Predictive modeling of die filling of the pharmaceutical granules using the flexible neural tree

In this work, a computational intelligence (CI) technique named flexible neural tree (FNT) was developed to predict die filling performance of pharmaceutical granules and to identify significant die filling process variables. FNT resembles feedforward neural network, which creates a tree-like structure by using genetic programming. To improve accuracy, FNT parameters were optimized by using differential evolution algorithm. The performance of the FNT-based CI model was evaluated and compared with other CI techniques: multilayer perceptron, Gaussian process regression, and reduced error pruning tree. The accuracy of the CI model was evaluated experimentally using die filling as a case study. The die filling experiments were performed using a model shoe system and three different grades of microcrystalline cellulose (MCC) powders (MCC PH 101, MCC PH 102, and MCC DG). The feed powders were roll-compacted and milled into granules. The granules were then sieved into samples of various size classes. The mass of granules deposited into the die at different shoe speeds was measured. From these experiments, a dataset consisting true density, mean diameter (d50), granule size, and shoe speed as the inputs and the deposited mass as the output was generated. Cross-validation (CV) methods such as 10FCV and 5x2FCV were applied to develop and to validate the predictive models. It was found that the FNT-based CI model (for both CV methods) performed much better than other CI models. Additionally, it was observed that process variables such as the granule size and the shoe speed had a higher impact on the predictability than that of the powder property such as d50. Furthermore, validation of model prediction with experimental data showed that the die filling behavior of coarse granules could be better predicted than that of fine granules

Modern computing: Vision and challenges

Over the past six decades, the computing systems field has experienced significant transformations, profoundly impacting society with transformational developments, such as the Internet and the commodification of computing. Underpinned by technological advancements, computer systems, far from being static, have been continuously evolving and adapting to cover multifaceted societal niches. This has led to new paradigms such as cloud, fog, edge computing, and the Internet of Things (IoT), which offer fresh economic and creative opportunities. Nevertheless, this rapid change poses complex research challenges, especially in maximizing potential and enhancing functionality. As such, to maintain an economical level of performance that meets ever-tighter requirements, one must understand the drivers of new model emergence and expansion, and how contemporary challenges differ from past ones. To that end, this article investigates and assesses the factors influencing the evolution of computing systems, covering established systems and architectures as well as newer developments, such as serverless computing, quantum computing, and on-device AI on edge devices. Trends emerge when one traces technological trajectory, which includes the rapid obsolescence of frameworks due to business and technical constraints, a move towards specialized systems and models, and varying approaches to centralized and decentralized control. This comprehensive review of modern computing systems looks ahead to the future of research in the field, highlighting key challenges and emerging trends, and underscoring their importance in cost-effectively driving technological progress

Evaluating the simulated radiative forcings, aerosol properties, and stratospheric warmings from the 1963 Mt Agung, 1982 El Chichón, and 1991 Mt Pinatubo volcanic aerosol clouds

Accurately quantifying volcanic impacts on climate is a key requirement for robust attribution of anthropogenic climate change. Here we use the Unified Model – United Kingdom Chemistry and Aerosol (UM-UKCA) composition–climate model to simulate the global dispersion of the volcanic aerosol clouds from the three largest eruptions of the 20th century: 1963 Mt Agung, 1982 El Chichón, and 1991 Mt Pinatubo. The model has interactive stratospheric chemistry and aerosol microphysics, with coupled aerosol–radiation interactions for realistic composition–dynamics feedbacks. Our simulations align with the design of the Interactive Stratospheric Aerosol Model Intercomparison (ISA-MIP) “Historical Eruption SO2 Emissions Assessment”. For each eruption, we perform three-member ensemble model experiments for upper, mid-point, and lower estimates of SO2 emission, each re-initialised from a control run to approximately match the observed transition in the phase of the quasi-biennial oscillation (QBO) in the 6 months after the eruptions. With this experimental design, we assess how each eruption's emitted SO2 translates into a tropical reservoir of volcanic aerosol and analyse the subsequent dispersion to mid-latitudes. We compare the simulations to the volcanic forcing datasets (e.g. Space-based Stratospheric Aerosol Climatology (GloSSAC); Sato et al., 1993, and Ammann et al., 2003) that are used in historical integrations for the two most recent Coupled Model Intercomparison Project (CMIP) assessments. For Pinatubo and El Chichón, we assess the vertical extent of the simulated volcanic clouds by comparing modelled extinction to the Stratospheric Aerosol and Gas Experiment (SAGE-II) v7.0 satellite measurements and to 1964–1965 Northern Hemisphere ground-based lidar measurements for Agung. As an independent test for the simulated volcanic forcing after Pinatubo, we also compare simulated shortwave (SW) and longwave (LW) top-of-the-atmosphere radiative forcings to the flux anomalies measured by the Earth Radiation Budget Experiment (ERBE) satellite instrument. For the Pinatubo simulations, an injection of 10 to 14 Tg SO2 gives the best match to the High Resolution Infrared Sounder (HIRS) satellite-derived global stratospheric sulfur burden, with good agreement also with SAGE-II mid-visible and near-infra-red extinction measurements. This 10–14 Tg range of emission also generates a heating of the tropical stratosphere that is consistent with the temperature anomaly present in the ERA-Interim reanalysis. For El Chichón, the simulations with 5 and 7 Tg SO2 emission give best agreement with the observations. However, these simulations predict a much deeper volcanic cloud than represented in the GloSSAC dataset, which is largely based on an interpolation between Stratospheric Aerosol Measurements (SAM-II) satellite and aircraft measurements. In contrast, these simulations show much better agreement during the SAGE-II period after October 1984. For 1963 Agung, the 9 Tg simulation compares best to the forcing datasets with the model capturing the lidar-observed signature of the altitude of peak extinction descending from 20 km in 1964 to 16 km in 1965. Overall, our results indicate that the downward adjustment to SO2 emission found to be required by several interactive modelling studies when simulating Pinatubo is also needed when simulating the Agung and El Chichón aerosol clouds. This strengthens the hypothesis that interactive stratospheric aerosol models may be missing an important removal or re-distribution process (e.g. effects of co-emitted ash) which changes how the tropical reservoir of volcanic aerosol evolves in the initial months after an eruption. Our model comparisons also identify potentially important inhomogeneities in the CMIP6 dataset for all three eruption periods that are hard to reconcile with variations predicted in the interactive stratospheric aerosol simulations. We also highlight large differences between the CMIP5 and CMIP6 volcanic aerosol datasets for the Agung and El Chichón periods. Future research should aim to reduce this uncertainty by reconciling the datasets with additional stratospheric aerosol observations

Acute WNT signalling activation perturbs differentiation within the adult stomach and rapidly leads to tumour formation

A role for WNT signalling in gastric carcinogenesis has been suggested due to two major observations. First, patients with germline mutations in adenomatous polyposis coli (APC) are susceptible to stomach polyps and second, in gastric cancer, WNT activation confers a poor prognosis. However, the functional significance of deregulated WNT signalling in gastric homoeostasis and cancer is still unclear. In this study we have addressed this by investigating the immediate effects of WNT signalling activation within the stomach epithelium. We have specifically activated the WNT signalling pathway within the mouse adult gastric epithelium via deletion of either glycogen synthase kinase 3 (GSK3) or APC or via expression of a constitutively active β-catenin protein. WNT pathway deregulation dramatically affects stomach homoeostasis at very short latencies. In the corpus, there is rapid loss of parietal cells with fundic gland polyp (FGP) formation and adenomatous change, which are similar to those observed in familial adenomatous polyposis. In the antrum, adenomas occur from 4 days post-WNT activation. Taken together, these data show a pivotal role for WNT signalling in gastric homoeostasis, FGP formation and adenomagenesis. Loss of the parietal cell population and corresponding FGP formation, an early event in gastric carcinogenesis, as well as antral adenoma formation are immediate effects of nuclear β-catenin translocation and WNT target gene expression. Furthermore, our inducible murine model will permit a better understanding of the molecular changes required to drive tumourigenesis in the stomach

Modulation of apoptosis in human hepatocellular carcinoma (HepG2 cells) by a standardized herbal decoction of Nigella sativa seeds, Hemidesmus indicus roots and Smilax glabra rhizomes with anti- hepatocarcinogenic effects

<p>Abstract</p> <p>Background</p> <p>A standardized poly-herbal decoction of <it>Nigella sativa </it>seeds, <it>Hemidesmus indicus </it>roots and <it>Smilax glabra </it>rhizomes used traditionally in Sri Lanka for cancer therapy has been demonstrated previously, to have anti-hepatocarcinogenic potential. Cytotoxicity, antioxidant activity, anti-inflammatory activity, and up regulation of p53 and p21 activities are considered to be some of the possible mechanisms through which the above decoction may mediate its anti-hepatocarcinogenic action. The main aim of the present study was to determine whether apoptosis is also a major mechanism by which the decoction mediates its anti-hepatocarcinogenic action.</p> <p>Methods</p> <p>Evaluation of apoptosis in HepG2 cells was carried out by (a) microscopic observations of cell morphology, (b) DNA fragmentation analysis, (c) activities of caspase 3 and 9, as well as by (d) analysis of the expression of pro-apoptotic (Bax) and anti-apoptotic (Bcl-2) proteins associated with cell death.</p> <p>Results</p> <p>The results demonstrated that in HepG2 cells, the decoction can induce (a) DNA fragmentation and (b) characteristic morphological changes associated with apoptosis (nuclear condensation, membrane blebbing, nuclear fragmentation and apoptotic bodies). The decoction could also, in a time and dose dependent manner, up regulate the expression of the pro-apoptotic gene <it>Bax </it>and down regulate expression of anti-apoptotic <it>Bcl-2 </it>gene (as evident from RT-PCR analysis, immunohistochemistry and western blotting). Further, the decoction significantly (<it>p </it>< .001) enhanced the activities of caspase-3 and caspase-9 in a time and dose dependent manner.</p> <p>Conclusions</p> <p>Overall findings provide confirmatory evidence to demonstrate that the decoction may mediate its reported anti-hepatocarcinogenic effect, at least in part, through modulation of apoptosis.</p

Revising the WHO verbal autopsy instrument to facilitate routine cause-of-death monitoring.

OBJECTIVE: Verbal autopsy (VA) is a systematic approach for determining causes of death (CoD) in populations without routine medical certification. It has mainly been used in research contexts and involved relatively lengthy interviews. Our objective here is to describe the process used to shorten, simplify, and standardise the VA process to make it feasible for application on a larger scale such as in routine civil registration and vital statistics (CRVS) systems. METHODS: A literature review of existing VA instruments was undertaken. The World Health Organization (WHO) then facilitated an international consultation process to review experiences with existing VA instruments, including those from WHO, the Demographic Evaluation of Populations and their Health in Developing Countries (INDEPTH) Network, InterVA, and the Population Health Metrics Research Consortium (PHMRC). In an expert meeting, consideration was given to formulating a workable VA CoD list [with mapping to the International Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) CoD] and to the viability and utility of existing VA interview questions, with a view to undertaking systematic simplification. FINDINGS: A revised VA CoD list was compiled enabling mapping of all ICD-10 CoD onto 62 VA cause categories, chosen on the grounds of public health significance as well as potential for ascertainment from VA. A set of 221 indicators for inclusion in the revised VA instrument was developed on the basis of accumulated experience, with appropriate skip patterns for various population sub-groups. The duration of a VA interview was reduced by about 40% with this new approach. CONCLUSIONS: The revised VA instrument resulting from this consultation process is presented here as a means of making it available for widespread use and evaluation. It is envisaged that this will be used in conjunction with automated models for assigning CoD from VA data, rather than involving physicians

Machupo Virus Glycoprotein Determinants for Human Transferrin Receptor 1 Binding and Cell Entry

Machupo virus (MACV) is a highly pathogenic New World arenavirus that causes hemorrhagic fever in humans. MACV, as well as other pathogenic New World arenaviruses, enter cells after their GP1 attachment glycoprotein binds to their cellular receptor, transferrin receptor 1 (TfR1). TfR1 residues essential for this interaction have been described, and a co-crystal of MACV GP1 bound to TfR1 suggests GP1 residues important for this association. We created MACV GP1 variants and tested their effect on TfR1 binding and virus entry to evaluate the functional significance of some of these and additional residues in human and simian cells. We found residues R111, D123, Y122, and F226 to be essential, D155, and P160 important, and D114, S116, D140, and K169 expendable for the GP1-TfR1 interaction and MACV entry. Several MACV GP1 residues that are critical for the interaction with TfR1 are conserved among other New World arenaviruses, indicating a common basis of receptor interaction. Our findings also open avenues for the rational development of viral entry inhibitors

Petri Nets Validation of Markovian Models of Emergency Department Arrivals

International audienceModeling of hospital’s Emergency Departments (ED) is vital for optimisation of health services offered to patients that shows up at an ED requiring treatments with different level of emergency. In this paper we present a modeling study whose contribution is twofold: first, based on a dataset relative to the ED of an Italian hospital, we derive different kinds of Markovian models capable to reproduce, at different extents, the statistical character of dataset arrivals; second, we validate the derived arrivals model by interfacing it with a Petri net model of the services an ED patient undergoes. The empirical assessment of a few key performance indicators allowed us to validate some of the derived arrival process model, thus confirming that they can be used for predicting the performance of an ED

Single Bead Affinity Detection (SINBAD) for the Analysis of Protein-Protein Interactions

We present a miniaturized pull-down method for the detection of protein-protein interactions using standard affinity chromatography reagents. Binding events between different proteins, which are color-coded with quantum dots (QDs), are visualized on single affinity chromatography beads by fluorescence microscopy. The use of QDs for single molecule detection allows the simultaneous analysis of multiple protein-protein binding events and reduces the amount of time and material needed to perform a pull-down experiment

Environmental Factors in the Relapse and Recurrence of Inflammatory Bowel Disease:A Review of the Literature

The causes of relapse in patients with Crohn's disease (CD) and ulcerative colitis (UC) are largely unknown. This paper reviews the epidemiological and clinical data on how medications (non-steroidal anti-inflammatory drugs, estrogens and antibiotics), lifestyle factors (smoking, psychological stress, diet and air pollution) may precipitate clinical relapses and recurrence. Potential biological mechanisms include: increasing thrombotic tendency, imbalances in prostaglandin synthesis, alterations in the composition of gut microbiota, and mucosal damage causing increased permeability