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Summary: Recalling the remarkable developmental similarities between cancer cells and embryonic tissues, this paper argues that, by the process of retrodifferentiation and heterochronization, stem cells that have become neoplastic could be said to have undergone “cellular heterochrony.” It theorizes, therefore, that hormones are the major factor in the non-random regulation of cellular heterochrony in tumourigenesis. Two recent articles confirm that there is low thyroxine and high prolactin in glioblastomas. Thyroxine metamorphoses vertebrates’ tissues so as to mature the tissues, e.g., in amphibian metamorphosis. In 1896, thyroxine (horse thyroid extract) was the first successful hormonal product to be used against a fulminating breast cancer. Recent work confirms the important role of prolactin in the induction and progression of mammary, prostate and colorectal tumours. Although the pituitary is the main source of prolactin in vertebrates, there is also placental production of prolactin, and paracrine production of prolactin by tumours themselves. Since tumours produce their own prolactin, shutting down the pituitary source has not proven wholly successful. Research to find prolactin receptor antagonists is ongoing. Therefore, prolactin inhibitors (dopamine agonists), prolactin receptor antagonists, plus thyroxine comprise a plausible metamorphic therapy for shrinking solid tumour mass. By contrast with “differentiation” therapies currently sought by stem cell oncologists, this paper advocates “metamorphic” therapies, to introduce hormonal oncological knowledge of how to modulate signalling pathways that are aberrant in the stem cells that give rise to tumours. Despite subtle differences in these signalling translation pathways and cascades, strategies exist that will allow these evolved populations, going back to their stem precursors, to “metamorphose” or perhaps apoptotically cease proliferation. [Copyright &y& Elsevier]

Reports the continues surgical removal of spleen in Europe. Effects of splenectomy on human body; Advantages of isotope scanning; Suggestion regarding the preservation of spleen according to a conservative management.

Focuses on the necessity of training for surgical care on physicians in developing countries. Requirements of physicians before administration of surgery; Government policy on training of physicians; Factors for restriction of training in Kenya; Role of surgical establishments on training and assessment of surgeons.

• There are many exemplars of success for high-achieving Indigenous primary and secondary students. • Academic self-concept predicts future academic success for high-achieving Indigenous and nonIndigenous students. • Academic self-concept and achievement are reciprocally related. • Results are consistent for high-achieving Indigenous and nonIndigenous students in math and English. • Results inform future policy/practice on the drivers of success for high-achieving Indigenous and nonIndigenous students. Indigenous Australians are highly disadvantaged educationally and on all socioeconomic indicators, but graduating from university largely closes this gap. However, despite clear examples of Indigenous success, little research has focused on the drivers of success of high-achieving Indigenous students to emulate their success. Thus, the explicit purpose of our study is to identify psychological drivers of Indigenous academic success for high-achieving students and compare these to those of high-achieving nonIndigenous students. To accomplish this purpose, we test the reciprocal effects model (REM) of self-concept and achievement for high-achieving Indigenous students (N = 493) and matched nonIndigenous students (N = 586) in primary and secondary schools. Academic achievement and self-concept were reciprocally related over three annual time waves, supporting the REM for high-achieving Indigenous and nonIndigenous students. Furthermore, results were invariant over two within-person facets (time and content-domain—math vs. English) and two between-person facets (Indigenous vs. nonIndigenous, and primary vs. secondary students). The results have important policy/practice implications for the drivers of success for high-achieving Indigenous students, education of high-achieving students more generally, and self-concept theory and research. [ABSTRACT FROM AUTHOR]

Interferons (IFNs) play a central role in immunity and emerging evidence suggests that IFN-signalling coordinately regulates sterol biosynthesis in macrophages, via Sterol Regulatory Element-Binding Protein (SREBP) dependent and independent pathways. However, the precise mechanisms and kinetic steps by which IFN controls sterol biosynthesis are as yet not fully understood. Here, we elucidate the molecular circuitry governing how IFN controls the first regulated step in the mevalonate-sterol pathway, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), through the synthesis of 25-Hydroxycholesterol (25-HC) from cholesterol by the IFN-inducible Cholesterol-25-Hydroxylase (CH25H). We show for the first 30-min of IFN stimulation of macrophages the rate of de novo synthesis of the Ch25h transcript is markedly increased but by 120-min becomes transcriptionally curtailed, coincident with induction of the Activating Transcription Factor 3 (ATF3) repressor. We demonstrate ATF3 induction by Toll-like receptors is strictly dependent on IFN-signalling. While the SREBP-pathway dependent rates of de novo transcription of Hmgcr are relatively unchanged in the first 90-min of IFN treatment, we find HMGCR enzyme levels undergo a rapid proteasomal-mediated degradation, defining a previously unappreciated SREBP-independent mechanism for IFN-action. These events precede a sustained marked reduction in Hmgcr RNA levels involving SREBP-dependent mechanisms. We demonstrate that HMGCR proteasomal-degradation by IFN strictly requires the synthesis of endogenous 25-HC and functionally couples HMGCR to CH25H to coordinately suppress sterol biosynthesis. In conclusion, we quantitatively delineate proteomic and transcriptional levels of IFN-mediated control of HMGCR, the primary enzymatic step of the mevalonate-sterol biosynthesis pathway, providing a foundational framework for mathematically modelling the therapeutic outcome of immune-metabolic pathways. [ABSTRACT FROM AUTHOR]

Abstract: Using a structure based design approach we have identified a series of indazole substituted pyrrolopyrazines, which are potent inhibitors of JAK3. Intramolecular electronic repulsion was used as a strategy to induce a strong conformational bias within the ligand. Compounds bearing this conformation participated in a favorable hydrophobic interaction with a cysteine residue in the JAK3 binding pocket, which imparted high selectivity versus the kinome and improved selectivity within the JAK family. [Copyright &y& Elsevier]

Chronic exposure to lower oxygen tension may increase cellular resistance to different types of acute metabolic stress. Here, we show that 24-h-long exposure to slightly decreased oxygen tension (partial pressure of oxygen (PO[sub 2]) of 100 mm Hg instead of normal 144 mm Hg) confers resistance against acute hypoxia/reoxygenation-induced Ca[sup 2+] loading in heart-derived H9c2 cells. The number of ATP-sensitive K[sup +] (K[sub ATP]) channels were increased in cells exposed to PO[sub 2] = 100 mm Hg relative to cells exposed to PO[sub 2] = 144 mm Hg. This was due to an increase in transcription of SUR2A, a K[sub ATP] channel regulatory subunit, but not Kir6.2, a K[sub ATP] channel poreforming subunit. PO[sub 2] = 100 mm Hg also increased the SUR2 gene promoter activity. Experiments with cells overexpressing wild type of hypoxia-inducible factor (HIF)-1α and dominant negative HIF-1β suggested that the HIF-1-signaling pathway did not participate in observed PO[sub 2]-mediated regulation of SUR2A expression. On the other hand, NADH inhibited the effect of PO[sub 2] = 100 mm Hg but not the effect of PO[sub 2] = 20 mm Hg. LY 294002 and PD 184 352 prevented PO[sub 2]-mediated regulation of K[sub ATP] channels, whereas rapamycin was without any effect. HMR 1098 inhibited the cytoprotective effect of PO[sub 2] = 100 mm Hg, and a decrease of PO[sub 2] from 144 to 100 mm Hg did not change the expression of any other gene, including those involved in stress and hypoxic response, as revealed by Affymetrix high density oligonucleotide arrays. We conclude that slight hypoxia activates HIF-1α-independent signaling cascade leading to an increase in SUR2A protein, a higher density of K[sub ATP] channels, and a cellular phenotype more resistant to acute metabolic stress. [ABSTRACT FROM AUTHOR]

The genus Coccolithovirus is a recently discovered group of viruses that infect the globally important marine calcifying microalga Emiliania huxleyi. Among the 472 predicted genes of the 407,339-base pair genome are a variety of unexpected genes, most notably those involved in biosynthesis of ceramide, a sphingolipid known to induce apoptosis. Uniquely for algal viruses, it also contains six RNA polymerase subunits and a novel promoter, suggesting this virus encodes its own transcription machinery. Microarray transcriptomic analysis reveals that 65% of the predicted virus-encoded genes are expressed during lytic infection of E. huxleyi. [ABSTRACT FROM AUTHOR]

"Delusions" are beliefs that are false and persistent. It is suggested here that these characteristics can emerge from interplays between two fundamental learning processes: (1) the allocation of attentional resources among stimuli; and (2) the effects of feedback on learning. The former of these has been operationalized in the learned irrelevance and latent inhibition paradigms; the latter in studies of the effects of persistence-training. Normally, the attentional process functions to constrain persistence-training effects so that only valid associations acquire persistence. But when persistence-training is less influenced in this way, its mechanisms can interact with a noisy environment to gradually insulate maladaptive associations from disconfirming feedback. When unchecked, these dynamics likely lead to a systematic distortion of beliefs that can become increasingly persistent regardless of their validity. Delusions are therefore predicted to tend to arise whenever the balance of (1) is weakened in favour of (2), whether by experimental manipulation, trait-related factors, cultural causes or evolutionary history. Existing evidence is consistent with the model and further implications are discussed., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The Janus kinases (JAKs) are involved in multiple signaling networks relevant to inflammatory diseases, and inhibition of one or more members of this class may modulate disease activity or progression. We optimized a new inhibitor scaffold, 3-amido-5-cyclopropylpyrrolopyrazines, to a potent example with reasonable kinome selectivity, including selectivity for JAK3 versus JAK1, and good biopharmaceutical properties. Evaluation of this analogue in cellular and in vivo models confirmed functional selectivity for modulation of a JAK3/JAK1-dependent IL-2 stimulated pathway over a JAK1/JAK2/Tyk2-dependent IL-6 stimulated pathway.

Genetic understanding of male-factor infertility requires knowledge of gene expression patterns associated with normal germ cell differentiation. The mouse is one of the best models of mammalian fertility due to its well-characterized genetics and the existence of many infertile mutants both naturally occurring and experimentally induced. We used cDNA microarrays firstly to investigate normal gene expression in the wild-type (wt) testis and secondly to gain a better insight into the effect of the disruption of the Dazl gene on spermatogenesis. We constructed a cDNA microarray from a subtracted and normalized adult testis library and focused on six developmental time-points during the initial synchronous wave of spermatogenesis. The results suggest that in the wild-type testis, 89.5% of genes on our chip change expression dramatically during the time-course. To identify patterns in the gene-expression data, a k-means clustering algorithm and principal component analysis were used. In the Dazl knockout testes, the majority of genes remain at baseline levels of expression, because absence of Dazl has a severe effect on cell-types present in the testis. Although in the prepubescent Dazl-null mice the final point reached in germ cell development is the leptotene-zygotene stage, the microarray results suggest that lack of Dazl expression has a detectable effect on the mRNA complement of germ cells as early as day 5 when only type A spermatogonia are present. Mol. Reprod. Dev. 67: 26-54, 2004., (Copyright 2004 Wiley-Liss, Inc.)