The Ontology of Intentional Agency in Light of Neurobiological Determinism: Philosophy Meets Folk Psychology

The moot point of the Western philosophical rhetoric about free will consists in examining whether the claim of authorship to intentional, deliberative actions fits into or is undermined by a one-way causal framework of determinism. Philosophers who think that reconciliation between the two is possible are known as metaphysical compatibilists. However, there are philosophers populating the other end of the spectrum, known as the metaphysical libertarians, who maintain that claim to intentional agency cannot be sustained unless it is assumed that indeterministic causal processes pervade the action-implementation apparatus employed by the agent. The metaphysical libertarians differ among themselves on the question of whether the indeterministic causal relation exists between the series of intentional states and processes, both conscious and unconscious, and the action, making claim for what has come to be known as the event-causal view, or between the agent and the action, arguing that a sort of agent causation is at work. In this paper, I have tried to propose that certain features of both event-causal and agent-causal libertarian views need to be combined in order to provide a more defendable compatibilist account accommodating deliberative actions with deterministic causation. The ‘‘agent-executed-eventcausal libertarianism’’, the account of agency I have tried to develop here, integrates certain plausible features of the two competing accounts of libertarianism turning them into a consistent whole. I hope to show in the process that the integration of these two variants of libertarianism does not challenge what some accounts of metaphysical compatibilism propose—that there exists a broader deterministic relation between the web of mental and extra-mental components constituting the agent’s dispositional system—the agent’s beliefs, desires, short-term and long-term goals based on them, the acquired social, cultural and religious beliefs, the general and immediate and situational environment in which the agent is placed, etc. on the one hand and the decisions she makes over her lifetime on the basis of these factors. While in the ‘‘Introduction’’ the philosophically assumed anomaly between deterministic causation and the intentional act of deciding has been briefly surveyed, the second section is devoted to the task of bridging the gap between compatibilism and libertarianism. The next section of the paper turns to an analysis of folk-psychological concepts and intuitions about the effects of neurochemical processes and prior mental events on the freedom of making choices. How philosophical insights can be beneficially informed by taking into consideration folk-psychological intuitions has also been discussed, thus setting up the background for such analysis. It has been suggested in the end that support for the proposed theory of intentional agency can be found in the folk-psychological intuitions, when they are taken in the right perspective

Service Level Constrained Inventory Systems

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151878/1/poms13060_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151878/2/poms13060.pd

Challenges of tuberculosis management in high and low prevalence countries in a mobile world

This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.In this issue of the PCRJ, Bishara et al. 1 present a case report about the treatment of a pregnant woman with tuberculosis (TB). She had emigrated from a country with a high prevalence of TB to one with a lower prevalence. This presented a challenge to her physicians who were faced with identifying and treating close contacts who were also infected. This Perspective article explores in more depth some of the questions raised by this case report. It discusses the role of primary care physicians in low prevalence countries who can implement evidence-based screening programmes, it discusses effective strategies for the diagnosis and treatment of TB in countries with high TB prevalence, and it presents insights from medical anthropology that can help practitioners overcome the barriers to TB diagnosis, treatment and screening described in the case report

Multiple effects of silymarin on the hepatitis C virus lifecycle

Silymarin, an extract from milk thistle (Silybum marianum), and its purified flavonolignans have been recently shown to inhibit hepatitis C virus (HCV) infection, both in vitro and in vivo. In the current study, we further characterized silymarin's antiviral actions. Silymarin had antiviral effects against hepatitis C virus cell culture (HCVcc) infection that included inhibition of virus entry, RNA and protein expression, and infectious virus production. Silymarin did not block HCVcc binding to cells but inhibited the entry of several viral pseudoparticles (pp), and fusion of HCVpp with liposomes. Silymarin but not silibinin inhibited genotype 2a NS5B RNA-dependent RNA polymerase (RdRp) activity at concentrations 5 to 10 times higher than required for anti-HCVcc effects. Furthermore, silymarin had inefficient activity on the genotype 1b BK and four 1b RDRPs derived from HCV-infected patients. Moreover, silymarin did not inhibit HCV replication in five independent genotype 1a, 1b, and 2a replicon cell lines that did not produce infectious virus. Silymarin inhibited microsomal triglyceride transfer protein activity, apolipoprotein B secretion, and infectious virion production into culture supernatants. Silymarin also blocked cell-to-cell spread of virus. CONCLUSION: Although inhibition of in vitro NS5B polymerase activity is demonstrable, the mechanisms of silymarin's antiviral action appear to include blocking of virus entry and transmission, possibly by targeting the host cell

An Agent-Based Approach to Self-Organized Production

The chapter describes the modeling of a material handling system with the production of individual units in a scheduled order. The units represent the agents in the model and are transported in the system which is abstracted as a directed graph. Since the hindrances of units on their path to the destination can lead to inefficiencies in the production, the blockages of units are to be reduced. Therefore, the units operate in the system by means of local interactions in the conveying elements and indirect interactions based on a measure of possible hindrances. If most of the units behave cooperatively ("socially"), the blockings in the system are reduced. A simulation based on the model shows the collective behavior of the units in the system. The transport processes in the simulation can be compared with the processes in a real plant, which gives conclusions about the consequencies for the production based on the superordinate planning.Comment: For related work see http://www.soms.ethz.c

Efficacy and safety of metabolic interventions for the treatment of severe COVID-19: in vitro, observational, and non-randomized open-label interventional study

Background: Viral infection is associated with a significant rewire of the host metabolic pathways, presenting attractive metabolic targets for intervention. Methods: We chart the metabolic response of lung epithelial cells to SARS-CoV-2 infection in primary cultures and COVID-19 patient samples and perform in vitro metabolism-focused drug screen on primary lung epithelial cells infected with different strains of the virus. We perform observational analysis of Israeli patients hospitalized due to COVID-19 and comparative epidemiological analysis from cohorts in Italy and the Veteran's Health Administration in the United States. In addition, we perform a prospective non-randomized interventional open-label study in which 15 patients hospitalized with severe COVID-19 were given 145 mg/day of nanocrystallized fenofibrate added to the standard of care. Results: SARS-CoV-2 infection produced transcriptional changes associated with increased glycolysis and lipid accumulation. Metabolism-focused drug screen showed that fenofibrate reversed lipid accumulation and blocked SARS-CoV-2 replication through a PPARα-dependent mechanism in both alpha and delta variants. Analysis of 3233 Israeli patients hospitalized due to COVID-19 supported in vitro findings. Patients taking fibrates showed significantly lower markers of immunoinflammation and faster recovery. Additional corroboration was received by comparative epidemiological analysis from cohorts in Europe and the United States. A subsequent prospective non-randomized interventional open-label study was carried out on 15 patients hospitalized with severe COVID-19. The patients were treated with 145 mg/day of nanocrystallized fenofibrate in addition to standard-of-care. Patients receiving fenofibrate demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to patients admitted during the same period. Conclusions: Taken together, our data suggest that pharmacological modulation of PPARα should be strongly considered as a potential therapeutic approach for SARS-CoV-2 infection and emphasizes the need to complete the study of fenofibrate in large randomized controlled clinical trials. Funding: Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). The interventional study was supported by Abbott (project FENOC0003). Clinical trial number: NCT04661930

Evaluation of the Genetic Association Between Adult Obesity and Neuropsychiatric Disease

Extreme obesity (EO, BMI>50) is frequently associated with neuropsychiatric disease (NPD). As both EO and NPD are heritable central nervous system disorders, we assessed the prevalence of protein truncating (PTV) and copy number variants (CNV) in genes/regions previously implicated in NPD, in adults with EO (n=149) referred for weight loss/bariatric surgery. We also assessed the prevalence of CNVs in patients referred to University College London Hospital (UCLH) with EO (n=218) and obesity (O, BMI 35-50, n=374) and a Swedish cohort of participants from the community with predominantly O (n=161). The prevalence of variants was compared to controls in ExAC/gnomAd database. In the discovery cohort (high NPD prevalence: 77%), the cumulative PTV/CNV allele frequency (AF) was 7.7 % vs 2.6% in controls (Odds Ratio (OR) 3.1, (95% CI 2-4.1, p<0.0001). In the UCLH EO cohort (intermediate NPD prevalence: 47%), CNV AF (1.8% vs 0.9% in controls, OR 1.95, 95% CI 0.96-3.93, p=0.06) was lower than the discovery cohort. CNV AF was not increased in the UCLH O cohort (0.8%). No CNVs were identified in the Swedish cohort with no NPD. These findings suggest PTV/CNVs, in genes/regions previously associated with NPD, may contribute to NPD in patients with EO

Modeling Supply Networks and Business Cycles as Unstable Transport Phenomena

Physical concepts developed to describe instabilities in traffic flows can be generalized in a way that allows one to understand the well-known instability of supply chains (the so-called ``bullwhip effect''). That is, small variations in the consumption rate can cause large variations in the production rate of companies generating the requested product. Interestingly, the resulting oscillations have characteristic frequencies which are considerably lower than the variations in the consumption rate. This suggests that instabilities of supply chains may be the reason for the existence of business cycles. At the same time, we establish some link to queuing theory and between micro- and macroeconomics.Comment: For related work see http://www.helbing.or

Integrating transposable elements in the 3D genome

Chromosome organisation is increasingly recognised as an essential component of genome regulation, cell fate and cell health. Within the realm of transposable elements (TEs) however, the spatial information of how genomes are folded is still only rarely integrated in experimental studies or accounted for in modelling. Whilst polymer physics is recognised as an important tool to understand the mechanisms of genome folding, in this commentary we discuss its potential applicability to aspects of TE biology. Based on recent works on the relationship between genome organisation and TE integration, we argue that existing polymer models may be extended to create a predictive framework for the study of TE integration patterns. We suggest that these models may offer orthogonal and generic insights into the integration profiles (or "topography") of TEs across organisms. In addition, we provide simple polymer physics arguments and preliminary molecular dynamics simulations of TEs inserting into heterogeneously flexible polymers. By considering this simple model, we show how polymer folding and local flexibility may generically affect TE integration patterns. The preliminary discussion reported in this commentary is aimed to lay the foundations for a large-scale analysis of TE integration dynamics and topography as a function of the three-dimensional host genome

Water dispersible microbicidal cellulose acetate phthalate film

BACKGROUND: Cellulose acetate phthalate (CAP) has been used for several decades in the pharmaceutical industry for enteric film coating of oral tablets and capsules. Micronized CAP, available commercially as "Aquateric" and containing additional ingredients required for micronization, used for tablet coating from water dispersions, was shown to adsorb and inactivate the human immunodeficiency virus (HIV-1), herpesviruses (HSV) and other sexually transmitted disease (STD) pathogens. Earlier studies indicate that a gel formulation of micronized CAP has a potential as a topical microbicide for prevention of STDs including the acquired immunodeficiency syndrome (AIDS). The objective of endeavors described here was to develop a water dispersible CAP film amenable to inexpensive industrial mass production. METHODS: CAP and hydroxypropyl cellulose (HPC) were dissolved in different organic solvent mixtures, poured into dishes, and the solvents evaporated. Graded quantities of a resulting selected film were mixed for 5 min at 37°C with HIV-1, HSV and other STD pathogens, respectively. Residual infectivity of the treated viruses and bacteria was determined. RESULTS: The prerequisites for producing CAP films which are soft, flexible and dispersible in water, resulting in smooth gels, are combining CAP with HPC (other cellulose derivatives are unsuitable), and casting from organic solvent mixtures containing ≈50 to ≈65% ethanol (EtOH). The films are ≈100 µ thick and have a textured surface with alternating protrusions and depressions revealed by scanning electron microscopy. The films, before complete conversion into a gel, rapidly inactivated HIV-1 and HSV and reduced the infectivity of non-viral STD pathogens >1,000-fold. CONCLUSIONS: Soft pliable CAP-HPC composite films can be generated by casting from organic solvent mixtures containing EtOH. The films rapidly reduce the infectivity of several STD pathogens, including HIV-1. They are converted into gels and thus do not have to be removed following application and use. In addition to their potential as topical microbicides, the films have promise for mucosal delivery of pharmaceuticals other than CAP