Commentary to 'surrogate decision making in crisis'

This is an accepted manuscript of an article published by BMJ in Journal of Medical Ethics on 15/03/2021, available online: http://dx.doi.org/10.1136/medethics-2020-107180 The accepted version of the publication may differ from the final published versionIn providing commentary to the case presented by DJC Wilkinson and T Pillay, we describe the uncertainties around complex decision making for the critically ill surrogate baby. We share our dilemma in recognizing that we, not the intended parents hold parental authority for Baby T. Despite this, we argue our case for compassionately including the intended parents in discussions and considering their perspectives in the complex decision making processes for Baby T.Published versio

Early and Accurate Prediction of Heart Disease Using Machine Learning Model

Heart disease is one of the critical health issues and many people across the world are suffering with this disease. It is important to identify this disease in early stages to save many lives. The purpose of this article is to design a model to predict the heart diseases using machine learning techniques. This model is developed using classification algorithms, as they play important role in prediction. The model is developed using different classification algorithms which include Logistic Regression, Random Forest, Support vector machine, Gaussian Naïve Bayes, Gradient boosting, K-nearest neighbours, Multinomial Naïve bayes and Decision trees. Cleveland data repository is used to train and test the classifiers. In addition to this, feature selection algorithm named chi square is used to select key features from the input data set, which will decrease the execution time and increases the performance of the classifiers. Out of all the classifiers evaluated using performance metrics, Random forest is giving good accuracy. So, the model built using Random forest is efficient and feasible solution in identifying heart diseases and it can be implemented in healthcare which plays key role in the stream of cardiology. &nbsp

A novel mitragynine analog with low-efficacy mu opioid receptor agonism displays antinociception with attenuated adverse effects

Mitragynine and 7-hydroxymitragynine (7OH) are the major alkaloids mediating the biological actions of the psychoactive plant kratom. To investigate the structure-activity relationships of mitragynine/7OH templates, we diversified the aromatic ring of the indole at the C9, C10, and C12 positions and investigated their G-protein and arrestin signaling mediated by mu opioid receptors (MOR). Three synthesized lead C9 analogs replacing the 9-OC

Biochar Reduced Nitrous Oxide and Carbon Dioxide Emissions from Soil with Different Water and Temperature Cycles

Interactions among biochar, respiration, nitrification, and soils can result in biochar increasing, decreasing, or not impacting greenhouse gas (GHG) emissions. This experiment determined the impact of water-filled porosity (WFP) and corn (Zea mays L.) stover biochar on CO2 and N2O emissions in May (spring) and August (summer). The May experiment contained two N rates [0 and 224 kg Ca(NO3)2–N ha–1], whereas the August had three N rates [0, 224 kg Ca(NO3)2–N ha–1, and 224 kg (NH4)2SO4–N ha–1]. The average temperatures in the May and Augusts 2014 experiments were 14 and 24°C, respectively. Biochar reduced CO2–C emissions in the high WFP Ca(NO3)2 treatment in the May and August experiments 15.4 and 16.3 kg ha–1, respectively. Associated with the CO2–C decrease was a 15.7% reduction in the soil solution dissolved organic C. In addition, N2O–N and CO2–C emissions were not correlated in the May Ca(NO3)2 ha–1 treatment, whereas in the August experiment, N2O–N and CO2–C emissions were correlated (r2 = 0.98, P \u3c 0.01). In August, biochar increased the apparent nitrification from 16 to 25 kg NH4–N (ha × d)–1 in the low WFP (NH4)2SO4treatment, and it did not influence the nitrification rate in the high WFP (NH4)2SO4 treatment. In general, N2O–N emissions increased with WFP and N rate and were reduced 21.7% by biochar. The findings suggest that multiple mechanisms contributed to N2O emissions and seasonal differences in soil temperature could result in biochar having a mixed impact on GHG emissions

Therapeutic Targeting of TFE3/IRS-1/PI3K/mTOR Axis in Translocation Renal Cell Carcinoma

Purpose: Translocation renal cell carcinoma (tRCC) represents a rare subtype of kidney cancer associated with various TFE3, TFEB, or MITF gene fusions that are not responsive to standard treatments for RCC. Therefore, the identification of new therapeutic targets represents an unmet need for this disease. Experimental Design: We have established and characterized a tRCC patient-derived xenograft, RP-R07, as a novel preclinical model for drug development by using next-generation sequencing and bioinformatics analysis. We then assessed the therapeutic potential of inhibiting the identified pathway using in vitro and in vivo models. Results: The presence of a SFPQ-TFE3 fusion [t(X;1) (p11.2; p34)] with chromosomal break-points was identified by RNA-seq and validated by RT-PCR. TFE3 chromatin immunoprecipitation followed by deep sequencing analysis indicated a strong enrichment for the PI3K/AKT/mTOR pathway. Consistently, miRNA microarray analysis also identified PI3K/AKT/mTOR as a highly enriched pathway in RP-R07. Upregulation of PI3/AKT/mTOR pathway in additional TFE3–tRCC models was confirmed by significantly higher expression of phospho-S6 (P < 0.0001) and phospho-4EBP1 (P < 0.0001) in established tRCC cell lines compared with clear cell RCC cells. Simultaneous vertical targeting of both PI3K/AKT and mTOR axis provided a greater antiproliferative effect both in vitro (P < 0.0001) and in vivo (P < 0.01) compared with single-node inhibition. Knockdown of TFE3 in RP-R07 resulted in decreased expression of IRS-1 and inhibited cell proliferation. Conclusions: These results identify TFE3/IRS-1/PI3K/AKT/mTOR as a potential dysregulated pathway in TFE3–tRCC, and suggest a therapeutic potential of vertical inhibition of this axis by using a dual PI3K/mTOR inhibitor for patients with TFE3–tRCC

Analyzing the Outdoor Performance of Different Types of PV Module Technologies

The purpose of the extension project is to find out the practical applicability and performance of various solar module innovations in real outdoor conditions. By systematically measuring voltage and monitoring electricity production, the research aims to produce valuable research data that can inform and guide local and global stakeholders in the optimization and implementation of various solar energy innovations. The research focuses on the comparative analysis of three visible PV module types - monocrystalline, polycrystalline and amorphous silicon. The study focuses on collecting daily routine performance parameters of these modules to provide meaningful and actionable information. The project recognizes the importance of evaluating solar panel technologies in real outdoor environments, as performance in controlled laboratory environments may not accurately reflect real-world conditions. Therefore, the research uses a comprehensive methodology that combines rigorous data collection techniques with advanced monitoring systems. To ensure the reliability and validity of the findings, a large experimental setup will be established in an outdoor environment that promotes the collection of solar energy. Each type of PV module is strategically placed to receive optimal sunlight throughout the day, minimizing potential shading and obstructions. An advanced data acquisition system continuously measures and records the voltage readings of the modules. In addition, the system closely monitors power generation to capture performance fluctuations over time

Inhibition of Reactive Gliosis Attenuates Excitotoxicity-Mediated Death of Retinal Ganglion Cells

Reactive gliosis is a hallmark of many retinal neurodegenerative conditions, including glaucoma. Although a majority of studies to date have concentrated on reactive gliosis in the optic nerve head, very few studies have been initiated to investigate the role of reactive gliosis in the retina. We have previously shown that reactive glial cells synthesize elevated levels of proteases, and these proteases, in turn, promote the death of retinal ganglion cells (RGCs). In this investigation, we have used two glial toxins to inhibit reactive gliosis and have evaluated their effect on protease-mediated death of RGCs. Kainic acid was injected into the vitreous humor of C57BL/6 mice to induce reactive gliosis and death of RGCs. C57BL/6 mice were also treated with glial toxins, alpha-aminoadipic acid (AAA) or Neurostatin, along with KA. Reactive gliosis was assessed by immunostaining of retinal cross sections and retinal flat-mounts with glial fibrillary acidic protein (GFAP) and vimentin antibodies. Apoptotic cell death was assessed by TUNEL assays. Loss of RGCs was determined by immunostaining of flat-mounted retinas with Brn3a antibodies. Proteolytic activities of matrix metalloproteinase-9 (MMP-9), tissue plasminogen activator (tPA), and urokinase plasminogen activator (uPA) were assessed by zymography assays. GFAP-immunoreactivity indicated that KA induced reactive gliosis in both retinal astrocytes and in Muller cells. AAA alone or in combination with KA decreased GFAP and vimentin-immunoreactivity in Mϋller cells, but not in astrocytes. In addition AAA failed to decrease KA-mediated protease levels and apoptotic death of RGCs. In contrast, Neurostatin either alone or in combination with KA, decreased reactive gliosis in both astrocytes and Mϋller cells. Furthermore, Neurostatin decreased protease levels and prevented apoptotic death of RGCs. Our findings, for the first time, indicate that inhibition of reactive gliosis decreases protease levels in the retina, prevents apoptotic death of retinal neurons, and provides substantial neuroprotection

Absence of system xc⁻ on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis

Background: Multiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System x(c)- or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration. Methods: Semi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system x(c)-, as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT(-/-)) mice and irradiated mice reconstituted in xCT(-/-) bone marrow (BM), to their proper wild type (xCT(+/+)) controls. Results: xCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT(+/+) mice, xCT(-/-) mice were equally susceptible to EAE, whereas mice transplanted with xCT(-/-) BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above-described conditions, demyelination, microglial activation, or infiltration of immune cells were affected. Conclusions: Our findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system x(c)- on immune cells invading the CNS participates to EAE. Since a total loss of system x(c)- had no net beneficial effects, these results have important implications for targeting system x(c)- for treatment of MS