort of 22 epilepsy patients to search for CNVs associated with epilepsy. Pathogenic rearrangements which include 6p12.1 microduplications in 5 patients covering a total region of 99.9kb and 7q32.3 microdeletions in 3 patients covering a total region of 63.9kb were detected. Two genes BMP5 and PODXL were located in the predicted duplicated and deleted regions respectively. Furthermore, these CNV findings were confirmed by qPCR.

Conclusion

We have described, for the first time, several novel CNVs/genes implicated in epilepsy in the Saudi population. These findings enable us to better describe the genetic variations in epilepsy, and could provide a foundation for understanding the critical regions of the genome which might be involved in the development of epilepsy.