TH-MYCN tumors, but not tumor-derived cell lines, are adrenergic lineage, GD2+, and responsive to anti-GD2 antibody therapy.

Neuroblastoma is a commonly lethal solid tumor of childhood and intensive chemoradiotherapy treatment cures ~50% of children with high-risk disease. The addition of immunotherapy using dinutuximab, a monoclonal antibody directed against the GD2 disialoganglioside expressed on neuroblasts, improves survival when incorporated into front-line therapy and shows robust activity in regressing relapsed disease when combined with chemotherapy. Still, many children succumb to neuroblastoma progression despite receiving dinutuximab-based immunotherapy, and efforts to counteract the immune suppressive signals responsible are warranted. Animal models of human cancers provide useful platforms to study immunotherapies. TH-MYCN transgenic mice are immunocompetent and develop neuroblastomas at autochthonous sites due to enforced MYCN expression in developing neural crest tissues. However, GD2-directed immunotherapy in this model has been underutilized due to the prevailing notion that TH-MYCN neuroblasts express insufficient GD2 to be targeted. We demonstrate that neuroblasts in TH-MYCN-driven tumors express GD2 at levels comparable to human neuroblastomas but rapidly lose GD2 expression when explanted ex vivo to establish tumor cell lines. This occurs in association with a transition from an adrenergic to mesenchymal differentiation state. Importantly, not only is GD2 expression retained on tumors in situ, treatment with a murine anti-GD2 antibody, 14G2a, markedly extends survival in such mice, including durable complete responses. Tumors in 14G2a-treated mice have fewer macrophage and myeloid-derived suppressor cells in their tumor microenvironment. Our findings support the utility of this model to inform immunotherapy approaches for neuroblastoma and potential opportunities to investigate drivers of adrenergic to mesenchymal fate decisions.

nSARS-Cov-2, pulmonary edema and thrombosis: possible molecular insights using miRNA-gene circuits in regulatory networks.

BACKGROUND: Given the worldwide spread of the novel Severe Acute Respiratory Syndrome Coronavirus 2 (nSARS-CoV-2) infection pandemic situation, research to repurpose drugs, identify novel drug targets, vaccine candidates have created a new race to curb the disease. While the molecular signature of nSARS-CoV-2 is still under investigation, growing literature shows similarity among nSARS-CoV-2, pulmonary edema, and thromboembolic disorders due to common symptomatic features. A network medicine approach is used to to explore the molecular complexity of the disease and to uncover common molecular trajectories of edema and thrombosis with nSARS-CoV-2. RESULTS AND CONCLUSION: A comprehensive nSARS-CoV-2 responsive miRNA: Transcription Factor (TF): gene co-regulatory network was built using host-responsive miRNAs and it's associated tripartite, Feed-Forward Loops (FFLs) regulatory circuits were identified. These regulatory circuits regulate signaling pathways like virus endocytosis, viral replication, inflammatory response, pulmonary vascularization, cell cycle control, virus spike protein stabilization, antigen presentation, etc. A unique miRNA-gene regulatory circuit containing a consortium of four hub FFL motifs is proposed to regulate the virus-endocytosis and antigen-presentation signaling pathways. These regulatory circuits also suggest potential correlations/similarity in the molecular mechanisms during nSARS-CoV-2 infection, pulmonary diseases and thromboembolic disorders and thus could pave way for repurposing of drugs. Some important miRNAs and genes have also been proposed as potential candidate markers. A detailed molecular snapshot of TGF signaling as the common pathway, that could play an important role in controlling common pathophysiologies among diseases, is also put forth. SUPPLEMENTARY INFORMATION: Supplementary information accompanies this paper at 10.1186/s41544-020-00057-y.

Role of miRNAs in hypoxia-related disorders.

Hypoxia is a complex pathophysiological condition. The physiological and molecular responses to this stress have been extensively studied. However, the management of its ill effects still poses a challenge to clinicians. MicroRNAs (miRNAs) are short non-coding RNA molecules that control post-transcriptional gene expression. The regulatory role of miRNAs in hypoxic environments has been studied in many hypoxia-related disorders, however a comprehensive compilation and analysis of all data and the significance of miRNAs in hypoxia adaption is still lacking. This review summarizes the miRNAs related to various hypoxia-related disorders and highlights the computational approaches to study them. This would help in designing novel strategies toward efficient management of hypoxia-related disorders.

Use of ADO II device in a large aorto-pulmonary collateral -an interesting case.

A 11month old girl was diagnosed to have a large aorto pulmonary collateral during evaluation for respiratory distress and seizures. Echocardiographic evaluation showed a large collateral from the descending aorta to left lung with ventricular dysfunction (left ventricular ejection fraction of 40%). This was confirmed on computed tomography angiogram (CT) scan. The collateral was closed with Amplatzer Ductal Occluder II device under fluoroscopic guidance. To the best of our knowledge, this is the first reported case of large aorto-pulmonary collateral closed successfully with an Amplatzer Ductal Occluder II device.

A diabetes scorecard does not improve HbA(1c), blood pressure, lipids, aspirin usage, exercise and diabetes knowledge over 9 months: a randomized controlled trial.

AIMS: To test (1) whether a diabetes scorecard can improve glycaemic control, blood pressure control, LDL cholesterol, aspirin usage and exercise; (2) if the scorecard will motivate and/or educate patients to improve their scores for subsequent visits; and (3) whether the scorecard will improve rates of clinical inertia. METHODS: Five physicians enrolled 103 patients ≥ 40 years old with uncontrolled Type 2 diabetes [HbA(1c) ≥ 64 mmol/mol (8.0%)] to randomly receive either a diabetes scorecard or not during four clinical visits over a 9-month period. The population was predominantly urban with a disproportionately higher percentage of black people than the general population. Our scorecard assigned points to six clinical variables, with a perfect total score of 100 points corresponding to meeting all targets. The primary outcomes were total scores and HbA(1c) in the scorecard and control groups at 9 months. RESULTS: There were no significant differences between the control and scorecard groups at visits 1 and 4 in total score, HbA(1c) , blood pressure, LDL cholesterol, aspirin usage, exercise or knowledge about diabetic targets. By visit 4 both the control and scorecard groups had statistically significant improvements with their mean total score (9 and 7 points, respectively), HbA(1c) [-9 mmol/mol (-0.8%) and -15 mmol/mol (-1.4%), respectively] and aspirin usage (33% increase and 16% increase, respectively). Rates of clinical inertia were low throughout the study. CONCLUSIONS: A diabetes scorecard did not improve glycaemic control, blood pressure control, LDL cholesterol, aspirin usage, exercise or diabetic knowledge in an urban population with uncontrolled Type 2 diabetes.

A description of transversely isotropic sound absorbing porous materials by transfer matrices.

A description of wave propagation in transversely isotropic porous materials saturated by air with a recent reformulation of the Biot theory is carried out. The description is performed in terms of a transfer matrix method (TMM). The anisotropy is taken into account in the mechanical parameters (elastic constants) and in the acoustical parameters (flow resistivity, tortuosity, and characteristic lengths). As an illustration, the normal surface impedance at normal and oblique incidences of transversely isotropic porous layers is predicted. Comparisons are performed with experimental results.

Evaluation of change in water quality with strong acid exchanger effluent conductivity.

Koradi Thermal Power Station requires 1-1.2 lakh m3 of water per day and pond No. 3 is the source of water supply of Koradi Thermal Power Station. This Pond No. 3 is being replenished by Pench Canal water, but water undergoes significant changes in quality after entering Pond No. 3 and hence this aspect may be crucial for raw water intake at Water Treatment Plant Stg-II of Koradi Thermal Power Station. Therefore, an attempt has been made to evaluate the change in water quality on the basis of Strong Acid Cation Exchanger Effluent Conductivity and its impact on demineralised water treatment plant.

Mapping of a major QTL for pre-harvest sprouting tolerance on chromosome 3A in bread wheat.

Quantitative trait loci (QTL) analysis was conducted for pre-harvest sprouting tolerance (PHST) in bread wheat for a solitary chromosome 3A, which was shown to be important for this trait in earlier studies. An inter-varietal mapping population in the form of recombinant inbred lines (RILs) developed from a cross between SPR8198 (a PHS tolerant genotype) and HD2329 (a PHS susceptible cultivar) was used for this purpose. The parents and the RIL population were grown in six different environments and the data on PHS were collected in each case. A framework linkage map of chromosome 3A with 13 markers was prepared and used for QTL analysis. A major QTL (QPhs.ccsu-3A.1) was detected on 3AL at a genetic distance of approximately 183 cM from centromere, the length of the map being 279.1 cM. The QTL explained 24.68% to 35.21% variation in individual environments and 78.03% of the variation across the environments (pooled data). The results of the present study are significant on two counts. Firstly, the detected QTL is a major QTL, explaining up to 78.03% of the variation and, secondly, the QTL showed up in all the six environments and also with the pooled data, which is rather rare in QTL analysis. The positive additive effects in the present study suggest that a superior allele of the QTL is available in the superior parent (SPR8198), which can be used for marker-aided selection for the transfer of this QTL allele to obtain PHS-tolerant progeny. It has also been shown that the red-coloured grain of PHS tolerant parent is not associated with the QTL for PHST identified during the present study, suggesting that PHS tolerant white-grained cultivars can be developed.

Structural characterization, expression analysis and evolution of the red/far-red sensing photoreceptor gene, phytochrome C (PHYC), localized on the 'B' genome of hexaploid wheat (Triticum aestivum L.).

Phytochromes are a family of red/far-red light perceiving photoreceptors. The monocot phytochrome family is represented by three members, PHYA, PHYB and PHYC. We have isolated and characterized the first PHY gene member (TaPHYC) from common wheat, Triticum aestivum var. CPAN1676. It codes for a species of the photoreceptor, phyC, which is known to be light-stable in all plants analyzed so far. A sequence of 7.2 kb has been determined, which includes 3.42 kb of coding region. This is the second full-length PHYC gene sequenced from a monocot (first was from rice). TaPHYC gene shares structural similarities with the rice PHYC containing four exons and three introns in the coding region. The 5' UTR is 1.0-kb-long and harbors an upstream open reading frame (URF) encoding 28 aa. Southern blot analysis of TaPHYC indicates that it represents single locus in the wheat genome, although the possibility of additional loci cannot be completely ruled out. Chromosomal localization using nullisomic-tetrasomic lines of Triticum aestivum var. Chinese Spring places TaPHYC on chromosome 4B. PHYC represents a constitutively expressed gene in all the organs tested and under light/dark conditions. However, PHYC was found to be developmentally regulated showing maximal expression in 3-day-old dark-grown seedlings, which declined thereafter. In silico analysis has also been done to compare TaPHYC gene with the partial sequences known from other wheat species and cultivars. The presence of a topoisomerase gene immediately downstream of the PHYC gene, both in rice and wheat genomes, presents yet another example of synteny in cereals and its possible significance has been discussed.

Investigation of the phase velocities of guided acoustic waves in soft porous layers.

A new experimental method for measuring the phase velocities of guided acoustic waves in soft poroelastic or poroviscoelastic plates is proposed. The method is based on the generation of standing waves in the material and on the spatial Fourier transform of the displacement profile of the upper surface. The plate is glued on a rigid substrate so that it has a free upper surface and a nonmoving lower surface. The displacement is measured with a laser Doppler vibrometer along a line corresponding to the direction of propagation of plane surface waves. A continuous sine with varying frequencies was chosen as excitation signal to maximize the precision of the measurements. The spatial Fourier transform provides the wave numbers, and the phase velocities are obtained from the relationship between wave number and frequency. The phase velocities of several guided modes could be measured in a highly porous foam saturated by air. The modes were also studied theoretically and, from the theoretical results, the experimental results, and a fitting procedure, it was possible to determine the frequency behavior of the complex shear modulus and of the complex Poisson ratio from 200 Hz to 1.4 kHz, in a frequency range higher than the traditional methods.

Agrobacterium tumefaciens-mediated transformation of Indian mulberry, Morus indica cv. K2: a time-phased screening strategy.

An efficient and reproducible protocol for the production of transgenic plants was developed for Morus indica cv. K2 by Agrobacterium tumefaciens-mediated transformation. The hypocotyls, cotyledon, leaf and leaf callus explants precultured for 5 days on regeneration medium were co-cultivated with a bacterial suspension at 10(9) cells/ml for 3 days in the dark. Infectivity of A. tumefaciens strain LBA4404 was more than that of strains GV2260 and A281, and among the various plasmids tried, pBI121 and pBI101:Act1 transformed nearly 100% of the explants followed closely by p35SGUSINT. About 90-100% of the explants tested positive in the beta-glucuronidase (GUS) histochemical assay performed after 3 days of co-cultivation. This high level of transient expression, however, decreased to 20-25% after 15 days. Gus activity was most stable in the callus explants, which emerged as the explant of choice for transformation. The transformed explants were selected on 50-75 mg/l kanamycin for 1 month, and 25-50% of the explants developed adventitious buds. On the basis of kanamycin-resistant shoots produced from the total number of explants inoculated, the transformation efficiency was 44%. After 1 month, 40% of these shoots displayed high gus activity as assessed by the GUS fluorometric assay. On a selection-free root induction medium, 80% of the shoots developed roots and 90% of the potted plantlets acclimatized to the growth room conditions. The 3-month-old regenerates showed gus and nptII(neomycin phosphotransferase II) gene activity as assayed by the GUS fluorometric assay and nptII enzyme assay, followed by PCR polymerase chain reaction (54.5%) analysis after 6-months. Transgene integration into the nuclear genome of 1-year-old regenerates was confirmed in 10 of the 18 transformants tested by Southern analysis. The transformation efficiency as defined by the number of transgenic plants produced from the total number of explants co-cultivated was 6%.

Hormone replacement therapy for prevention of coronary heart disease: current evidence.

Postmenopausal estrogen replacement, with or without progestin therapy, has a generally favorable impact on lipids, improves endothelial function, and has anti-inflammatory and antioxidant effects. These properties should favorably impact coronary risk; indeed, epidemiologic studies have consistently associated hormone replacement therapy with reduced coronary risk. Nonetheless, the Heart & Estrogen/progestin Replacement Study (HERS), a randomized, placebo-controlled, secondary prevention trial of conjugated estrogen with progestin, found no overall reduction in coronary events among women assigned to active hormone treatment. This review explores the role of estrogen replacement among interventions intended to prevent coronary heart disease in the post-HERS era.

Germins and germin like proteins: an overview.

Molecular investigations during wheat germination have revealed unique developmentally regulated proteins, designated as germins, which show remarkable resistance to broad specificity proteases and to dissociation in SDS. Germins in cereals have an oxalate oxidase activity, which generates H2O2 from the oxidative breakdown of oxalate thereby playing a significant role in plant development and defense. Germin like proteins (GLPs) exhibit sequence and structural similarity with the cereal germins but mostly lack oxalate oxidase activity. Germins and germin like proteins (GLPs) are a class of developmentally regulated glycoproteins characterized by a beta-barrel core structure, a signal peptide, and are associated with the cell wall. GLPs exhibit a broad range of diversity in their occurrence and activity in organisms ranging from myxomycetes, bryophytes, pteridophytes, gymnosperms and angiosperms. Germins and GLPs are thought to play a significant role during zygotic and somatic embryogenesis (wheat and Pinus, respectively), salt stress (barley and Mesembryanthemum crystallinum), pathogen elicitation (wheat and barley), and heavy metal stress, etc. Characterization and cloning of some of the genes encoding germins and GLPs has facilitated a better understanding of their regulation and raised their potential of biotechnological application.

Teratomas in infancy and childhood.

A 10-year-experience with 42 cases of teratomas in paediatric age group is presented. The commonest type of teratoma was sacrococcygeal followed by ovarian and retroperitoneal teratomas. An analysis of clinical profile, malignant potential, management, prognostic factors and follow up is discussed with review of literature.

Regeneration from leaf protoplasts of Arabidopsis thaliana ecotype estland.

Protoplasts (2 x 10(7)/g fresh wt) were isolated from leaves of A. thaliana ecotype estland, with a viability of more than 90%. Protoplasts cultured in calcium alginate beads or layers showed division while culture in liquid or agarose beads failed to elicit any division. Effect of culture density showed highest frequency of division occurring at 5 x 10(5) while no division was seen when cultured at a density of 5 x 10(4). Culture in MS medium resulted in higher division frequency and better sustenance of microcolonies as compared to B5 medium. Under optimized conditions, macrocolonies were formed at a frequency of 1.8%. Shoot regeneration was seen in 50% of microcalli transferred to shoot induction medium for regeneration. Shoots were rooted and plantlets transferred to pots. The plants produced flowers and were fertile.

Choledochal cyst: a 10-year experience.

A retrospective study of 11 cases of choledochal cyst over a period of 10 years is presented. There were 8 females and 3 males in a ratio of 2.67:1. The classical triad of jaundice, mass and abdominal pain was seen in none of our patients. Ultrasonography was diagnostic in 9 out of 11 (80%) patients. Surgical procedures performed were, complete excision of the cyst with Roux en Y hepaticojejunostomy (nine cases), internal drainage of the cyst (one case) and excision of the extrahepatic cyst with Roux en Y hepaticojejunostomy in one case of Type IV choledochal cyst. One patient died in the immediate postoperative period. Others have remained well upto 10 years follow-up. We recommend total cyst excision with hepaticojejunostomy as the treatment of choice.