Search Results (16)

The natural evolution of consciousness in different animal species mandates that conscious experiences are causally potent in order to confer any advantage in the struggle for survival. Any endeavor to construct a physical theory of consciousness based on emergence within the framework of classical physics, however, leads to causally impotent conscious experiences in direct contradiction to evolutionary theory since epiphenomenal consciousness cannot evolve through natural selection. Here, we review recent theoretical advances in describing sentience and free will as fundamental aspects of reality granted by quantum physical laws. Modern quantum information theory considers quantum states as a physical resource that endows quantum systems with the capacity to perform physical tasks that are classically impossible. Reductive identification of conscious experiences with the quantum information comprised in quantum brain states allows for causally potent consciousness that is capable of performing genuine choices for future courses of physical action. The consequent evolution of brain cortical networks contributes to increased computational power, memory capacity, and cognitive intelligence of the living organisms. Full article

ABCB4 is almost exclusively expressed in the liver, where it plays an essential role in bile formation by transporting phospholipids into the bile. ABCB4 polymorphisms and deficiencies in humans are associated with a wide spectrum of hepatobiliary disorders, attesting to its crucial physiological function. Inhibition of ABCB4 by drugs may lead to cholestasis and drug-induced liver injury (DILI), although compared with other drug transporters, there are only a few identified substrates and inhibitors of ABCB4. Since ABCB4 shares up to 76% identity and 86% similarity in the amino acid sequence with ABCB1, also known to have common drug substrates and inhibitors, we aimed to develop an ABCB4 expressing Abcb1-knockout MDCKII cell line for transcellular transport assays. This in vitro system allows the screening of ABCB4-specific drug substrates and inhibitors independently of ABCB1 activity. Abcb1KO-MDCKII-ABCB4 cells constitute a reproducible, conclusive, and easy to use assay to study drug interactions with digoxin as a substrate. Screening a set of drugs with different DILI outcomes proved that this assay is applicable to test ABCB4 inhibitory potency. Our results are consistent with prior findings concerning hepatotoxicity causality and provide new insights for identifying drugs as potential ABCB4 inhibitors and substrates. Full article

As global interest in the therapeutic potential of cannabis and its’ derivatives for the management of selected diseases increases, it is increasingly imperative that the toxic profile of cannabinoids be thoroughly understood in order to correctly assess the balance between the therapeutic risks and benefits. Modern studies across a number of jurisdictions, including Canada, Australia, the US and Europe have confirmed that some of the most worrying and severe historical reports of both congenital anomalies and cancer induction following cannabis exposure actually underestimate the multisystem thousand megabase-scale transgenerational genetic damage. These findings from teratogenic and carcinogenic literature are supported by recent data showing the accelerated patterns of chronic disease and the advanced DNA methylation epigenomic clock age in cannabis exposed patients. Together, the increased multisystem carcinogenesis, teratogenesis and accelerated aging point strongly to cannabinoid-related genotoxicity being much more clinically significant than it is widely supposed and, thus, of very considerable public health and multigenerational impact. Recently reported longitudinal epigenome-wide association studies elegantly explain many of these observed effects with considerable methodological sophistication, including multiple pathways for the inhibition of the normal chromosomal segregation and DNA repair, the inhibition of the basic epigenetic machinery for DNA methylation and the demethylation and telomerase acceleration of the epigenomic promoter hypermethylation characterizing aging. For cancer, 810 hits were also noted. The types of malignancy which were observed have all been documented epidemiologically. Detailed epigenomic explications of the brain, heart, face, uronephrological, gastrointestinal and limb development were provided, which amply explained the observed teratological patterns, including the inhibition of the key morphogenic gradients. Hence, these major epigenomic insights constituted a powerful new series of arguments which advanced both our understanding of the downstream sequalae of multisystem multigenerational cannabinoid genotoxicity and also, since mechanisms are key to the causal argument, inveighed strongly in favor of the causal nature of the relationship. In this introductory conceptual overview, we present the various aspects of this novel synthetic paradigmatic framework. Such concepts suggest and, indeed, indicate numerous fields for further investigation and basic science research to advance the exploration of many important issues in biology, clinical medicine and population health. Given this, it is imperative we correctly appraise the risk–benefit ratio for each potential cannabis application, considering the potency, severity of disease, stage of human development and duration of use. Full article

The R334W (c.1000C>T, p.Arg334Trp) is a rare cystic fibrosis (CF)-causing mutation for which no causal therapy is currently approved. This mutation leads to a significant reduction of CF transmembrane conductance regulator (CFTR) channel conductance that still allows for residual function. Potentiators are small molecules that interact with CFTR protein at the plasma membrane to enhance CFTR-dependent chloride secretion, representing thus pharmacotherapies targeting the root cause of the disease. Here, we generated a new CF bronchial epithelial (CFBE) cell line to screen a collection of compounds and identify novel potentiators for R334W-CFTR. The active compounds were then validated by electrophysiological assays and their additive effects in combination with VX-770, genistein, or VX-445 were exploited in this cell line and further confirmed in intestinal organoids. Four compounds (LSO-24, LSO-25, LSO-38, and LSO-77) were active in the functional primary screen and their ability to enhance R334W-CFTR-dependent chloride secretion was confirmed using electrophysiological measurements. In silico ADME analyses demonstrated that these compounds follow Lipinski’s rule of five and are thus suggested to be orally bioavailable. Dose–response relationships revealed nevertheless suboptimal efficacy and weak potency exerted by these compounds. VX-770 and genistein also displayed a small potentiation of R334W-CFTR function, while VX-445 demonstrated no potentiator activity for this mutation. In the R334W-expressing cell line, CFTR function was further enhanced by the combination of LSO-24, LSO-25, LSO-38, or LSO-77 with VX-770, but not with genistein. The efficacy of potentiator VX-770 combined with active LSO compounds was further confirmed in intestinal organoids (R334W/R334W genotype). Taken together, these molecules were demonstrated to potentiate R334W-CFTR function by a different mechanism than that of VX-770. They may provide a feasible starting point for the design of analogs with improved CFTR-potentiator activity. Full article

Introduction: Laboratory data link cannabinoid exposure to chromosomal mis-segregation errors. Recent epidemiological reports confirm this link and raise concern that elevated chromosomal congenital anomaly rates (CCAR) may be occurring in Europe which is experiencing increased cannabis use, daily intensity of use and cannabinoid potency. Methods: CCAR data from Eurocat. Drug use data from the European Monitoring Centre for Drugs and Drug Addiction. Income from World Bank. Bivariate, multivariate, panel and geotemporospatial regressions analyzed. Inverse probability weighting of panel models and E-values used as major quantitative causal inferential methodologies. Results: In countries where daily cannabis use was rising the trend for CCA’s was upwards whereas in those where daily use was declining it was usually downwards (p = 0.0002). In inverse probability weighted panel models terms for cannabis metrics were significant for chromosomal disorders, trisomies 21 and 13 and Klinefelters syndrome from p < 2.2 × 10⁻¹⁶. In spatiotemporal models cannabis terms were positive and significant for chromosomal disorders, genetic disorders, trisomies 21, 18 and 13, Turners and Klinefelters syndromes from 4.28 × 10⁻⁶, 5.79 × 10⁻¹², 1.26 × 10⁻¹¹, 1.12 × 10⁻⁷, 7.52 × 10⁻⁹, 7.19 × 10⁻⁷ and 7.27 × 10⁻⁷. 83.7% of E-value estimates and 74.4% of minimum E-values (mEV) > 9 including four values each at infinity. Considering E-values: the sensitivity of the individual disorders was trisomy 13 > trisomy 21 > Klinefelters > chromosomal disorders > Turners > genetic syndromes > trisomy 18 with mEV’s 1.91 × 10²⁵ to 59.31; and daily cannabis use was the most powerful covariate (median mEV = 1.91 × 10²⁵). Conclusions: Data indicate that, consistent with reports from Hawaii, Canada, Colorado, Australia and USA, CCARs are causally and spatiotemporally related to metrics and intensity of cannabis exposure, directly impact 645 MB (21.5%) of the human genome and may implicate epigenomic-centrosomal mechanisms. Full article

The progressive accumulation of misfolded α-synuclein (α-syn) in the brain is widely considered to be causal for the debilitating clinical manifestations of synucleinopathies including, most notably, Parkinson’s disease (PD). Immunotherapies, both active and passive, against α-syn have been developed and are promising novel treatment strategies for such disorders. To increase the potency and specificity of PD vaccination, we created the ‘Win the Skin Immune System Trick’ (WISIT) vaccine platform designed to target skin-resident dendritic cells, inducing superior B and T cell responses. Of the six tested WISIT candidates, all elicited higher immune responses compared to conventional, aluminum adjuvanted peptide-carrier conjugate PD vaccines, in BALB/c mice. WISIT-induced antibodies displayed higher selectivity for α-syn aggregates than those induced by conventional vaccines. Additionally, antibodies induced by two selected candidates were shown to inhibit α-syn aggregation in a dose-dependent manner in vitro. To determine if α-syn fibril formation could also be inhibited in vivo, WISIT candidate type 1 (CW-type 1) was tested in an established synucleinopathy seeding model and demonstrated reduced propagation of synucleinopathy in vivo. Our studies provide proof-of-concept for the efficacy of the WISIT vaccine technology platform and support further preclinical and clinical development of this vaccine candidate. Full article

As body wall congenital anomalies (BWCAs) have a long history of being associated with prenatal or community cannabis exposure (CCE), it was of interest to investigate these epidemiological relationships in Europe given the recent increases in cannabis use prevalence, daily intensity, and Δ9-tetrahydrocannabinol (THC) potency. Methods: This study makes use of BWCA data from Eurocat, drug exposure data from the European Monitoring Centre for Drugs and Drug Addiction, and income from the World Bank. Results: The mapping analysis showed that BWCARs increased in France, Spain, and the Netherlands. The bivariate mapping analysis showed that the BWCA rates (BWCAR) and the cannabis resin THC concentration rose simultaneously in France, the Netherlands, Bulgaria, Sweden, and Norway. The bivariate ranking of the BWCARs by median minimum E-value (mEV) was omphalocele > diaphragmatic hernia > abdominal wall defects > gastroschisis. With inverse probability weighted multivariable panel regression, the series of BWCAs, including gastroschisis, omphalocele, and diaphragmatic hernia, was positively related to various metrics of cannabis use from p = 2.45 × 10⁻¹⁴, 4.77 × 10⁻⁷ and <2.2 × 10⁻¹⁶. With geospatial regression, the same series of BWCAs was related to cannabis metrics from p = 0.0016, 5.28 × 10⁻⁶ and 4.88 × 10⁻⁹. Seventeen out of twenty-eight (60.7%) of the E-value estimates were >9 (high range), as were 14/28 (50.0%) of the mEVs. Conclusion: The data confirm the close relationship of the BWCARs with the metrics of CCE, fulfill the quantitative criteria of causal inference, and underscore the salience of the public health impacts of cannabinoid teratogenicity. Of major concern is the rising CCE impacting exponential cannabinoid genotoxic dose-response relationships. CCE should be carefully restricted to protect the food chain, the genome, and the epigenome of coming generations. Full article

Protein arginine methyltransferase 5 (PRMT5) is an attractive molecular target in anticancer drug discovery due to its extensive involvement in transcriptional control, RNA processing, and other cellular pathways that are causally related to tumor initiation and progression. In recent years, various compounds have been screened or designed to target either the substrate- or cofactor-binding site of PRMT5. To expand the diversity of chemotypes for inhibitory binding to PRMT5 and other AdoMet-dependent methyltransferases, in this work, we designed a series of triazole-containing adenosine analogs aimed at targeting the cofactor-binding site of PRMT5. Triazole rings have commonly been utilized in drug discovery due to their ease of synthesis and functionalization as bioisosteres of amide bonds. Herein, we utilized the electronic properties of the triazole ring as a novel way to specifically target the cofactor-binding site of PRMT5. A total of about 30 compounds were synthesized using the modular alkyne-azide cycloaddition reaction. Biochemical tests showed that these compounds exhibited inhibitory activity of PRMT5 at varying degrees and several showed single micromolar potency, with clear selectivity for PRMT5 over PRMT1. Docking-based structural analysis showed that the triazole ring plays a key role in binding to the characteristic residue Phe327 in the active pocket of PRMT5, explaining the compounds’ selectivity for this type-II enzyme. Overall, this work provides new structure–activity relationship information on the design of AdoMet analogs for selective inhibition of PRMT5. Further structural optimization work will further improve the potency of the top leads. Full article

The ongoing COVID-19 pandemic has impacted the mental health of populations and highlighted the limitations of mental health care systems. As the trajectory of the pandemic and the economic recovery are still uncertain, decision tools are needed to help evaluate the best interventions to improve mental health outcomes. We developed a system dynamics model that captures causal relationships among population, demographics, post-secondary education, health services, COVID-19 impact, and mental health outcomes. The study was conducted in the Australian state of Victoria. The model was calibrated using historical data and was stratified by age group and by geographic remoteness. Findings demonstrate that the most effective intervention combination includes economic, social, and health sector initiatives. Assertive post-suicide attempt care is the most impactful health sector intervention, but delaying implementation reduces the potency of its impact. Some evidence-based interventions, such as population-wide community awareness campaigns, are projected to worsen mental health outcomes when implemented on their own. Systems modelling offers a powerful decision-support tool to test alternative strategies for improving mental health outcomes in the Victorian context. Full article

The COVID-19 pandemic has halted economic activities and made business dynamics much more challenging by introducing several additional operational, structural, and managerial constraints. The problem has affected global supply chains in many ways, and has questioned their long-term continuity. On the other hand, Industry 4.0 is an emerging phenomenon. However, there is a need to investigate how Industry 4.0 technologies may play a potential role in sustaining business operations to ease unprecedented causalities. The current research aims to investigate the potentiality of Industry 4.0 technologies to solve the COVID-19 challenges for long term sustainability. From an exploratory literature analysis coupled with the Delphi method, keeping in view the situation of the pandemic, ten challenge groups that have affected global business dynamics were identified. A questionnaire was developed with the aim of accumulating industrial and academic experts to evaluate the degree of influence and interrelationship among the identified challenges. The Decision Making, Trial and Evaluation Laboratory (DEMATEL) approach was deployed to further analyze the challenges for the categorization of these into causes and effects, further prioritizing them for better decision making. The prioritized challenges from the list of causes were governmental policies and support, followed by real access to customers and a lack of infrastructure. Additionally, these challenges were further evaluated through the expert opinion of Industry 4.0 systems experts and strategic-level supply chain experts to potentially gauge the potency of Industry 4.0 technologies to solve COVID-19-induced challenges. The outcomes of this research (which used Delphi integrated with a DEMATEL approach) are expected to support businesses in formulating strategies with the aim of business continuity in combating future disruptions caused by COVID-19-like pandemics. Full article

Recently, many airline companies have trialed introducing team systems to manage crew members and enhance competitiveness systematically through the efficiency of manpower operation. Cabin crew members share in a sense of unity when spending time with team members outside of work hours. Cabin crews must be able to resolve unexpected issues—fires, aircraft defects, medical emergencies, and sudden airflow changes—quickly and accurately. As unexpected issues may result in major accidents, it is crucial that cabin crew members can take responsibility for passenger safety and offer satisfactory services to customers. Furthermore, most cabin duties require cooperation and are highly interdependent; thus, respect and teamwork are essential. This empirical study aims to identify and examine the positive factors of the team system used to evaluate causalities in job satisfaction, team potency, and mental health. The research model is developed based on a theoretical review, focusing on five positive factors—sense of belonging, mutual support, communication, motivation, and work flexibility—and dependent variables: job satisfaction, team potency, and mental health. Sense of belonging, communication, and work flexibility significantly affected team potency along with job satisfaction. This study has practical implications, providing guidance for the sustainable development of team systems for airline crew management. Full article

Erythema multiforme (EM) is an immune-mediated condition that classically presents with discrete targetoid lesions and can involve both mucosal and cutaneous sites. While EM is typically preceded by viral infections, most notably herpes simplex virus (HSV), and certain medications, a large portion of cases are due to an unidentifiable cause. EM can be confused with other more serious conditions like Stevens–Johnson syndrome (SJS); however, clinical research has provided significant evidence to classify EM and SJS as separate disorders. Treatment of EM is highly variable, depending on the etiology, the involvement of mucosal sites, and the chronicity (acute vs. recurring) of the disease. If the etiology or causal medication/infection is identified, then the medication is stopped and/or the infection is treated prior to initiating symptomatic treatment. Treatment for acute EM is focused on relieving symptoms with topical steroids or antihistamines. Treatment for recurrent EM is most successful when tailored to individual patients. First line treatment for recurrent EM includes both systemic and topical therapies. Systemic therapies include corticosteroid therapy and antiviral prophylaxis. Topical therapies include high-potency corticosteroids, and antiseptic or anesthetic solutions for mucosal involvement. Second-line therapies for patients who do not respond to antiviral medications include immunosuppressive agents, antibiotics, anthelmintics, and antimalarials Full article

Plasmalemmal solute carriers (SLCs) gauge and control solute abundance across cellular membranes. By virtue of this action, they play an important role in numerous physiological processes. Mutations in genes encoding the SLCs alter amino acid sequence that often leads to impaired protein function and onset of monogenic disorders. To understand how these altered proteins cause disease, it is necessary to undertake relevant functional assays. These experiments reveal descriptors of SLC function such as the maximal transport velocity (V_max), the Michaelis constant for solute uptake (K_M), potencies for inhibition of transporter function (IC₅₀/EC₅₀), and many more. In several instances, the mutated versions of different SLC transporters differ from their wild-type counterparts in the value of these descriptors. While determination of these experimental parameters can provide conjecture as to how the mutation gives rise to disease, they seldom provide any definitive insights on how a variant differ from the wild-type transporter in its operation. This is because the experimental determination of association between values of the descriptors and several partial reactions a transporter undergoes is casual, but not causal, at best. In the present study, we employ kinetic models that allow us to derive explicit mathematical terms and provide experimental descriptors as a function of the rate constants used to parameterize the kinetic model of the transport cycle. We show that it is possible to utilize these mathematical expressions to deduce, from experimental outcomes, how the mutation has impinged on partial reactions in the transport cycle. Full article

A tailored series of coumarin-based ferrocenyl 1,3-oxazine hybrid compounds was synthesized and investigated for potential antiparasitic activity, drawing inspiration from the established biological efficacy of the constituent chemical motifs. The structural identity of the synthesized compounds was confirmed by common spectroscopic techniques: NMR, HRMS and IR. Biological evaluation studies reveal that the compounds exhibit higher in vitro antiparasitic potency against the chemosensitive malarial strain (3D7 P. falciparum) over the investigated trypanosomiasis causal agent (T. b. brucei 427) with mostly single digit micromolar IC₅₀ values. When read in tandem with the biological performance of previously reported structurally similar non-coumarin, phenyl derivatives (i.e., ferrocenyl 1,3-benzoxazines and α-aminocresols), structure-activity relationship analyses suggest that the presence of the coumarin nucleus is tolerated for biological activity though this may lead to reduced efficacy. Preliminary mechanistic studies with the most promising compound (11b) support hemozoin inhibition and DNA interaction as likely mechanistic modalities by which this class of compounds may act to produce plasmocidal and antitrypanosomal effects. Full article

The development of malignant effusions such as ascites reflects a massive progression of a malignant disease. In patients with ovarian carcinoma, a high amount of ascites (>500 mL) is an independent negative prognostic marker. The composition and constituents of ascites reflect the inflammatory environment of the underlying tumor. Increased cellular resistance of ascites-derived tumor cells and the development of venous thromboembolic events (VTE) are major risks for these patients, especially in patients with advanced ovarian carcinoma. In this study, we discuss the release of tissue factor-bearing extracellular vesicles (TF⁺ EVs) from tumor cells into the environment (ascites fluid) and their systemic spreading as a possible causal explanation of the pathologic coagulation status in these patients. We obtained ascites from patients with advanced ovarian carcinoma, collected during surgery or therapeutic paracentesis (n = 20). Larger ectosome-like EVs were isolated using sequential centrifugation, quantified by high-resolution flow cytometry and analyzed using nanoparticle tracking analysis. Furthermore, the pro-coagulant properties (TF activity) of EVs were determined. Compared to published TF activities of EVs from healthy persons, TF activities of EVs derived from ascites of patients with ovarian cancer were very high, with a median of 80 pg/mL. The rate of VTE, as reported in the patient files, was high as well (35%, 7 out of 20). Furthermore, all but one patient with VTE had EV concentrations above the median within their ascetic fluid (p < 0.02). Since VTE continues to be a frequent cause of death in cancer patients, prophylactic antithrombotic treatment might be worth considering in these patients. However, given the risk of bleeding, more clinical data are warranted. Although the study is too small to enable reaching a conclusion on direct clinical implementation, it can well serve as a proof of principle and a rationale to initiate a prospective clinical study with different patient subgroups. We also show ex vivo that these larger ectosome-like EVs induce intracellular ERK phosphorylation and tumor cell migration, which is not directly related to their pro-coagulative potency, but might help to understand why cancer patients with thromboembolic events have a poorer prognosis. Full article