Modeling of Optimizing Multi-hole Drilling Toolpath Distance with Multiple Tool Dimension

Multi-hole Drilling with Multiple Tool dimensions (MDMT) is a crucial technique in today's industry, allowing manufacturers to satisfy the increasing demand for precise and high-quality components while adopting the latest technological advancements and environmental standards. This paper introduces and validates a computational model for MDMT, offering numerous advantages over conventional drilling methods, including enhanced efficiency, accuracy, cost-effectiveness, and flexibility. The computational model was developed for the MDMT problem using the Travelling Salesman Problem (TSP) concept to measure the total toolpath distance. The Ant Colony Optimization (ACO), Particle Swarm Optimization (PSO), and Genetic Algorithm (GA) are applied to solving 12 cases of MDMT problems with varying numbers of holes, classified as small, medium, and large, using MATLAB software R2022b. Note that the algorithms were evaluated based on their solution quality, with lower fitness values indicating better performance. Overall, GA performed the best across most hole configurations, achieving the optimal fitness value in 5 out of 12 cases (small, medium, and large), ACO performed better in 4 out of 12 cases (small and medium) and PSO performed better in 3 out of 12 cases (medium and large). The research emphasizes the potential of multi-dimensional tools for accomplishing intricate drilling tasks. Other than that, this paper contributes to the existing literature on MDMT and highlights the importance of multi-dimensional tools in modern manufacturing. Future research could optimize the proposed computational model for various materials and drilling scenarios in MDMT

Pesticide free coating for papaya (Carica papaya 'Eksotika II')

Mature green stage (Index 2) papaya (Carica papaya L. ‘Eksotika II’) fruits were treated either with 2.5% calcium chloride infiltration, 0.75% chitosan coating, calcium infiltration at 2.5% then subsequently chitosan coating at 0.75% or with distilled water as the control. The fruits were then stored at 13±1°C for up to five weeks. Calcium infiltration was effective in maintaining the firmness and weight loss of the fruits. Firmness was 2.7 fold higher than the control and water loss was about 3% less. However, the chitosan coating had less effect on maintaining firmness (only 1.7 fold higher firmness) but had more effect in preventing weight loss resulting in 5.6% less weight loss. The chitosan coating treatment markedly slowed the ripening of papaya as shown by their reduced weight loss, delayed changes in their external colour (which is normally closely correlated with the internal colour) and other quality aspects. However, when calcium infiltration was combined with chitosan coating, this treatment further extended the storage life up to five weeks with better retention of fruits firmness and water loss control compared to the single treatments

Influence of the initial chemical conditions on the rational design of silica particles

The influence of the water content in the initial composition on the size of silica particles produced using the Stöber process is well known. We have shown that there are three morphological regimes defined by compositional boundaries. At low water levels (below stoichiometric ratio of water:tetraethoxysilane), very high surface area and aggregated structures are formed; at high water content (>40 wt%) similar structures are also seen. Between these two boundary conditions, discrete particles are formed whose size are dictated by the water content. Within the compositional regime that enables the classical Stöber silica, the structural evolution shows a more rapid attainment of final particle size than the rate of formation of silica supporting the monomer addition hypothesis. The clearer understanding of the role of the initial composition on the output of this synthesis method will be of considerable use for the establishment of reliable reproducible silica production for future industrial adoption

Brain tumor location influences the onset of acute psychiatric adverse events of levetiracetam therapy: an observational study.

To explore possible correlations among brain lesion location, development of psychiatric symptoms and the use of antiepileptic drugs (AEDs) in a population of patients with brain tumor and epilepsy. The medical records of 283 patients with various types of brain tumor (161 M/122 F, mean age 64.9 years) were analysed retrospectively. Patients with grade III and IV glioma, previous history of epileptic seizures and/or psychiatric disorders were excluded. Psychiatric symptoms occurring after initiation of AED therapy were considered as treatment emergent psychiatric adverse events (TE-PAEs) if they fulfilled the following conditions: (1) onset within 4 weeks after the beginning of AED therapy; (2) disappearance on drug discontinuation; (3) absence of any other identified possible concurrent cause. The possible influence of the following variables were analysed: (a) AED drug and dose; (b) location and neuroradiologic features of the tumor, (c) location and type of EEG epileptic abnormalities, (d) tumor excision already or not yet performed; (e) initiation or not of radiotherapy. TE-PAEs occurred in 27 of the 175 AED-treated patients (15.4%). Multivariate analysis showed a significant association of TE-PAEs occurrence with location of the tumor in the frontal lobe (Odds ratio: 5.56; 95% confidence interval 1.95-15.82; p value: 0.005) and treatment with levetiracetam (Odds ratio: 3.61; 95% confidence interval 1.48-8.2; p value: 0.001). Drug-unrelated acute psychiatric symptoms were observed in 4 of the 108 AED-untreated patients (3.7%) and in 7 of the 175 AED-treated patients (4%). The results of the present study suggest that an AED alternative to levetiracetam should be chosen to treat epileptic seizures in patients with a brain tumor located in the frontal lobe to minimize the possible onset of TE-PAEs

Neisseria meningitidis Differentially Controls Host Cell Motility through PilC1 and PilC2 Components of Type IV Pili

Neisseria meningitidis is a strictly human pathogen that has two facets since asymptomatic carriage can unpredictably turn into fulminant forms of infection. Meningococcal pathogenesis relies on the ability of the bacteria to break host epithelial or endothelial cellular barriers. Highly restrictive, yet poorly understood, mechanisms allow meningococcal adhesion to cells of only human origin. Adhesion of encapsulated and virulent meningococci to human cells relies on the expression of bacterial type four pili (T4P) that trigger intense host cell signalling. Among the components of the meningococcal T4P, the concomitantly expressed PilC1 and PilC2 proteins regulate pili exposure at the bacterial surface, and until now, PilC1 was believed to be specifically responsible for T4P-mediated meningococcal adhesion to human cells. Contrary to previous reports, we show that, like PilC1, the meningococcal PilC2 component is capable of mediating adhesion to human ME180 epithelial cells, with cortical plaque formation and F-actin condensation. However, PilC1 and PilC2 promote different effects on infected cells. Cellular tracking analysis revealed that PilC1-expressing meningococci caused a severe reduction in the motility of infected cells, which was not the case when cells were infected with PilC2-expressing strains. The amount of both total and phosphorylated forms of EGFR was dramatically reduced in cells upon PilC1-mediated infection. In contrast, PilC2-mediated infection did not notably affect the EGFR pathway, and these specificities were shared among unrelated meningococcal strains. These results suggest that meningococci have evolved a highly discriminative tool for differential adhesion in specific microenvironments where different cell types are present. Moreover, the fine-tuning of cellular control through the combined action of two concomitantly expressed, but distinctly regulated, T4P-associated variants of the same molecule (i.e. PilC1 and PilC2) brings a new model to light for the analysis of the interplay between pathogenic bacteria and human host cells

LPS-induced NF??B enhanceosome requires TonEBP/NFAT5 without DNA binding

NF??B is a central mediator of inflammation. Present inhibitors of NF??B are mostly based on inhibition of essential machinery such as proteasome and protein kinases, or activation of nuclear receptors; as such, they are of limited therapeutic use due to severe toxicity. Here we report an LPS-induced NF??B enhanceosome in which TonEBP is required for the recruitment of p300. Increased expression of TonEBP enhances the NF??B activity and reduced TonEBP expression lowers it. Recombinant TonEBP molecules incapable of recruiting p300 do not stimulate NF??B. Myeloid-specific deletion of TonEBP results in milder inflammation and sepsis. We discover that a natural small molecule cerulenin specifically disrupts the enhanceosome without affecting the activation of NF??B itself. Cerulenin suppresses the pro-inflammatory activation of macrophages and sepsis without detectable toxicity. Thus, the NF??B enhanceosome offers a promising target for useful anti-inflammatory agents.ope

Low-risk susceptibility alleles in 40 human breast cancer cell lines

Background: Low-risk breast cancer susceptibility alleles or SNPs confer only modest breast cancer risks ranging from just over 1.0 to 1.3 fold. Yet, they are common among most populations and therefore are involved in the development of essentially all breast cancers. The mechanism by which the low-risk SNPs confer breast cancer risks is currently unclear. The breast cancer association consortium BCAC has hypothesized that the low-risk SNPs modulate expression levels of nearby located genes. Methods: Genotypes of five low-risk SNPs were determined for 40 human breast cancer cell lines, by direct sequencing of PCR-amplified genomic templates. We have analyzed expression of the four genes that are located nearby the low-risk SNPs, by using real-time RT-PCR and Human Exon microarrays. Results: The SNP genotypes and additional phenotypic data on the breast cancer cell lines are presented. We did not detect any effect of the SNP genotypes on expression levels of the nearby-located genes MAP3K1, FGFR2, TNRC9 and LSP1. Conclusion: The SNP genotypes provide a base line for functional studies in a well-characterized cohort of 40 human breast cancer cell lines. Our expression analyses suggest that a putative disease mechanism through gene expression modulation is not operative in breast cancer cell lines

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Prevalence, Features and Risk Factors for Malaria Co-Infections amongst Visceral Leishmaniasis Patients from Amudat Hospital, Uganda

Visceral leishmaniasis (VL) and malaria are two major parasitic diseases sharing a similar demographic and geographical distribution. In areas where both diseases are endemic, such as Sudan, Uganda, India and Bangladesh, co-infection cases have been reported, but features and risk factors associated with these co-morbidities remain poorly characterized. In the present study, routinely collected data of VL patients admitted to Amudat Hospital, Uganda, were used to investigate the magnitude of VL-malaria co-infections and identify possible risk factors. Nearly 20% of the patients included in this study were found to be co-infected with VL and malaria, indicating that this is a common condition among VL patients living in malaria endemic areas. Young age (≤9 years) was identified as an important risk factor for contracting the VL-malaria co-infection, while being anemic or carrying a skin infection appeared to negatively correlate with the co-morbidity. Co-infected patients presented with slightly more severe symptoms compared to mono-infected patients, but had a similar prognosis, possibly due to early diagnosis of malaria as a result of systematic testing. In conclusion, these results emphasize the importance of performing malaria screening amongst VL patients living in malaria-endemic areas and suggest that close monitoring of co-infected patients should be implemented

Disease Progression in MRL/lpr Lupus-Prone Mice Is Reduced by NCS 613, a Specific Cyclic Nucleotide Phosphodiesterase Type 4 (PDE4) Inhibitor

Systemic lupus erythematosus is a polymorphic and multigenic inflammatory autoimmune disease. Cyclic AMP (cAMP) modulates inflammation and the inhibition of cyclic nucleotide phosphodiesterase type 4 (PDE4), which specifically hydrolyzes cAMP, inhibits TNFα secretion. This study was aimed at investigating the evolution of PDE activity and expression levels during the course of the disease in MRL/lpr lupus-prone mice, and to evaluate in these mice the biological and clinical effects of treatments with pentoxifylline, denbufylline and NCS 613 PDE inhibitors. This study reveals that compared to CBA/J control mice, kidney PDE4 activity of MRL/lpr mice increases with the disease progression. Furthermore, it showed that the most potent and selective PDE4 inhibitor NCS 613 is also the most effective molecule in decreasing proteinuria and increasing survival rate of MRL/lpr mice. NCS 613 is a potent inhibitor, which is more selective for the PDE4C subtype (IC50 = 1.4 nM) than the other subtypes (PDE4A, IC50 = 44 nM; PDE4B, IC50 = 48 nM; and PDE4D, IC50 = 14 nM). Interestingly, its affinity for the High Affinity Rolipram Binding Site is relatively low (Ki = 148 nM) in comparison to rolipram (Ki = 3 nM). Finally, as also observed using MRL/lpr peripheral blood lymphocytes (PBLs), NCS 613 inhibits basal and LPS-induced TNFα secretion from PBLs of lupus patients, suggesting a therapeutic potential of NCS 613 in systemic lupus. This study reveals that PDE4 represent a potential therapeutic target in lupus disease