In silico identification of small molecules as new cdc25 inhibitors through the correlation between chemosensitivity and protein expression pattern

The cell division cycle 25 (Cdc25) protein family plays a crucial role in controlling cell proliferation, making it an excellent target for cancer therapy. In this work, a set of small molecules were identified as Cdc25 modulators by applying a mixed ligand-structure-based approach and taking advantage of the correlation between the chemosensitivity of selected structures and the protein expression pattern of the proposed target. In the first step of the in silico protocol, a set of molecules acting as Cdc25 inhibitors were identified through a new ligand-based protocol and the evaluation of a large database of molecular structures. Subsequently, induced-fit docking (IFD) studies allowed us to further reduce the number of compounds biologically screened. In vitro antiproliferative and enzymatic inhibition assays on the selected compounds led to the identification of new structurally heterogeneous inhibitors of Cdc25 proteins. Among them, J3955, the most active inhibitor, showed concentration-dependent antiproliferative activity against HepG2 cells, with GI50 in the low micromolar range. When J3955 was tested in cell-cycle perturbation experiments, it caused mitotic failure by G2/M-phase cell-cycle arrest. Finally, Western blotting analysis showed an increment of phosphorylated Cdk1 levels in cells exposed to J3955, indicating its specific influence in cellular pathways involving Cdc25 proteins

Inverse Classification for Comparison-based Interpretability in Machine Learning

In the context of post-hoc interpretability, this paper addresses the task of explaining the prediction of a classifier, considering the case where no information is available, neither on the classifier itself, nor on the processed data (neither the training nor the test data). It proposes an instance-based approach whose principle consists in determining the minimal changes needed to alter a prediction: given a data point whose classification must be explained, the proposed method consists in identifying a close neighbour classified differently, where the closeness definition integrates a sparsity constraint. This principle is implemented using observation generation in the Growing Spheres algorithm. Experimental results on two datasets illustrate the relevance of the proposed approach that can be used to gain knowledge about the classifier.Comment: preprin

Field-Testing a PC Electronic Documentation System using the Clinical Care Classification© System with Nursing Students

Schools of nursing are slow in training their students to keep up with the fast approaching era of electronic healthcare documentation. This paper discusses the importance of nursing documentation, and describes the field-testing of an electronic health record, the Sabacare Clinical Care Classification (CCC©) system. The PC-CCC©, designed as a Microsoft Access® application, is an evidence-based electronic documentation system available via free download from the internet. A sample of baccalaureate nursing students from a mid-Atlantic private college used this program to document the nursing care they provided to patients during their sophomore level clinical experience. This paper summarizes the design, training, and evaluation of using the system in practice

AAAI: an Argument Against Artificial Intelligence

The ethical concerns regarding the successful development of an Artificial Intelligence have received a lot of attention lately. The idea is that even if we have good reason to believe that it is very unlikely, the mere possibility of an AI causing extreme human suffering is important enough to warrant serious consideration. Others look at this problem from the opposite perspective, namely that of the AI itself. Here the idea is that even if we have good reason to believe that it is very unlikely, the mere possibility of humanity causing extreme suffering to an AI is important enough to warrant serious consideration. This paper starts from the observation that both concerns rely on problematic philosophical assumptions. Rather than tackling these assumptions directly, it proceeds to present an argument that if one takes these assumptions seriously, then one has a moral obligation to advocate for a ban on the development of a conscious AI

An additional record of Kyphosus vaigiensis (Quoy & Gaimard, 1825) (Osteichthyes, Kyphosidae) from Sicily clarifies the confused situation of the Mediterranean kyphosids

The lowfin chub, Kyphosus vaigiensis, is reported for the first time off Favignana Island, Sicily, central Mediterranean Sea. The specimen was identified on the basis of morphometric and meristic characters as well as mitochondrial DNA sequences (COI and 16S-rDNA). Two, perhaps three, Kyphosus species - K. bigibbus, K. sectatrix and K. vaigiensis - have been occasionally recorded in the Mediterranean. These species occur both in the Atlantic and Indo-Pacific regions but it is likely they entered the Mediterranean through the Strait of Gibraltar. However, it is unclear whether they have established reproductive native populations in the Mediterranean

Investigational systemic drugs for moderate to severe plaque psoriasis: What’s new?

Introduction: The therapeutic armamentarium for the treatment of psoriasis, a chronic inflammatory skin disease, is now reasonably broad and structured, with several therapeutic agents that demonstrated a successful long-term control of this condition. However, there are still unfulfilled gaps resulting from the inherent limitations of existing therapies, which have paved the way for the identification of new therapeutic strategies or the improvement of the existing ones. Areas covered: The aim of this review is to thoroughly explore new therapeutic strategies and novel drugs that are currently in the pipeline for the treatment of psoriasis, focusing primarily on agents that are currently in phase I/II of clinical development. Some of which retrace already existing therapeutic approaches, such as the IL23/Th17 pathway inhibition, while others unveil new and yet unexplored ones. Expert opinion: Since the therapeutic landscape of psoriasis is wide, it is not yet clear whether novel agents will fill the remaining gaps in the context of a broader and more diversified set of oral and biologic therapies. Nevertheless, with the development of precision medicine approaches, the development of innovative targeted drugs will still have a therapeutic rationale in psoriasis

A Systematic Review and Meta-Analysis of Interventions Used to Reduce Exposure to House Dust and Their Effect on the Development and Severity of Asthma

We assessed whether any household dust reduction intervention has the effect of increasing or decreasing the development or severity of atopic disease. Electronic searches on household intervention and atopic disease were conducted in 2007 in EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials. We included randomized controlled trials comparing asthma outcomes in a household intervention group with either placebo intervention or no intervention. Meta-analyses on the prevention studies found that the interventions made no difference to the onset of wheeze but made a significant reduction in physician-diagnosed asthma. Meta-analysis of lung function outcomes indicated no improvement due to the interventions but found a reduction in symptom days. Qualitatively, health care was used less in those receiving interventions. However, in one study that compared intervention, placebo, and control arms, the reduction in heath care use was similar in the placebo and intervention arms. This review suggests that there is not sufficient evidence to suggest implementing hygiene measures in an attempt to improve outcomes in existing atopic disease, but interventions from birth in those at high risk of atopy are useful in preventing diagnosed asthma but not parental-reported wheeze

Shallow BF2 implants in Xe-bombardment-preamorphized Si: the interaction between Xe and F

Si(100) samples, preamorphized to a depth of ~30 nm using 20 keV Xe ions to a nominal fluence of 2×1014 cm-2 were implanted with 1 and 3 keV BF2 ions to fluences of 7×1014 cm-2. Following annealing over a range of temperatures (from 600 to 1130 °C) and times the implant redistribution was investigated using medium-energy ion scattering (MEIS), secondary ion mass spectrometry (SIMS), and energy filtered transmission electron microscopy (EFTEM). MEIS studies showed that for all annealing conditions leading to solid phase epitaxial regrowth, approximately half of the Xe had accumulated at depths of 7 nm for the 1 keV and at 13 nm for the 3 keV BF2 implant. These depths correspond to the end of range of the B and F within the amorphous Si. SIMS showed that in the preamorphized samples, approximately 10% of the F migrates into the bulk and is trapped at the same depths in a ~1:1 ratio to Xe. These observations indicate an interaction between the Xe and F implants and a damage structure that becomes a trapping site. A small fraction of the implanted B is also trapped at this depth. EXTEM micrographs suggest the development of Xe agglomerates at the depths determined by MEIS. The effect is interpreted in terms of the formation of a volume defect structure within the amorphized Si, leading to F stabilized Xe agglomerates or XeF precipitates