An Integrated theory of false insights and beliefs under psychedelics.

Psychedelics are recognised for their potential to re-orient beliefs. We propose a model of how psychedelics can, in some cases, lead to false insights and thus false beliefs. We first review experimental work on laboratory-based false insights and false memories. We then connect this to insights and belief formation under psychedelics using the active inference framework. We propose that subjective and brain-based alterations caused by psychedelics increases the quantity and subjective intensity of insights and thence beliefs, including false ones. We offer directions for future research in minimising the risk of false and potentially harmful beliefs arising from psychedelics. Ultimately, knowing how psychedelics may facilitate false insights and beliefs is crucial if we are to optimally leverage their therapeutic potential.

Design and implementation of single switch integrated boost and flyback converter for renewable and sustainable energy.

Renewable resources are being explored to meet the increasing energy demand in the world. The development of RES and their integration into the grid necessitate a voltage conversion to match with the grid voltage. This conversion can be implemented using DC-DC converters. A high-gain DC-DC Converter with low loss is proposed in this article. Thus, the proposed integrated converter is obtained by incorporating a boost converter at the primary side of the flyback converter (FLC) and a VM cell at the secondary side to perform a elevated voltage gain at a lower duty ratio. The Switched Capacitor network is implemented to elevate the voltage gain. The dynamic performance of a controller can be enhanced using an FOPID controller. A comparison analysis has been done using the most recent topologies in order to confirm the superiority of the Proposed converter. A 100W experimental prototype model has been constructed in order to further validate the simulation results. The efficiency of this converter is demonstrably significantly higher than the current topology, according to measured performance. Therefore, it can be said that this topology can be used for applications involving renewable and sustainable energy.

Potential inhibitors of SARS-CoV-2 (COVID 19) spike protein of the delta and delta plus variant: In silico studies of medicinal plants of North-East India.

Phytochemicals of 38 Medicinal plants of North-East India, with anti-viral, anti-oxidant or anti-bacterial properties were screened for properties of drug likeness. 231 phytochemicals were screened with LIPINSKI rule of five to obtain 131 candidates, which were further screened with SWISS-ADME, to obtain 50 phytochemicals. These phytochemicals were docked with the spike protein of the Delta variant (B.1.617.2) and Delta-Plus (AY.1) variant of SARS-CoV-2 using Autodock Vina and MOE 09. The target proteins were constructed by homology modeling using Swiss-Model. Hydroxychloroquine, taken as a standard in docking analysis, exhibited a binding energy of -6.5 â€‹kcal/mol and -6.1 â€‹kcal/mol with respect to the Delta variant and Delta-Plus variant respectively. Among the 50 docked results most flavones showed very good docking scores. 3,5,8-Trimethoxy-6,7,4,5-bis(methylenedioxy)flavone, a Poly-Methoxyflavone, produced a highest docking score of -8.7 â€‹kcal/mol with respect to both the spike protein targets. Poly-Methoxyflavones and Poly-Ethoxyflavones exhibited good binding affinity for the target spike protein of SARS-CoV-2, and can be potential anti-viral drug candidates against the existing Delta variant of the SARS-CoV-2.

Differences in the Early Development of Human and Mouse Embryonic Stem Cells.

We performed a systematic analysis of gene expression features in early (10-21 days) development of human vs mouse embryonic cells (hESCs vs mESCs). Many development features were found to be conserved, and a majority of differentially regulated genes have similar expression change in both organisms. The similarity is especially evident, when gene expression profiles are clustered together and properties of clustered groups of genes are compared. First 10 days of mESC development match the features of hESC development within 21 days, in accordance with the differences in population doubling time in human and mouse ESCs. At the same time, several important differences are seen. There is a clear difference in initial expression change of transcription factors and stimulus responsive genes, which may be caused by the difference in experimental procedures. However, we also found that some biological processes develop differently; this can clearly be shown, for example, for neuron and sensory organ development. Some groups of genes show peaks of the expression levels during the development and these peaks cannot be claimed to happen at the same time points in the two organisms, as well as for the same groups of (orthologous) genes. We also detected a larger number of upregulated genes during development of mESCs as compared to hESCs. The differences were quantified by comparing promoters of related genes. Most of gene groups behave similarly and have similar transcription factor (TF) binding sites on their promoters. A few groups of genes have similar promoters, but are expressed differently in two species. Interestingly, there are groups of genes expressed similarly, although they have different promoters, which can be shown by comparing their TF binding sites. Namely, a large group of similarly expressed cell cycle-related genes is found to have discrepant TF binding properties in mouse vs human.

Synthesis, electronic structure investigation of 3-pentyl-2,6-di(furan-2-yl)piperidin-4-one by FT-IR, FT-Raman and UV-Visible spectral studies and ab initio/DFT calculations.

FT-IR and FT-Raman spectra of 3-pentyl-2,6-di(furan-2-yl) piperidin-4-one (3-PFPO) were recorded in the solid phase. The structural and spectroscopic analyses of 3-PFPO were made by using B3LYP/HF level with 6-311++G(d, p) basis set. The fundamental vibrations are assigned on the basis of the total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanics (SQM) method and PQS program. Comparison of the observed fundamental vibrational frequencies of 3-PFPO with calculated results by HF and DFT methods indicates that B3LYP is superior to HF method for molecular vibrational problems. The electronic properties such as excitation energies, oscillator strength, wavelengths and HOMO-LUMO energies were obtained by time-dependent DFT (TD-DFT) approach. The polarizability and first order hyperpolarizability of the title molecule were calculated and interpreted. The hyperconjugative interaction energy (E((2))) and electron densities of donor (i) and acceptor (j) bonds were calculated using NBO analysis. In addition, MEP and atomic charges of carbon, nitrogen, oxygen and hydrogen were calculated using B3LYP/6-311++G(d, p) level theory. Moreover, thermodynamic properties (heat capacities, entropy and enthalpy) of the title compound at different temperatures were calculated in gas phase.

Synthesis, spectroscopic (FT-IR, FT-Raman, UV and NMR) and computational studies on 3t-pentyl-2r,6c-diphenylpiperidin-4-one semicarbazone.

The structural and spectroscopic studies of 3t-pentyl-2r,6c-diphenylpiperidin-4-one semicarbazone (PDPOSC) were made by adopting B3LYP/HF levels theory using 6-311++G(d,p) basis set. The FT-IR and Raman spectra were recorded in solid phase, the fundamental vibrations were assigned on the basis of the total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanics (SQM) method and PQS program. DFT method indicates that B3LYP is superior to HF method for molecular vibrational analysis. UV-vis spectrum of the compound was recorded in different solvents in the region of 200-800 nm and the electronic properties such as excitation energies, oscillator strength, wavelengths, HOMO and LUMO energies were evaluated by time-dependent DFT (TD-DFT) approach. The polarizability and first order hyperpolarizability of the title molecule were calculated and interpreted. The hyperconjugative interaction energy (E((2))) and electron densities of donor (i) and acceptor (j) bonds were calculated using NBO analysis. In addition, MEP and atomic charges of carbon, nitrogen and oxygen were calculated using B3LYP/6-311++G(d,p) level theory. Moreover, thermodynamic properties of the title compound were calculated by B3LYP/HF, levels using 6-311++G(d,p) basis set. The (1)H and (13)C nuclear magnetic resonance (NMR) chemical shifts of the molecule were calculated by the gauge independent atomic orbital (GIAO) method and compared with experimental results.

Synthesis, spectroscopic investigation and computational study of 3-(1-(((methoxycarbonyl)oxy)imino)ethyl)-2H-chromen-2-one.

The molecular structure and vibrational modes of 3-acetylcoumarin oxime carbonate (abbreviated as 3-ACOC) have been investigated by FT-IR, FT-Raman, NMR spectra and also by computational methods using HF and B3LYP with 6-311++G(d,p) basis set. The optimized geometric parameters (bond lengths, bond angles and dihedral angles) were in good agreement with the corresponding experimental values of 3-ACOC. The calculated vibrational frequencies of normal modes from DFT method matched well with the experimental values. The complete assignments were made on the basis of the total energy distribution (TED) of the vibrational modes. NMR ((1)H and (13)C) chemical shifts were calculated by GIAO method and the results were compared with the experimental values. The other parameters like dipole moment, polarizability, first order hyperpolarizability, zero-point vibrational energy, E(HOMO), E(LUMO), heat capacity and entropy have also been computed.

Is removal of calcium bar during mitral valve surgery safe? Long-term clinical outcome of 109 consecutive patients.

AIM: Risk factors for adverse outcome after decalcification and patch-reconstruction of the mitral annulus during mitral valve surgery are yet to be defined. For this purpose and for the report of long term results we reviewed our institutional data from over 10 years of mitral valve surgery in the presence of mitral annulus calcification. METHODS: A total of 109 consecutive patients with a mean age of 66.4±14 years (Mean logistic EURO-Score: 18.6%) underwent mitral valve surgery in the presence of extensive calcification of mitral annulus between 1996 and 2008. After decalcification and patch-reconstruction of the mitral annulus, mitral valve repair was performed in 53 cases (49%) and the remaining 56 patients (51%) received a mitral valve replacement. Multivariate logistic regression analysis was performed to identify independent predictors of adverse outcome. RESULTS: Inhospital-mortality was 8.3% and the actuarial survival rate at 8 years 76.2%. Echocardiographic follow up was complete. 65 survivors (94.5%) showed none or only trivial mitral valve insufficiency. The freedom of reoperation at 8 years was 91.8%. We found hypertension, diabetes mellitus, age older than 65 years, NYHA class IV, end stage renal failure, failure to preserve the subvalvular apparatus as well as concomitant aortic valve replacement to be associated with a significant increase of early or/and late mortality. CONCLUSION: Despite the complexity of this pathology, decalcification and patch-reconstruction of the mitral annulus during mitral valve surgery can be performed with low technical risk and acceptable long-term results.

Spectroscopic (FT-IR, FT-Raman) and quantum mechanical studies of 3t-pentyl-2r,6c-diphenylpiperidin-4-one thiosemicarbazone.

In this study, the molecular structure and vibrational spectra of 3t-pentyl2r,6c-diphenylpiperidin-4-one thiosemicarbazone (PDPOTSC) were studied. The ground-state molecular geometry was ascertained by using the density functional theory (DFT)/B3LYP method using 6-31++G(d,p) as a basis set. The vibrational (FT-IR and FT-Raman) spectra of PDPOTSC were computed using DFT/B3LYP and HF methods with 6-31++G(d,p) basis set. The fundamental vibrations were assigned on the basis of the total energy distribution (TED⩾10%) of the vibrational modes, calculated with scaled quantum mechanics (SQM) methods PQS program. The electrical dipole moment (µ) and first hyperpolarizability (ßo) values have been computed using DFT/B3LYP and HF methods. The calculated result (ßo) shows that the title molecule might have nonlinear optical (NLO) behavior. Atomic charges of C, N, S and molecular electrostatic potential (MEP) were calculated using B3LYP/6-31G++(d,p). The HOMO-LUMO energies were calculated and natural bonding orbital (NBO) analysis has also been carried out.

Fam40b is required for lineage commitment of murine embryonic stem cells.

FAM40B (STRIP2) is a member of the striatin-interacting phosphatase and kinase (STRIPAK) complex that is involved in the regulation of various processes such as cell proliferation and differentiation. Its role for differentiation processes in embryonic stem cells (ESCs) is till now completely unknown. Short hairpin RNA (shRNA)-mediated silencing of Fam40b expression in ESCs and differentiating embryoid bodies (EBs) led to perturbed differentiation to embryonic germ layers and their derivatives including a complete abrogation of cardiomyogenesis. Pluripotency factors such as Nanog, Oct4 and Sox2 as well as epigenetic factors such as histone acetyltransferase type B (HAT1) and DNA (cytosine-5)-methyltransferase 3-ß (Dnmt3b) were highly upregulated in Fam40b knockdown EBs as compared with control and scrambled EBs. To examine the relevance of Fam40b for development in vivo, Fam40b was knocked down in developing zebrafish. Morpholino-mediated knockdown of Fam40b led to severe abnormalities of the cardiovascular system, including an impaired expression of ventricular myosin heavy chain (vmhc) and of cardiac myosin light chain 2 (cmlc2) in the heart. We identified the gene product of Fam40b in ESCs as a perinuclear and nucleolar protein with a molecular weight of 96 kDa. We conclude that the expression of Fam40b is essential for the lineage commitment of murine embryonic stem cells (mESCs) into differentiated somatic cells via mechanisms involving pluripotency and epigenetic networks.

3D inpatient dose reconstruction from the PET-CT imaging of 90Y microspheres for metastatic cancer to the liver: feasibility study.

PURPOSE: The introduction of radioembolization with microspheres represents a significant step forward in the treatment of patients with metastatic disease to the liver. This technique uses semiempirical formulae based on body surface area or liver and target volumes to calculate the required total activity for a given patient. However, this treatment modality lacks extremely important information, which is the three-dimensional (3D) dose delivered by microspheres to different organs after their administration. The absence of this information dramatically limits the clinical efficacy of this modality, specifically the predictive power of the treatment. Therefore, the aim of this study is to develop a 3D dose calculation technique that is based on the PET imaging of the infused microspheres. METHODS: The Fluka Monte Carlo code was used to calculate the voxel dose kernel for 90Y source with voxel size equal to that of the PET scan. The measured PET activity distribution was converted to total activity distribution for the subsequent convolution with the voxel dose kernel to obtain the 3D dose distribution. In addition, dose-volume histograms were generated to analyze the dose to the tumor and critical structures. RESULTS: The 3D inpatient dose distribution can be reconstructed from the PET data of a patient scanned after the infusion of microspheres. A total of seven patients have been analyzed so far using the proposed reconstruction method. Four patients underwent treatment with SIR-Spheres for liver metastases from colorectal cancer and three patients were treated with Therasphere for hepatocellular cancer. A total of 14 target tumors were contoured on post-treatment PET-CT scans for dosimetric evaluation. Mean prescription activity was 1.7 GBq (range: 0.58-3.8 GBq). The resulting mean maximum measured dose to targets was 167 Gy (range: 71-311 Gy). Mean minimum dose to 70% of target (D70) was 68 Gy (range: 25-155 Gy). Mean minimum dose to 90% of target (D90) was 53 Gy (range: 13-125 Gy). CONCLUSIONS: A three-dimensional inpatient dose reconstruction method has been developed that is based on the PET/CT data of a patient treated with 90Y microspheres. It allows for a complete description of the absorbed dose by the tumor and critical structures. It represents the first step in building predictive models for treatment outcomes for patients receiving this therapeutic modality as well as it allows for better analysis of patients' dose response and will ultimately improve future treatment administration.

[Mitral valve surgery in patients with extensively calcified mitral annulus: long-term echocardiographic and clinical follow-up]. / Mitralklappenchirurgie bei schwer verkalktem Mitralklappenanulus: Echokardiographische und klinische Evaluation im Langzeitverlauf.

OBJECTIVE: The aim of this study was the analysis of long-term results in patients with hemodynamically significant mitral valve disease due to extensively calcified mitral annulus who underwent decalcification and patch reconstruction. PATIENTS AND METHODS: Between 1996 and 2008 a total of 109 patients underwent surgery for extensive calcification and severe mitral insufficiency and mitral stenosis. The mean age of the patients (65 women and 44 men) was 66.4 ± 13.8 years. In 53 patients (49%) mitral valve repair was performed and the remaining 56 patients (51%) received a mitral valve replacement. Of the patients 64 (59%) required concomitant surgery. The mean follow up time was 96 ± 48 months. RESULTS: The in-hospital and late mortality was 8.3% (9 patients) and 25.6% (28 patients), respectively. The actuarial survival rates at 5, 8 and 12 years were 88.1%, 76.2% and 66.1%, respectively. Echocardiographic follow-up presented a mitral insufficiency grade III in 4 patients (6%). None of the patients had a mitral insufficiency grade IV. A significant reduction of left atrium diameter, of the LVEDD as well as the mean transvalvular gradient was observed. Freedom from reoperation at 5 and 8 years was 96.4% and 91.8%, respectively. Systemic hypertension, diabetes mellitus, age older than 65 years, concomitant aortic valve replacement, concomitant procedures, chronic renal insufficiency and cardiac decompensation in the medical history were found to be predictors for significantly increased early or late mortality. CONCLUSION: The long-term results strongly suggest that en bloc decalcification and patch reconstruction of the mitral annulus can be safely undertaken in high risk patients.

[Long-term echocardiographic and clinical follow-up after mitral valve surgery in patients with extensive calcified mitral annulus]. / Echokardiographische und klinische Evaluation nach Mitralklappenchirurgie bei schwer verkalktem Mitralklappenanulus im Langzeitverlauf.

OBJECTIVE: The aim of this study is the analysis of long-term results in patients with hemodynamically significant mitral valve disease due to extensive calcified mitral annulus who underwent decalcification and patch reconstruction. PATIENTS AND METHODS: Between 1996 and 2008 a total of 109 patients underwent surgery in the presence of extensive calcification, severe mitral insufficiency and mitral stenosis. The mean age of patients (65 women, 44 men) was 66.4±13.8 years. Mitral valve repair was performed in 53 patients (49%), while the remaining 56 patients (51%) received a mitral valve replacement. In all, 64 patients (59%) required concomitant surgery. The mean follow-up time was 96±48 months. RESULTS: Inpatient and late mortality rates were 8.3% (nine patients) and 25.6% (28 patients), respectively. The actuarial survival rates at 5, 8 and 12 years were 88.1%, 76.2% and 66.1%. Echocardiographic follow-up demonstrated mitral insufficiency III in four patients (6%). No patients had mitral insufficiency IV. We observed a significant reduction in left atrium diameter, LVEDD as well as mean transvalvular gradient. Freedom from reoperation at 5 and 8 years was 96.4% and 91.8%, respectively. We found systemic hypertension, diabetes mellitus, age above 65 years, concomitant aortic valve replacement, concomitant procedures, chronic renal insufficiency and cardiac decompensation in the medical history as predictors for significantly increased early or late mortality. CONCLUSION: The long-term results strongly suggest that en bloc decalcification and patch reconstruction of the mitral annulus can be safely undertaken in high-risk patients.

[Porphyrias]. / Porphyrien.

Porphyrias are metabolic disorders of the heme biosynthesis. Clinically, they can be differentiated into acute and non-acute porphyrias. The symptomatic phase of acute hepatic porphyrias is characterized by overproduction of neurotoxic porphyrin precursors and porphyrins. Acute intermittent porphyria, Variegate porphyria, Hereditary coproporphyria and Doss porphyria belong to this group of metabolic disorders. The clinical presentation of the acute hepatic porphyria syndrome includes abdominal, psychiatric, neurological and cardiovascular symptoms. The diagnosis is based on a tenfold increased urinary excretion of porphobilinogen (apart from Doss porphyria). Besides symptomatic therapy with non-porphyrinogenic drugs, electrolyte compensation and intensive monitoring, intravenous administration of glucose and heme arginate is established for treatment. Among the non-acute types like Porphyria cutanea tarda, Erythropoietic protoporphyria and Congenital erythropoietic porphyria, the accumulated porphyrins cause photosensitivity of the skin up to severe liver damage. The location of the deficient enzyme within the heme biosynthesic pathway determines the pattern of the accumulated porphyrins. Besides light protection, there are different therapies depending on the type of non-acute porphyria. Ultimately, liver transplantation may be considered in therapy-resistant cases of acute hepatic porphyrias and bone marrow transplantation in severe cases of erythropoietic porphyrias.

Induced pluripotent stem cells as a model for accelerated patient- and disease-specific drug discovery.

Human induced pluripotent stem (iPS) cells hold great promise for therapy of a number of degenerative diseases such as ischemic heart failure, Parkinson's disease, Alzheimer's disease, diabetes mellitus, sickle cell anemia and Huntington disease. They also have the potential to accelerate drug discovery in 3 ways. The first involves the delineation of chemical components for efficient reprogramming of patient's blood cells or cells from biopsies, obviating the need for cellular delivery of reprogramming exogenous transgenes, thereby converting hope into reality for patients suffering from degenerative diseases. Patients worldwide stand to benefit from the clinical applicability of iPS cell-based cell replacement therapy for a number of degenerative diseases. The second is the potential for discovering novel drugs in a high throughput manner using patient-specific iPS cell-derived somatic cells possessing the etiology of the specific disease. The third is their suitability for toxicological testing of drugs and environmental factors. This review focuses on these potential applications of iPS cells with special emphasis on recent updates of iPS cell research contributing to the accelerated drug discovery.

Safe and probably safe drugs in acute hepatic porphyria.

Acute porphyrias are caused by enzyme defects along the heme synthesis pathway. Patients usually present with abdominal pain, impaired intestinal motility, neurological and psychiatric symptoms, hypertension, tachycardia, hyponatriemia and reddish urine. This article gives an overview over drugs that are recommended in patients with acute hepatic porphyrias and represents a compilation of four so far existing lists.

Artificial chordae for mitral valve repair: mid-term clinical and echocardiographic results.

BACKGROUND: This paper reports on the mid-term clinical and echocardiographic results of mitral valve repair with chordal replacement. METHODS: Sixty-nine patients (mean age 61 +/- 14 years) underwent mitral valve repair with chordal replacement. The etiology was degenerative in 53 (77 %), rheumatic in 7 (10 %), ischemic in 6 (9 %) and infective in 3 (4 %). Mean ejection fraction was 58 +/- 14. In 35 patients (51 %), a minimally invasive approach was used. Mean follow-up time was 45 +/- 27 months. RESULTS: Anterior leaflet chordae were replaced in 58 (84 %) patients. There were 3 operative deaths. Freedom from non-trivial recurrent mitral regurgitation (MR) was 81.3 +/- 8.7 % at 97 months. Follow-up echocardiographic controls showed mild recurrent MR in 5 (8 %) patients and moderate in 2 (3.2 %). These two patients required reoperation due to mitral annulus redilation after suture annuloplasty. Competent neochordae were found at reoperation. Freedom from reoperation at 97 months was 96.6 +/- 2.4 %. Four patients died during follow-up resulting in an actuarial survival of 87 +/- 6.2 %. CONCLUSION: The replacement of chordae tendineae with ePTFE sutures during mitral valve repair has shown good mid-term results. The implantation of the neochordae can be also performed safely using minimally invasive procedures.

Decalcification of the mitral annulus: surgical experience in 81 patients.

OBJECTIVE: Mitral valve surgery in the presence of extensive calcification of the mitral annulus is a technical challenge and increases perioperative risk. This study reviews our experience with decalcification of the mitral annulus in patients undergoing mitral valve reconstruction or replacement. METHODS: From 1995 to 2003, 81 patients (mean age 64 +/- 13 years, 30 male, 51 female) with extensive calcification of the mitral annulus underwent mitral valve repair (n = 42) or replacement (biological n = 20, mechanical n = 19). The mean follow-up was 24 months. Patients presented with a mean EuroSCORE of 7. Concomitant surgical procedures were performed in 62 %. Patient outcomes were retrospectively assessed. RESULTS: Perioperative survival was 97.5 % (n = 79) and hospital survival was 91.3 % (n = 74). Two-year survival was 88.9 %. Eight patients needed reexploration due to bleeding and five patients required prolonged mechanical ventilation. No perioperative stroke was observed. Freedom from reoperation was 90.2 % (n = 73). Early reoperation for recurrent incompetence was necessary in 3 patients and late reoperation in 5 patients. CONCLUSIONS: Despite the elevated perioperative risk and the high risk of reoperation with this procedure, decalcification of the annulus and repair/replacement of the mitral valve could be performed with good clinical results.