Parameter estimation is one of the central challenges in computational biology. In this paper, we present an approach to estimate model parameters and assess their identifiability in cases where only partial knowledge of the system structure is available. The partially known model is embedded into a system of hybrid neural ordinary differential equations, with neural networks capturing unknown system components.
View Article and Find Full Text PDFThis study aimed to evaluate the dietary administration of a blend composed of carvacrol, tannic acid derived from Castanea sativa mill and Glycyrrhiza glabra, medium chain fatty acids (MCFAs) glycerides for weanling piglets. An in vitro digestion followed by total phenolic content (TPC) and total antioxidant activity (TAC) assessment was performed before the in vivo application. At weaning, a total of 210 piglets were randomly allocated to two experimental treatments (7 replicates/15 piglets for each replicate).
View Article and Find Full Text PDFSubstrate channeling could be very useful for plant metabolic engineering; hence, we propose that functionalized supramolecular self-assembly scaffolds can act as enzymatic hubs able to perform reactions in close contiguity. Virus nanoparticles (VNPs) offer an opportunity in this context, and we present a functionalization strategy to display different enzymes on the outer surface of three different VNPs produced in plants. Tomato bushy stunt virus (TBSV) and Potato virus X (PVX) plant viruses were functionalized by the genetic fusion of the E-coil peptide coding sequence to their respective coat proteins genes, while the enzyme lichenase was tagged with the K-coil peptide.
View Article and Find Full Text PDFUnderstanding drug exposure at disease target sites is pivotal to profiling new drug candidates in terms of tolerability and efficacy. Such quantification is particularly tedious for anti-tuberculosis (TB) compounds as the heterogeneous pulmonary microenvironment due to the infection may alter lung permeability and affect drug disposition. Murine models have been a longstanding support in TB research so far and are here used as human surrogates to unveil the distribution of several anti-TB compounds at the site-of-action via a novel and centralized PBPK design framework.
View Article and Find Full Text PDFDetailed preclinical characterization of metabolites formed in vivo from candidate drug substances is mandatory prior to the initiation of clinical trials. Therefore, inexpensive and efficient methods for drug metabolite synthesis are of high importance for rapid advancement of the drug development process. A large fraction of small molecule drugs is modified by monooxygenase cytochrome P450 3A4 produced in the human liver and intestine.
View Article and Find Full Text PDFSonic hedgehog medulloblastoma (SHH-MB) accounts for 25-30% of all MBs, and conventional therapy results in severe long-term side effects. New targeted therapeutic approaches are urgently needed, drawing also on the fields of nanoparticles (NPs). Among these, plant viruses are very promising, and we previously demonstrated that tomato bushy stunt virus (TBSV), functionalized on the surface with CooP peptide, specifically targets MB cells.
View Article and Find Full Text PDFHoming peptides are widely used to improve the delivery of drugs, imaging agents, and nanoparticles (NPs) to their target sites. Plant virus-based particles represent an emerging class of structurally diverse nanocarriers that are biocompatible, biodegradable, safe, and cost-effective. Similar to synthetic NPs, these particles can be loaded with imaging agents and/or drugs and functionalized with affinity ligands for targeted delivery.
View Article and Find Full Text PDFControlling the continuum limit and extracting effective gravitational physics are shared challenges for quantum gravity approaches based on quantum discrete structures. The description of quantum gravity in terms of tensorial group field theory (TGFT) has recently led to much progress in its application to phenomenology, in particular, cosmology. This application relies on the assumption of a phase transition to a nontrivial vacuum (condensate) state describable by mean-field theory, an assumption that is difficult to corroborate by a full RG flow analysis due to the complexity of the relevant TGFT models.
View Article and Find Full Text PDFThe growth of the world population has prompted research to investigate new food/feed alternatives. Hemp-based products can be considered excellent candidates. Hemp ( L.
View Article and Find Full Text PDFPhosphorylated neurofilament heavy subunit (pNfH) has been recently identified as a promising biomarker of disease onset and treatment efficacy in spinal muscular atrophy (SMA). This study introduces a quantitative systems pharmacology model representing the SMA pediatric scenario in the age range of 0-20 years with and without treatment with the antisense oligonucleotide nusinersen. Physiological changes typical of the pediatric age and the contribution of SMA and its treatment to the peripheral pNfH levels were included in the model by extending the equations of a previously developed mathematical model describing the neurofilament trafficking in healthy adults.
View Article and Find Full Text PDFIn this paper, a logical-based mathematical model of the cellular pathways involved in the COVID-19 infection has been developed to study various drug treatments (single or in combination), in different illness scenarios, providing insights into their mechanisms of action. Drug simulations suggest that the effects of single drugs are limited, or depending on the scenario counterproductive, whereas better results appear combining different treatments. Specifically, the combination of the anti-inflammatory Baricitinib and the anti-viral Remdesivir showed significant benefits while a stronger efficacy emerged from the triple combination of Baricitinib, Remdesivir, and the corticosteroid Dexamethasone.
View Article and Find Full Text PDFRecent reports have shown a link between radiation exposure and non-cancer diseases such as radiation-induced heart disease (RIHD). Radiation exposures are often inhomogeneous, and out-of-target effects have been studied in terms of cancer risk, but very few studies have been carried out for non-cancer diseases. Here, the role of miRNAs in the pathogenesis of RIHD was investigated.
View Article and Find Full Text PDFIn this article, we present our research achievements regarding the development of a remote sensing system for motor pulse acquisition, as a first step towards a complete neuroprosthetic arm. We present the fabrication process of an implantable electrode for nerve impulse acquisition, together with an innovative wirelessly controlled system. In our study, these were combined into an implantable device for attachment to peripheral nerves.
View Article and Find Full Text PDFBispecific T-cell engaging therapies harness the immune system to elicit an effective anticancer response. Modulating the immune activation avoiding potential adverse effects such as cytokine release syndrome (CRS) is a critical aspect to realizing the full potential of this therapy. The use of suitable exogenous intervention strategies to mitigate the CRS risk without compromising the antitumoral capability of bispecific antibody treatment is crucial.
View Article and Find Full Text PDFWe report enantioselective one-carbon ring expansion of aziridines to make azetidines as a new-to-nature activity of engineered "carbene transferase" enzymes. A laboratory-evolved variant of cytochrome P450, P411-AzetS, not only exerts unparalleled stereocontrol (99:1 er) over a [1,2]-Stevens rearrangement but also overrides the inherent reactivity of aziridinium ylides, cheletropic extrusion of olefins, to perform a [1,2]-Stevens rearrangement. By controlling the fate of the highly reactive aziridinium ylide intermediates, these evolvable biocatalysts promote a transformation which cannot currently be performed using other catalyst classes.
View Article and Find Full Text PDFTher Adv Med Oncol
November 2021
Background: The evolution of therapeutic landscape of human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC) has led to an unprecedented outcome improvement, even if the optimal sequence strategy is still debated. To address this issue and to provide a picture of the advancement of anti-HER2 treatments, we performed a large, multicenter, retrospective study of HER2-positive BC patients.
Methods: The observational PANHER study included 1,328 HER2-positive advanced BC patients treated with HER2 blocking agents since June 2000 throughout July 2020.
CPT Pharmacometrics Syst Pharmacol
April 2022
Neurofilaments (Nfs) are the major structural component of neurons. Their role as a potential biomarker of several neurodegenerative diseases has been investigated in past years with promising results. However, even under physiological conditions, little is known about the leaking of Nfs from the neuronal system and their detection in the cerebrospinal fluid (CSF) and blood.
View Article and Find Full Text PDFProstate cancer (PCa) is one of the most frequent cancer in male population. Androgen deprivation therapy is the first-line strategy for the metastatic stage of the disease, but, inevitably, PCa develops resistance to castration (CRPC), becoming incurable. In recent years, clinical trials are testing the efficacy of anti-CTLA4 on CRPC.
View Article and Find Full Text PDFFront Mol Biosci
December 2021
Mathematical modeling allows using different formalisms to describe, investigate, and understand biological processes. However, despite the advent of high-throughput experimental techniques, quantitative information is still a challenge when looking for data to calibrate model parameters. Furthermore, quantitative formalisms must cope with stiffness and tractability problems, more so if used to describe multicellular systems.
View Article and Find Full Text PDFPurpose: Immunotherapy has shown activity in patients with brain metastases (BM) and leptomeningeal disease (LMD). We have evaluated LMD and intraparenchymal control rates for patients with resected BM receiving postoperative stereotactic radiosurgery (SRS) and immunotherapy or postoperative SRS alone. We hypothesize that postoperative SRS and immunotherapy will result in a lower rate of LMD with acceptable toxicity compared with postoperative SRS.
View Article and Find Full Text PDFMedulloblastoma (MB) is a primary central nervous system tumor affecting mainly young children. New strategies of drug delivery are urgent to treat MB and, in particular, the SHH-dependent subtype-the most common in infants-in whom radiotherapy is precluded due to the severe neurological side effects. Plant virus nanoparticles (NPs) represent an innovative solution for this challenge.
View Article and Find Full Text PDFRNA vaccines represent a milestone in the history of vaccinology. They provide several advantages over more traditional approaches to vaccine development, showing strong immunogenicity and an overall favorable safety profile. While preclinical testing has provided some key insights on how RNA vaccines interact with the innate immune system, their mechanism of action appears to be fragmented amid the literature, making it difficult to formulate new hypotheses to be tested in clinical settings and ultimately improve this technology platform.
View Article and Find Full Text PDFThe migration of CD4 effector/memory T cells across the blood-brain barrier (BBB) is a critical step in MS or its animal model, EAE. T-cell diapedesis across the BBB can occur paracellular, via the complex BBB tight junctions or transcellular via a pore through the brain endothelial cell body. Making use of primary mouse brain microvascular endothelial cells (pMBMECs) as in vitro model of the BBB, we here directly compared the transcriptome profile of pMBMECs favoring transcellular or paracellular T-cell diapedesis by RNA sequencing (RNA-seq).
View Article and Find Full Text PDFMathematical models have grown in size and complexity becoming often computationally intractable. In sensitivity analysis and optimization phases, critical for tuning, validation and qualification, these models may be run thousands of times. Scientific programming languages popular for prototyping, such as MATLAB and R, can be a bottleneck in terms of performance.
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