This study investigates preservice teachers’ knowledge of elements and rationale for Nature of Science (NOS). Skill gap is established in the literature on pedagogical practices of preservice as well ...as novice teachers of science, reflecting deficiency in their professional training and eventual classroom practice. Examining preservice teachers’ knowledge in these aspects (elements & rationale) of NOS through a quasi-experiment of one-group pretest and post-test design was done. Instructional intervention over two years along with assignments and presentation with researchers as moderators on the science pedagogy module (History of Science and Philosophy of Science) serves as stimuli over the period. Three research questions and two hypotheses were raised to guide this study. One hundred and thirty-six (112 Life Science and 24 Physical Science) preservice teachers were the participants. Element of NOS (ENOS) and Rationale for NOS (RNOS) were the instruments. Reliability of the instruments yielded Cronbach alpha values of .83, .91 and .86 across dimensions of clarity, coherence and relevance by fifteen experienced science educators. Data was analysed using t-test and ANCOVA. The study found the intervention to effectively improve the knowledge of elements and rationale for NOS. Better prepared teachers (More Knowledge Order MKO have the potential to improved Zone of Proximal Development ZPD in learners) by implication have the competence to guide learners for qualitative and effective learning. The instruments in this study is recommended for foundational training of preservice teachers on NOS for enhanced instruction.
Background
Hepatocellular carcinoma (HCC) is a rare cancer in children, with various histologic subtypes and a paucity of data to guide clinical management and predict prognosis.
Methods
A ...multi‐institutional review of children with hepatocellular neoplasms was performed, including demographic, staging, treatment, and outcomes data. Patients were categorized as having conventional HCC (cHCC) with or without underlying liver disease, fibrolamellar carcinoma (FLC), and hepatoblastoma with HCC features (HB‐HCC). Univariate and multivariate analyses identified predictors of mortality and relapse.
RESULTS
In total, 262 children were identified; and an institutional histologic review revealed 110 cHCCs (42%; 69 normal background liver, 34 inflammatory/cirrhotic, 7 unknown), 119 FLCs (45%), and 33 HB‐HCCs (12%). The authors observed notable differences in presentation and behavior among tumor subtypes, including increased lymph node involvement in FLC and higher stage in cHCC. Factors associated with mortality included cHCC (hazard ratio HR, 1.63; P = .038), elevated α‐fetoprotein (HR, 3.1; P = .014), multifocality (HR, 2.4; P < .001), and PRETEXT (pretreatment extent of disease) stage IV (HR, 5.76; P < .001). Multivariate analysis identified increased mortality in cHCC versus FLC (HR, 2.2; P = .004) and in unresectable tumors (HR, 3.4; P < .001). Disease‐free status at any point predicted survival.
Conclusions
This multi‐institutional, detailed data set allowed a comprehensive analysis of outcomes for children with these rare hepatocellular neoplasms. The current data demonstrated that pediatric HCC subtypes are not equivalent entities because FLC and cHCC have distinct anatomic patterns and outcomes in concert with their known molecular differences. This data set will be further used to elucidate the impact of histology on specific treatment responses, with the goal of designing risk‐stratified algorithms for children with HCC.
Lay Summary
This is the largest reported granular data set on children with hepatocellular carcinoma.
The study evaluates different subtypes of hepatocellular carcinoma and identifies key differences between subtypes.
This information is pivotal in improving understanding of these rare cancers and may be used to improve clinical management and subsequent outcome in children with these rare malignancies.
Data from this study demonstrated that pediatric hepatocellular carcinoma subtypes are not equivalent entities. This data set of more than 250 children with hepatocellular carcinoma may be used to guide treatment and impact outcomes in children.
Research on NO in plants has gained considerable attention in recent years mainly due to its function in plant growth and development and as a key signalling molecule in different intracellular ...processes in plants. The NO emission from plants is known since the 1970s, and now there is abundant information on the multiple effects of exogenously applied NO on different physiological and biochemical processes of plants. The physiological function of NO in plants mainly involves the induction of different processes, including the expression of defence-related genes against pathogens and apoptosis/programmed cell death (PCD), maturation and senescence, stomatal closure, seed germination, root development and the induction of ethylene emission. NO can be produced in plants by non-enzymatic and enzymatic systems. The NO-producing enzymes identified in plants are nitrate reductase, and several nitric oxide synthase-like activities, including one localized in peroxisomes which has been biochemically characterized. Recently, two genes of plant proteins with NOS activity have been isolated and characterized for the first time, and both proteins do not have sequence similarities to any mammalian NOS isoform. However, different evidence available indicate that there are other potential enzymatic sources of NO in plants, including xanthine oxidoreductase, peroxidase, cytochrome P450, and some hemeproteins. In plants, the enzymatic production of the signal molecule NO, either constitutive or induced by different biotic/abiotic stresses, may be a much more common event than was initially thought.
Nitric oxide (NO) has a key signalling role in plant growth and development processes, and in plant defense responses. The NO-producing enzymes identified are nitrate reductase, and several NOS-like activities. Two genes of plant proteins with NOS activity have been recently characterized, and they do not have sequence similarities to any mammalian NOS. However, there are other potential enzymatic sources of NO. The enzymatic generation of this signal molecule, may be a much more common event than was initially thought.
Nitric oxide (II) (NO) is the most important mediator of a wide range of physiological and pathophysiological processes. It is synthesized by NO synthases (NOSs), which have three main isoforms ...differing from each other in terms of activation and inhibition features, levels of NO production, subcellular localization, etc. At the same time, all isoforms are structurally very similar, and these differences are determined by NOS autoregulatory elements. The article presents an analysis of the autoregulatory and autoinhibitory mechanisms of the NOS reductase domain that determine differences in the productivity of isoforms, as well as their dependence on the concentration of Ca
ions. The main regulatory elements in NOS that modulate the electron transfer from flavin to heme include calmodulin (CaM), an autoinhibitory insert (AI), and the C-terminal tail (C-tail). Hydrophobic interactions of CaM with the surface of the NOS oxidase domain are assumed to facilitate electron transfer from flavin mononucleotide (FMN). CaM binding causes a change in the inter-domain distances, a shift of AI and the C-tail, and, as a result, a decrease in their inhibitory effect. CaM also shifts the conformational equilibrium of the reductase domain towards more open conformations, reduces the lifetime of conformations, their stereometric distribution, and accelerates the flow of electrons through the reductase domain. The AI element, apparently, induces a conformational change that hinders electron transfer within the reductase domain, similar to the hinge domain in cytochrome P450. Together with CaM, the C-tail regulates the electron flow between flavins, the distance and relative orientation of isoalloxane rings, and also modulates the electron flow from FMN to the terminal acceptor. Together with the C-tail, AI also predetermines the dependence of neuronal and endothelial forms of NOS on the concentration of Ca
ions, and the C-tail length affects differences in the productivity of NO synthesis. The inhibitory effect of the C-tail is likely to be reduced by CaM binding due to the C-tail shift due to the electrostatic repulsive forces of the negatively charged phosphate and aspartate residues. The autoregulatory elements of NOS require further study, since the mechanisms of their interaction are complex and multidirectional, and hence provide a wide range of characteristics of the observed isoforms.
RHOAG17V mutation has been implicated in peripheral T-cell lymphomas (PTCL), characteristically angioimmunoblastic T-cell lymphomas (AITL). However, the association of the dominant-negative control ...with clinicopathological profile of the neoplasm is yet not clear.
To study the impact of RHOAG17V on the clinicopathological presentation and prognostication of T-follicular helper (TFH) cell-derived PTCL and PTCL-NOS.
This was an ambispective study over six years (2015–2020), including 88 patients with diagnoses of PTCL-NOS (44), AITL (37), PTCL-TFH phenotype (P-TFH; 6), and follicular T-cell lymphoma (1) from the archives of Department of Pathology (AIIMS, New Delhi). Mutational analysis was performed using allele-specific polymerase chain reaction (PCR), validated by the sequencing of cloned products, along with conventional Sanger sequencing. Detailed clinicopathological correlation was done.
The association between the presence of mutation and diagnosis, clinical factors (demographics, performance status, organomegaly, IPI/PIT score, stage, marrow involvement), histologic and immunophenotypic presentation (pattern, high endothelial venules HEV, immunopositivity for TFH markers CD10, ICOS, PD1, BCL6, and others, CD30, and EBER ISH), and survival (overall and progression-free survival) was analyzed.
RHOAG17V mutation was present in association with diagnosis of AITL (51.35%) in comparison to PTCL-NOS (25%) and P-TFH (16.67%; p-value=0.027). Sanger sequencing of conventional PCR did not yield any mutations, and the results were based on allele-specific PCR. Mutant cases of AITL had an overall worse performance status at presentation (p-value=0.045), along with a diffuse pattern of nodal involvement (p-value=0.046). Two diffuse large B-cell lymphoma-transformed cases harbored the mutation. Amongst the PTCL-NOS patients, immunopositivity for ICOS (p-value=0.045), along with the presence of increased HEV (p-value=0.035), was noted. None of these factors showed any association with P-TFH. On multivariate analysis, wild-type status predicted an inferior OS (p-value=0.029) in AITL, whereas no significant difference was noted in PFS. Mutation did not confer a survival advantage in PTCL-NOS or P-TFH.
RHOAG17V mutation, though not specific, shows an association with diagnosis of AITL and has been studied as a lineage-assigning marker for the TFH phenotype, as implicated by ICOS immunopositivity and HEVs in PTCL-NOS. Low variant allelic frequency could lead to false-negative results with conventional PCR products. Mutant status can have prognostic implications with translational relevance and requires larger cohorts for validation.
Thanks to Science Engineering Research Board and AIIMS Research section (SERB-EEQ/2016/402, AIIMS A-653).
In the 2017 World Health Organization (WHO) classification, chronic eosinophilic leukemia, not otherwise specified (CEL, NOS), is included as one of 7 distinct diagnostic entities under the major ...category of myeloproliferative neoplasms (MPNs).1 WHO defining criteria for CEL, NOS include: (a) peripheral blood eosinophilia >1.5×109/L; (b) evidence of clonal cytogenetic or molecular genetic abnormality, and/or (c) presence of excess myeloblasts (<20%) in the peripheral blood (≥2%) or bone marrow (≥5%). In addition, other eosinophilia-associated hematolymphoid neoplasms require exclusion, particularly myeloid malignancies associated with eosinophilia such as acute myeloid leukemia with inv(16)(p13.1q22) or t(16;16)(p13.1;q22) CBFB-MYH11, MPNs including chronic myeloid leukemia, myelodysplastic syndromes MDS, MDS/MPNs, and myeloid/lymphoid neoplasms with eosinophilia and fusion genes involving tyrosine kinases (e.g., PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2; see SOHO abstract by Reiter et al). CEL, NOS is a very rare neoplasm among patients presenting with eosinophilia. For example, in a Mayo Clinic series of 1416 patients with peripheral blood eosinophilia who were evaluated between 2008 and 2019, only 17 patients (1.2%) fulfilled the WHO diagnostic criteria for CEL, NOS.2 An analysis of the Surveillance, Epidemiology, and End Results (SEER) data between 2004 and 2015 revealed a stable incidence rate of 0.4 cases/1,000,000 persons.3
► nNOS reductase conformations are characterized by FMN fluorescence lifetimes. ► Calmodulin conformationally activates electron transfer and NO synthesis. ► CaM binding shifts nNOS from input ...conformations to “open” and output states. ► The DG810 mutant of nNOS is less conformationally constrained than wild type.
We recently showed that inducible nitric oxide synthase conformational intermediates can be resolved via FMN fluorescence lifetimes. Here we show that neuronal NOS activation by calmodulin removes constraints favoring a closed ‘input state’, increasing occupation of other states and facilitating conformational transitions. The 90ps FMN input state lifetime distinguishes it from ∼4ns ‘open’ states in which FMN does not interact strongly with other groups, or 0.9ns output states in which FMN interacts with ferriheme. Enablement of the conformational cycle is an important paradigm for control in nNOS and related enzymes, and may extend to other control modalities.
To determine the molecular differences between iMCD-thrombocytopenia, anasarca, fevers, reticulin myelofibrosis, organomegaly (TAFRO), and iMCD-not otherwise specified (NOS).
CD4-positive T cells ...were isolated from two iMCD-TAFRO and two iMCD-NOS patients for RNA sequencing comparison. Serum proteins of two iMCD-TAFRO and four iMCD-NOS patients were comprehensively analyzed to identify pathogenesis-associated proteins. IGFBP-1 protein, extracted from serum analysis, was compared to healthy controls, iMCD, systemic lupus erythematosus, and rheumatoid arthritis patients.
RNA sequencing of CD4-positive T cells revealed enhanced mTOR-related signaling in iMCD-TAFRO compared to iMCD-NOS. Comprehensive serum analysis found IGFBP-1 linked to iMCD pathogenesis, significantly higher in iMCD-TAFRO. This protein may be elevated in patients with iMCD caused by an enhanced mTOR pathway.
The mTOR pathway is suggested to be activated in iMCD-TAFRO compared to iMCD-NOS, which may elevate the protein IGFBP-1. This protein may be a biomarker to distinguish iMCD-TAFRO from iMCD-NOS.
•The mTOR pathway is suggested to be activated in iMCD-TAFRO compared to iMCD-NOS.•Elevated serum IGFBP-1 may be associated with activation of the mTOR pathway.•Serum IGFBP-1 may be a biomarker to distinguish between iMCD-TAFRO and iMCD-NOS.
83 Structures of human nNOS, 55 structures of human eNOS, 13 structures of iNOS, and about 126 reported NOS-bound compounds are summarized and analyzed. Structural and statistical analysis show that, ...at least one copy of each analyzed compound binds to the active site (the substrate arginine binding site) of human NOS. And binding features of the three isoforms show differences, but the binding preference of compounds is not in the way helpful for inhibitor design targeting nNOS and iNOS, or for activator design targeting eNOS. This research shows that there is a strong structural and functional similarity between oxygenase domains of human NOS isoforms, especially the architecture, residue composition, size, shape, and distribution profile of hydrophobicity, polarity and charge of the active site. The selectivity and efficacy of inhibitors over the rest of isoforms rely a lot on chance and randomness. Further increase of selectivity via rational improvement is uncertain, unpredictable and unreliable, therefore, to achieve high selectivity through targeting this site is complicated and requires combinative investigation. After analysis on the current two targeting sites in NOS, the highly conserved arginine binding pocket and H4B binding pocket, new potential drug-targeting sites are proposed based on structure and sequence profiling. This comprehensive analysis on the structure and interaction profiles of human NOS and bound compounds provides fresh insights for drug discovery and pharmacological research, and the new discovery here is practically applied to guide protein-structure based drug discovery.
This review offers a systematic understanding about how polyphenols target multiple inflammatory components and lead to anti-inflammatory mechanisms. It provides a clear understanding of the ...molecular mechanisms of action of phenolic compounds. Polyphenols regulate immunity by interfering with immune cell regulation, proinflammatory cytokines' synthesis, and gene expression. They inactivate NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and modulate mitogen-activated protein Kinase (MAPk) and arachidonic acids pathways. Polyphenolic compounds inhibit phosphatidylinositide 3-kinases/protein kinase B (PI3K/AkT), inhibitor of kappa kinase/c-Jun amino-terminal kinases (IKK/JNK), mammalian target of rapamycin complex 1 (mTORC1) which is a protein complex that controls protein synthesis, and JAK/STAT. They can suppress toll-like receptor (TLR) and pro-inflammatory genes' expression. Their antioxidant activity and ability to inhibit enzymes involved in the production of eicosanoids contribute as well to their anti-inflammation properties. They inhibit certain enzymes involved in reactive oxygen species ROS production like xanthine oxidase and NADPH oxidase (NOX) while they upregulate other endogenous antioxidant enzymes like superoxide dismutase (SOD), catalase, and glutathione (GSH) peroxidase (Px). Furthermore, they inhibit phospholipase A2 (PLA2), cyclooxygenase (COX) and lipoxygenase (LOX) leading to a reduction in the production of prostaglandins (PGs) and leukotrienes (LTs) and inflammation antagonism. The effects of these biologically active compounds on the immune system are associated with extended health benefits for different chronic inflammatory diseases. Studies of plant extracts and compounds show that polyphenols can play a beneficial role in the prevention and the progress of chronic diseases related to inflammation such as diabetes, obesity, neurodegeneration, cancers, and cardiovascular diseases, among other conditions.
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