For several decades, nature of Science (NOS) has been advocated as the fourth dimension of science teaching and is a fundamental source of in-depth learning and teaching. In addition to improving ...learning and teaching of science, the explicit inclusion of NOS in science curricula helps the creation of a responsible citizenry. Here, we analyze the representation of NOS aspects in science curricula, particularly in the physics syllabi in four East African Community (EAC) countries: Burundi, Rwanda, Tanzania, and Uganda. These EAC countries have been purposively selected because of sharing similar culture and history as neighboring countries. To compare NOS representation in the physics content, five major topic areas (mechanics, heat and thermodynamics, oscillations and waves, electricity, and atomic physics) were randomly selected from the syllabi used in advanced level secondary schools. The paper critically analyzes the representation of NOS aspects throughout front matter (introductions and rationales) and back matter (appendices and references), content, teaching methods, and assessment procedures proposed in these physics’ syllabi. Based on the analysis of data, the findings reveal that NOS aspects are not explicitly represented in the four physics syllabi analyzed. This study also found that in four syllabi reviewed, competencies were given much attention without any overt connection to the work of scientists. Finally, we suggest possible ways to improve NOS representation in the science curriculum.
Nitric oxide (NO) has been implicated in migraine pathogenesis based on the delayed development of typical migraine headache 4–6 h after infusing the NO donor nitroglycerin glyceryl trinitrate (GTN) ...to migraineurs. Furthermore, inhibiting the synthesis of NO by treatment with a NO synthase (NOS) inhibitor attenuates spontaneous migraine headaches in 67% of subjects. Because NO has been linked to inflammation and cytokine expression, we investigated the delayed consequences of brief GTN infusion (30 min) on the development of meningeal inflammation in a rat model using doses relevant to the human model. We found dose-dependent Type II NOS inducible NOS (iNOS) mRNA upregulation in dura mater beginning at 2 h and an increase in the corresponding protein expression at 4, 6 and 10 h after infusion. Type II NOS immunoreactivity was expressed chiefly within resident meningeal macrophages. Consistent with development of a delayed inflammatory response, we detected induction of interleukin 1β in dura mater at 2 and 6 h and increased interleukin 6 in dural macrophages and in rat cerebrospinal fluid at 6 h after GTN infusion. Myeloperoxidase-positive cells were rarely found. Leakage of plasma proteins from dural blood vessels was first detected 4 h after GTN infusion, and this was suppressed by administering a specific Type II NOS inhibitor L-N(6)-(1-iminoethyl)-lysine (L-NIL). In addition to cytokine induction, macrophage iNOS upregulation and oedema formation after GTN infusion, dural mast cells exhibited granular changes consistent with secretion at 4 and 6 h. Because iNOS was expressed in dural macrophages following topical GTN, and in the spleen after intravenous injection, the data suggest that the inflammatory response is mediated by direct actions on the dura and does not develop secondary to events within the brain. Our findings point to the importance of new gene expression and cytokine expression as fundamental to the delayed response following GTN infusion, and support the hypothesis that a similar response develops in human meninges after GTN challenge.
Arginine-dependent immune responses Martí i Líndez, Adrià-Arnau; Reith, Walter
Cellular and molecular life sciences : CMLS,
07/2021, Letnik:
78, Številka:
13
Journal Article
Recenzirano
Odprti dostop
A growing body of evidence indicates that, over the course of evolution of the immune system, arginine has been selected as a node for the regulation of immune responses. An appropriate supply of ...arginine has long been associated with the improvement of immune responses. In addition to being a building block for protein synthesis, arginine serves as a substrate for distinct metabolic pathways that profoundly affect immune cell biology; especially macrophage, dendritic cell and T cell immunobiology. Arginine availability, synthesis, and catabolism are highly interrelated aspects of immune responses and their fine-tuning can dictate divergent pro-inflammatory or anti-inflammatory immune outcomes. Here, we review the organismal pathways of arginine metabolism in humans and rodents, as essential modulators of the availability of this semi-essential amino acid for immune cells. We subsequently review well-established and novel findings on the functional impact of arginine biosynthetic and catabolic pathways on the main immune cell lineages. Finally, as arginine has emerged as a molecule impacting on a plethora of immune functions, we integrate key notions on how the disruption or perversion of arginine metabolism is implicated in pathologies ranging from infectious diseases to autoimmunity and cancer.
The first few hours and days after subarachnoid hemorrhage (SAH) are characterized by cerebral ischemia, spasms of pial arterioles, and a significant reduction of cerebral microperfusion, however, ...the mechanisms of this early microcirculatory dysfunction are still unknown. Endothelial nitric oxide production is reduced after SAH and exogenous application of NO reduces post-hemorrhagic microvasospasm. Therefore, we hypothesize that the endothelial NO-synthase (eNOS) may be involved in the formation of microvasospasms, microcirculatory dysfunction, and unfavorable outcome after SAH. SAH was induced in male eNOS deficient (eNOS–/–) mice by endovascular MCA perforation. Three hours later, the cerebral microcirculation was visualized using in vivo 2-photon-microscopy. eNOS–/– mice had more severe SAHs, more severe ischemia, three time more rebleedings, and a massively increased mortality (50 vs. 0%) as compared to wild type (WT) littermate controls. Three hours after SAH eNOS–/– mice had fewer perfused microvessels and 40% more microvasospasms than WT mice. The current study indicates that a proper function of eNOS plays a key role for a favorable outcome after SAH and helps to explain why patients suffering from hypertension or other conditions associated with impaired eNOS function, have a higher risk of unfavorable outcome after SAH.
In previous studies, the inhibitory effect of chloroquine on NLRP3 inflammasome and heme production was documented. This may be employed as a double-bladed sword in schistosomiasis (anti-inflammatory ...and parasiticidal). In this study, chloroquine's impact on schistosomiasis mansoni was investigated. The parasitic load (worm/egg counts and reproductive capacity index RCI), i-Nos/Arg-1 expression, splenomegaly, hepatic insult and NLRP3-immunohistochemical expression were assessed in infected mice after receiving early and late repeated doses of chloroquine alone or dually with praziquantel. By early treatment, the least RCI was reported in dually treated mice (41.48 ± 28.58) with a significant reduction in worm/egg counts (3.50 ± 1.29/2550 ± 479.58), compared with either drug alone. A marked reduction in the splenic index was achieved by prolonged chloroquine administration (alone: 43.15 ± 5.67, dually: 36.03 ± 5.27), with significantly less fibrosis (15 ± 3.37, 14.25 ± 2.22) than after praziquantel alone (20.5 ± 2.65). Regarding inflammation, despite the praziquantel-induced significant decrease in NLRP3 expression, the inhibitory effect was marked after dual and chloroquine administration (liver: 3.13 ± 1.21/3.45 ± 1.23, spleen: 5.7 ± 1.6/4.63 ± 2.41). i-Nos RNA peaked with early/late chloroquine administration (liver: 68.53 ± 1.8/57.78 ± 7.14, spleen: 63.22 ± 2.06/62.5 ± 3.05). High i-Nos echoed with a parasiticidal and hepatoprotective effect and may indicate macrophage-1 polarisation. On the flip side, the chloroquine-induced low Arg-1 seemed to abate immune tolerance and probably macrophage-2 polarisation. Collectively, chloroquine synergised the praziquantel-schistosomicidal effect and minimised tissue inflammation, splenomegaly and hepatic fibrosis.
Recombinase polymerase amplification (RPA) was first reported in 2006 and has recently been shown to improve the detection of genetically modified organisms (GMOs). This study developed a more ...efficient RPA-based and lateral flow test strip (LFD)-based platform for the detection of P–35S and T-nos for GMOs, circumventing the need for expensive instruments and technicians. Other methods were compared to our assay. The RPA forward and reverse primers were labeled with the fluorophore biotin, digoxin, and FITC at the 5′ end and quickly determined whether the sample contains P–35S and T-nos of GMOs using the RPA-LFD method at room temperature. Nine events of GMOs were collected to determine the specificity of the RPA-LFD method, including KMD1, MON531, Rf1, Kefeng6, RRS, Bt11, MON863, Bt176, and Ms1. The results showed that the limit of detection of RPA-LFD was 50 copies and 100 copies, which was consistent with the limit of detection of RPA-AGE. The specificity and stability among the nine events were consistent, respectively. Finally, the perfect fitness for the detection of the nine double-blind samples indicated that the detection method is practical. In conclusion, we developed a more sensitive, specific, and stable field screening method for determining the GMO content with large-scale field applications.
•This study developed the RPA-LFD methods for 35s and nos elements detection.•The RPA primers were labeled with fluorophore biotin, digoxin, and FITC.•The limit of detection of RPA-LFD was 50 copies and 100 copies.•The RPA-LFD method is fit for rapid GMOs detection in the field.
Treatment of severe eczema in patients with primary immunodeficiencies can be particularly challenging as there are no guidelines with regards to these conditions. Dupilumab is an interleukin ...(IL)‐4Rα antagonist that inhibits both IL‐4 and IL‐13 and is approved for the treatment of atopic dermatitis in pediatric patients. In this report, we describe a patient with a case of severe eczema in the context of Wiskott–Aldrich syndrome‐related disorder, who was successfully treated with dupilumab.
Primary cutaneous acral CD8(+) lymphoma (AL) has been accepted as primary cutaneous acral CD8-positive T-cell lymphoproliferative disorder in the revised WHO and updated WHO-EORTC lymphoma ...classifications. Commonly arising on the ears and comprising a clonal cytotoxic CD8 + T-cell infiltrate, almost all cases follow an indolent clinical course. A single aggressive case reported in the literature had a deletion at the CDKN2 locus at 9p21. We report an atypical CD8 + T-cell proliferation arising on the chest of an elderly man who had some similarities to AL but with a very high proliferation rate, absent p16 protein expression, and homozygous loss of the CDKN2 locus using FISH analysis. A diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL NOS) was preferred. Analyses of 4 cases of AL demonstrated often low p16 protein expression but intact CDKN2 loci. This case raises the problems of the boundaries between AL and PTCL NOS, and a possible role in the loss of p16 function in pathogenesis.
Peripheral T-cell lymphomas derived from the mature T-cells are a heterogeneous group with varying biological and clinical behaviour.
We analysed the epidemiological, clinical, histomorphological, ...immunophenotypic, and mutational characteristics of PTCLs in our centre.
This was a retrospective study including all cases of PTCL from 2015 to 2019 retrieved from the archive of Department of Pathology, AIIMS, New Delhi. The cases were reclassified according the WHO 2016 classification. Additional immunohistochemistry (PD1, ICOS, Bcl6 and CD10), EBERish, and mutational studies for IDHR172 and RHOA G17V) were done in cases diagnosed as PTCL-NOS and AITL. The clinical profile was correlated with the above factors and the prognostication index.
Of the total 441 lymphoma cases diagnosed of T-cell lineage, 35.37% were of the precursor type, and the rest were mature T-cell lymphomas. A male predominance was noted. PTCL-NOS was the most common subtype among the mature type (n=76; 17.23%) followed by ALCL, ALK+ (n=70; 15.87%), extranodal NK-/T-cell lymphomas (n=58, 13.15%), and AITL (n=16; 3.63%). They were dominant in the adult age (19–65 years, n=207), followed by pediatric and adolescents (n=43) and elderly (n=35) populations. The primary site of involvement was a mixture of nodal (n=138) and extranodal (n=147). The patients presented in advanced stages with a mean IPI score of 3/5. High LDH levels with direct Coombs test positivity was noted among AITL patients. With the help of immunohistochemistry, a few of the diagnosed PTCL-NOS were reclassified as AITL, and one of the diagnosed AITL was reclassified as PTCL with TFH phenotype. A few of the diagnosed AITL cases immunonegative for EBV-LMP1 proved their causal relationship with EBERish positivity. An overall mean survival of 20 months was noted among 30 cases with a maximal follow up of 3 years.
A higher prevalence of immature cell neoplasm and ALCL was noted among the Indian population. Though morphologically there may be an overlap in the diagnosis among the various PTCL subtypes, immunohistochemistry and molecular studies can help in reaching the definite diagnosis.
Thanks to the Science Engineering Research Board (EEQ/2016/402, ECR /2015/452) and All India Institute of Medical Science Research Section (A-653).
A new treatment approach for urothelial cancers (UCa) is described in the preclinical and clinical settings. In brief, the friendly tumor microenvironment (TME) is selectively diverted into a massive ...generator of deleterious reactive nitrogen species (RNS) by vascular targeted photodynamic therapy (VTP) with WST11 (padeliporfin, TOOKAD). Light induced oxygen radical generation in the tumor circulation, is accompanied by Instantaneous hypoxia, ten-fold amplification of nitric oxide synthase expression by eNOS and iNOS and release of nitric oxide. Nitrotyrozination of the tumor endothelium, followed by vascular permeabilization and collapse initiates self-propagating paraptosis that culminates in coagulative necrosis of the entire tumor within few hours. Concomitant release of danger associated molecular patterns (DAMP) alarms the innate immunity. Massive infiltration of cytotoxic lymphocytes through the broken endothelial barrier accomplishes the local tumor eradication and initiate prolonged adaptive immunity. Differences in the nitric oxide synthase expression within the TME and surrounding normal tissue underscore the selective tumor eradication in animals and human alike. Based on the phase I clinical results, WST11-VTP, renamed Padelliporfin ImPACT (Immune PhotoActivated Cancer Therapy), has gained fast tract approval and orphan drug status for phase III clinical trials on patients with upper tract urothelial cancer.
The development of new light delivering systems for reaching tumors in other organs (lungs, pancreas and bladder) combined with compelling treatment results of orthotopic animal models (pancreas, lung, bladder and colon) provide the ground for Phase 1 clinical trials in additional solid tumor indications.
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