Explore the vast range of titles available.

Background Numerous drugs have the potential to be affected by cytochrome P450 (CYP) 2B6-mediated drug–drug interactions (DDIs). Objectives In this work, we extend a static approach to the prediction of the extent of pharmacokinetics DDIs between substrates and inhibitors or inducers of CYP2B6. Methods This approach is based on the calculation of two parameters (the contribution ratio [CR], representing the fraction of dose of the substrate metabolized via this pathway and the inhibitory or inducing potency of the perpetrator [IR or IC, respectively]) calculated from the area under the concentration–time curve (AUC) ratios obtained in in-vivo DDI studies. Results Forty-eight studies involving 5 substrates, 11 inhibitors and 18 inducers of CYP2B6 (overall 15 inhibition and 33 induction studies) were divided into test and validation sets and considered for estimation of the parameters. The proposed approach demonstrated a fair accuracy for predicting the extent of DDI related to CYP2B6 inhibition and induction, all predictions related to the validation test ( N  = 18) being 50–200% of the observed ratios. Conclusions This methodology can be used for proposing initial dose adaptations to be adopted, for example in clinical use or for designing DDI studies involving this enzyme.

The paper discusses some formal difficulties concerning the theory of universals of Trope-Only ontologies, from which the formal theory of predication advanced by Trope-Only theorists seems to be irremediably affected. It is impossible to lay out a successful defense of a Trope-Only theory without Russellian types, but such types are ontologically inconsistent with tropes’ nominalism. Historically, Tropists’ first way to avoid the problem is appealing to the supervenience claim, which however fails on its terms and, thus, fails as a ground for a solution to the higher-order or ‘type’ problem. A later solution involves the invariance of primitive equivalence relations in order to make universals ontologically innocuous. However, I argue that this latter solution fails to meet the requirements imposed on an ontologically unbiased nominalist attitude. So, this paper discusses how Trope-Only theories alter standard formal moves in Nominalism, and also is interested in clarifying further the formal assumptions for these problems.

Nominalism in formal ontology is still the thesis that the only acceptable domain of quantification is the first-order domain of particulars. Nominalists may assert that second-order well-formed formulas can be fully and completely interpreted within the first-order domain, thereby avoiding any ontological commitment to second-order entities, by means of an appropriate semantics called “substitutional”. In this paper I argue that the success of this strategy depends on the ability of Nominalists to maintain that identity, and equivalence relations more in general, is first-order and invariant. Firstly, I explain why Nominalists are formally bound to this first-order concept of identity. Secondly, I show that the resources needed to justify identity, a certain conception of identity invariance, are out of the Nominalist’s reach.

The Principle of the Identity of Indiscernibles (PII) asserts that if putative objects x and y share all properties P, then they must be one and the same entity. Since the usual formal rendering of the PII has the same formal structure as the Leibniz Identity, it may be unclear whether it can be used to define identity and objectuality. As identity and objectuality are closely related, this study aims to examine their relationship within the framework of formal ontology. Crucial for the discussion are issues about type and range of quantification and the invariance of the identity predicate coourring in the PII. Ultimately, the analysis reveals that the appeal to PII is insufficient for providing both identity and objectuality. Some further considerations about how the PII sensitively constrains the range of available ontologies or metaphysics are formulated.

Background and Objective: Predicting drug–drug interactions (DDIs) in pediatric patients remains a major challenge in clinical pharmacology. This study aimed to evaluate and compare three empirical approaches for extrapolating adult cytochrome P450 (CYP)-mediated DDI pharmacokinetics (PK) data to predict the extent of the corresponding DDIs in children across different age groups. Methods: The approaches assessed were: (A) the direct use of adult area under the plasma concentration–time curve ratios (AUCRs) as estimators of pediatric values; (B) the application of a correction accounting for the ontogeny of the involved CYP enzyme; and (C) the application of corrections for both enzyme ontogeny and allometric scaling. Twenty-five pediatric AUCRs were predicted from adult AUCR data. Predictive performance was evaluated by comparing predicted AUCRpediatric values with observed values, using a 50–200% acceptability range. Results: Approach C demonstrated superior predictive capability, with only one out of 25 predictions falling outside the acceptability range. In contrast, both approaches A and B resulted in three values each outside this range. Further visual exploration and detailed performance analyses confirmed the enhanced accuracy of approach C in predicting pediatric DDIs compared with the other approaches. Conclusions: This study demonstrates that the proposed approach of considering both ontogeny and allometric scaling represents a robust and reasonable method to anticipate the extent of pediatric CYP-based DDIs when adult PK data are available.

Six tools to call chromatin interactions and seven tools for topologically associating domain calling are systematically compared with real and simulated data. The strengths and weaknesses of each tool are discussed. Hi-C is a genome-wide sequencing technique used to investigate 3D chromatin conformation inside the nucleus. Computational methods are required to analyze Hi-C data and identify chromatin interactions and topologically associating domains (TADs) from genome-wide contact probability maps. We quantitatively compared the performance of 13 algorithms in their analyses of Hi-C data from six landmark studies and simulations. This comparison revealed differences in the performance of methods for chromatin interaction identification, but more comparable results for TAD detection between algorithms.

The initial mechanism for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is the binding of the virus to the membrane-bound form of ACE2, which is mainly expressed in the lung. Since the heart and the vessels also express ACE2, they both could become targets of the virus. However, at present the extent and importance of this potential involvement are unknown. Cardiac troponin levels are significantly higher in patients with more severe infections, patients admitted to intensive care units or in those who have died. In the setting of COVID-19, myocardial injury, defined by an increased troponin level, occurs especially due to non-ischaemic myocardial processes, including severe respiratory infection with hypoxia, sepsis, systemic inflammation, pulmonary thrombosis and embolism, cardiac adrenergic hyperstimulation during cytokine storm syndrome, and myocarditis. At present, there are limited reports on definite diagnosis of myocarditis caused by SARS-CoV-2 in humans and limited demonstration of the virus in the myocardium. In conclusion, although the heart and the vessels are potential targets in COVID-19, there is currently limited evidence on the direct infection of the myocardium by SARS-CoV-2. Additional pathological studies and autopsy series will be very helpful to clarify the potentiality of COVID-19 to directly infect the myocardium and cause myocarditis.

The present research aims at gaining a better insight on the psychological barriers to the introduction of social robots in society at large. Based on social psychological research on intergroup distinctiveness, we suggested that concerns toward this technology are related to how we define and defend our human identity. A threat to distinctiveness hypothesis was advanced. We predicted that too much perceived similarity between social robots and humans triggers concerns about the negative impact of this technology on humans, as a group, and their identity more generally because similarity blurs category boundaries, undermining human uniqueness. Focusing on the appearance of robots, in two studies we tested the validity of this hypothesis. In both studies, participants were presented with pictures of three types of robots that differed in their anthropomorphic appearance varying from no resemblance to humans (mechanical robots), to some body shape resemblance (biped humanoids) to a perfect copy of human body (androids). Androids raised the highest concerns for the potential damage to humans, followed by humanoids and then mechanical robots. In Study 1, we further demonstrated that robot anthropomorphic appearance (and not the attribution of mind and human nature) was responsible for the perceived damage that the robot could cause. In Study 2, we gained a clearer insight in the processes underlying this effect by showing that androids were also judged as most threatening to the human–robot distinction and that this perception was responsible for the higher perceived damage to humans. Implications of these findings for social robotics are discussed.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is associated with disorders affecting the peripheral and the central nervous system. A high number of patients develop post-COVID-19 syndrome with the persistence of a large spectrum of symptoms, including neurological, beyond 4 weeks after infection. Several potential mechanisms in the acute phase have been hypothesized, including damage of the blood-brain-barrier (BBB). We tested weather markers of BBB damage in association with markers of brain injury and systemic inflammation may help in identifying a blood signature for disease severity and neurological complications. Blood biomarkers of BBB disruption (MMP-9, GFAP), neuronal damage (NFL) and systemic inflammation (PPIA, IL-10, TNFα) were measured in two COVID-19 patient cohorts with high disease severity (ICUCovid; n=79) and with neurological complications (NeuroCovid; n=78), and in two control groups free from COVID-19 history, healthy subjects (n=20) and patients with amyotrophic lateral sclerosis (ALS; n=51). Samples from COVID-19 patients were collected during the first and the second wave of COVID-19 pandemic in Lombardy, Italy. Evaluations were done at acute and chronic phases of the COVID-19 infection. Blood biomarkers of BBB disruption and neuronal damage are high in COVID-19 patients with levels similar to or higher than ALS. NeuroCovid patients display lower levels of the cytokine storm inducer PPIA but higher levels of MMP-9 than ICUCovid patients. There was evidence of different temporal dynamics in ICUCovid compared to NeuroCovid patients with PPIA and IL-10 showing the highest levels in ICUCovid patients at acute phase. On the contrary, MMP-9 was higher at acute phase in NeuroCovid patients, with a severity dependency in the long-term. We also found a clear severity dependency of NFL and GFAP levels, with deceased patients showing the highest levels. The overall picture points to an increased risk for neurological complications in association with high levels of biomarkers of BBB disruption. Our observations may provide hints for therapeutic approaches mitigating BBB disruption to reduce the neurological damage in the acute phase and potential dysfunction in the long-term.

Cellular differentiation involves profound remodelling of chromatic landscapes, yet the mechanisms by which somatic cell identity is subsequently maintained remain incompletely understood. To further elucidate regulatory pathways that safeguard the somatic state, we performed two comprehensive RNA interference (RNAi) screens targeting chromatin factors during transcription-factor-mediated reprogramming of mouse fibroblasts to induced pluripotent stem cells (iPS cells). Subunits of the chromatin assembly factor-1 (CAF-1) complex, including Chaf1a and Chaf1b, emerged as the most prominent hits from both screens, followed by modulators of lysine sumoylation and heterochromatin maintenance. Optimal modulation of both CAF-1 and transcription factor levels increased reprogramming efficiency by several orders of magnitude and facilitated iPS cell formation in as little as 4 days. Mechanistically, CAF-1 suppression led to a more accessible chromatin structure at enhancer elements early during reprogramming. These changes were accompanied by a decrease in somatic heterochromatin domains, increased binding of Sox2 to pluripotency-specific targets and activation of associated genes. Notably, suppression of CAF-1 also enhanced the direct conversion of B cells into macrophages and fibroblasts into neurons. Together, our findings reveal the histone chaperone CAF-1 to be a novel regulator of somatic cell identity during transcription-factor-induced cell-fate transitions and provide a potential strategy to modulate cellular plasticity in a regenerative setting. RNA interference screens were used to identify chromatin-associated factors that impede reprogramming of somatic cells into iPS cells; suppression of the chromatin assembly factor CAF-1 enhances the generation of iPS cells by rendering chromatin more accessible to pluripotency transcription factors. CAF-1 is a barrier to cell fate change Lineage fate determination in development, and reprogramming to a different fate in the laboratory, depend on gene expression programs that are regulated by factors influencing the chromatin landscape. Konrad Hochedlinger and colleagues have performed two RNA-interference-based screens to search for chromatin-associated factors that impede reprogramming. They identify the chromatin assembly factor-1 (CAF-1) complex as an important regulator of this process, acting by rendering the chromatin inaccessible to transcription factors. Suppression of CAF-1 function thus facilitates chromatin access to reprogramming factors, both during reprogramming to pluripotency and in direct fate conversion.