Oligosaccharyltransferase Inhibition Induces Senescence in RTK-Driven Tumor Cells

Asparagine (N)-linked glycosylation is a protein modification critical for glycoprotein folding, stability, and cellular localization. To identify small molecules that inhibit new targets in this biosynthetic pathway, we initiated a cell-based high throughput screen and lead compound optimization campaign that delivered a cell permeable inhibitor (NGI-1). NGI-1 targets the oligosaccharyltransferase (OST), a hetero-oligomeric enzyme that exists in multiple isoforms and transfers oligosaccharides to recipient proteins. In non-small cell lung cancer cells NGI-1 blocks cell surface localization and signaling of the EGFR glycoprotein, but selectively arrests proliferation in only those cell lines that are dependent on EGFR (or FGFR) for survival. In these cell lines OST inhibition causes cell cycle arrest accompanied by induction of p21, autofluorescence, and changes in cell morphology; all hallmarks of senescence. These results identify OST inhibition as a potential therapeutic approach for treating receptor tyrosine kinase-dependent tumors and provides a chemical probe for reversibly regulating N-linked glycosylation in mammalian cells

Lipids induce expression of serum-responsive transmembrane kinase EhTMKB1-9 in an early branching eukaryote Entamoeba histolytica

Mechanisms underlying the initiation of proliferative response are known only for a few organisms, and are not understood for the medically important organisms including Entamoeba histolytica. The trans membrane kinase EhTMKB1-9 of E. histolytica is one of the early indicators of proliferation and its' expression is regulated by serum, one of the components necessary for cellular proliferation in vitro. In this study we show that bovine serum albumin (BSA) can induce EhTMKB1-9 expression in place of serum, and that both follow the same mechanism. Both serum and BSA use the same promoter element and the activation process is initiated through a PI3 kinase-mediated pathway. We further show that BSA activates EhTMKB1-9 due to the lipids associated with it and that unsaturated fatty acids are responsible for activation. These results suggest that lipid molecules are ligand(s) for initiation of a signaling system that stimulates EhTMKB1-9 expression

International Liver Transplantation Society Global Census:First Look at Pediatric Liver Transplantation Activity Around the World

Background. Over 16 000 children under the age of 15 died worldwide in 2017 because of liver disease. Pediatric liver transplantation (PLT) is currently the standard of care for these patients. The aim of this study is to describe global PLT activity and identify variations between regions. Methods. A survey was conducted from May 2018 to August 2019 to determine the current state of PLT. Transplant centers were categorized into quintile categories according to the year they performed their first PLT. Countries were classified according to gross national income per capita. Results. One hundred eight programs from 38 countries were included (68% response rate). 10 619 PLTs were performed within the last 5 y. High-income countries performed 4992 (46.4%) PLT, followed by upper-middle- (4704 [44·3%]) and lower-middle (993 [9·4%])-income countries. The most frequently used type of grafts worldwide are living donor grafts. A higher proportion of lower-middle-income countries (68·7%) performed ≥25 living donor liver transplants over the last 5 y compared to high-income countries (36%; P = 0.019). A greater proportion of programs from high-income countries have performed ≥25 whole liver transplants (52.4% versus 6.2%; P = 0.001) and ≥25 split/reduced liver transplants (53.2% versus 6.2%; P &lt; 0.001) compared to lower-middle-income countries. Conclusions. This study represents, to our knowledge, the most geographically comprehensive report on PLT activity and a first step toward global collaboration and data sharing for the greater good of children with liver disease; it is imperative that these centers share the lead in PLT.</p

Serum-Dependent Selective Expression of EhTMKB1-9, a Member of Entamoeba histolytica B1 Family of Transmembrane Kinases

Entamoeba histolytica transmembrane kinases (EhTMKs) can be grouped into six distinct families on the basis of motifs and sequences. Analysis of the E. histolytica genome revealed the presence of 35 EhTMKB1 members on the basis of sequence identity (≥95%). Only six homologs were full length containing an extracellular domain, a transmembrane segment and an intracellular kinase domain. Reverse transcription followed by polymerase chain reaction (RT-PCR) of the kinase domain was used to generate a library of expressed sequences. Sequencing of randomly picked clones from this library revealed that about 95% of the clones were identical with a single member, EhTMKB1-9, in proliferating cells. On serum starvation, the relative number of EhTMKB1-9 derived sequences decreased with concomitant increase in the sequences derived from another member, EhTMKB1-18. The change in their relative expression was quantified by real time PCR. Northern analysis and RNase protection assay were used to study the temporal nature of EhTMKB1-9 expression after serum replenishment of starved cells. The results showed that the expression of EhTMKB1-9 was sinusoidal. Specific transcriptional induction of EhTMKB1-9 upon serum replenishment was further confirmed by reporter gene (luciferase) expression and the upstream sequence responsible for serum responsiveness was identified. EhTMKB1-9 is one of the first examples of an inducible gene in Entamoeba. The protein encoded by this member was functionally characterized. The recombinant kinase domain of EhTMKB1-9 displayed protein kinase activity. It is likely to have dual specificity as judged from its sensitivity to different kinase inhibitors. Immuno-localization showed EhTMKB1-9 to be a surface protein which decreased on serum starvation and got relocalized on serum replenishment. Cell lines expressing either EhTMKB1-9 without kinase domain, or EhTMKB1-9 antisense RNA, showed decreased cellular proliferation and target cell killing. Our results suggest that E. histolytica TMKs of B1 family are functional kinases likely to be involved in serum response and cellular proliferation

Artificial Intelligence - New Era

After conducting a systemic research on Artificial Intelligence, we are safe to conclude that the world is about to experience the splash of the greatest technology made so far. We are about to face perhaps the biggest technological revolution. Artificial Intelligence is the zenith of the currently prospering technological systems, which in the near future shall revolutionize the existing portal of information processes and the way humans perceive automation. This research serves as a befitting response to the question -How the world is running on AI behind the curtains and further provides an insight to the evolution of AI over the period. This paper gives a deep sense of understanding of various applications and implementations of Artificial Intelligence in different fields and the manner in which the aforementioned evolution shall root advancement into every aspect of life. It also demonstrates the negative aspects of the implementation by providing legitimate evidence from prominent scientists and acclaimed people in this arena of science. In a nutshell, this paper will illustrate the different possibilities of aspects of the development of Artificial Intelligence in the coming future

Role of Histopathology in the Diagnosis of Lytic Lesions of Bone: A Five Year Retrospective and Prospective Study

Background: The clinical and radiological features of many bone lesions overlap. Some benign processes such as osteomyelitis can mimic malignant tumors, a callus with an associated fracture can mimic osteosarcoma, whereas some malignant and metastatic lesions may mimic benign lesions. Even an orthopedic surgeon and radiologist together cannot come to a conclusion precisely. Therefore, the histopathological examination is the final guide to the orthopedic surgeon for the treatment of patients. The aim of this study to evaluate the histopathological examination of osteolytic lesions with assessment of their morphological pattern and their correlation with the clinicoradiological diagnosis. Materials &amp; Methods: A retrospective and prospective analytical study done on all patients with the radiological diagnosis of lytic lesion of bone (as evaluated by a plain x-ray) attending the OPD of the orthopedics department, and admitted to Mahatma Gandhi Hospital and Mathura Das Mathur Hospital, Jodhpur during the period of July 2009- June 2014. Their biopsies were sent to the Department of Pathology, Dr. S.N.Medical College, Jodhpur. Data was entered and analyzed by using Microsoft Excel version 2007 and Statistical Package for social science ver.16(SPSS.16) and necessary and appropriate statistical tests were applied and p value less than 0.05 was considered statistically significant.Results: Our study shows that males were affected more commonly than females in most of the age groups except at the extremities of age where males and females were equally 1.Thebenign tumors when taken together were the most frequent lesions encountered (33.02%) followed by tumor like lesions (23.58%) and inflammatory lesions (22.65%). 16.98% cases were of malignant tumors and a small percentage (3.77%) were of metastasis from other sites.Pain was the most common presenting symptom singly as well as associated with other complaints like swelling, fever etc.The histopathological diagnosis was similar to the radiological diagnosis in 86 (81.1%) cases whereas it was not similar to the radiological diagnosis in 20 (18.9%) cases. Conclusion: We concluded that light microscopy or histopathology is the gold standard in the diagnosis of bone lesions and invariably accurate when correlated with clinicoradiological features

Synthesis and characterization of some transition metal complexes of trimeric and tetrameric aminocyclophosphazenes

528-533Reactions of aminocyclotri-and aminocyclotetra-phosphazenes, viz., N3P3L6 and N4P4L8 (L = -HN(sec - C4H9), -NHC6H11, -HNC8H17,-NC5H10 and -NC4H8O) with hydrated Cu(II), Co(II), Ni(II) and Fe(III) chlorides have been studied. CuCl2.2H2O give only [(N3P3L6H or N4P4L8H)CuCl3] whereas with CoCl2.6H2O, a mixture of two products, namely, [(N3P3L6H or N4P4L8H)CoCl3] and , [(N3P3L6H or N4P4L8H)]2[CoCl4] are recovered. FeCl3.6H2O and NiCl2.6H2O give only ionic products of the type [(N3P3L6H)][FeCl4] and [(N3P3L6H)]2[NiCl4]. A few reactions of N3P3L6(L= -HN(sec-C4H9), -HNC6H13 and –HNC8H17) with Mo(CO)6, have also been carried out. In these reactions [(N3P3L6)Mo(CO)3] derivatives are obtained. The complexes have been characterized by analytical data, conductivity, magnetic and IR measurements