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Hybrid layered manufacturing (HLM) is one of the most efficient rapid tooling processes that uses a metal inert gas, tungsten inert gas or laser cladding processes for producing near-net shape and machining operations for finishing on the same platform. Materials saving, elimination of rough machining, reduction of programming time, ability to make conformal cooling channels (CCCs), and bimetallic objects are some of the significant advantages of HLM in tooling applications. CCCs, as against the straight cooling channels, reduce the cycle time and distortion and improve the matrix integrity. Bimetallic objects, as compared to monolithic objects, reduce the overall cost by replacing the interior with cheaper material. In this work, the HLM has been investigated for realizing bimetallic structures of P20 tool steel and mild steel. A complex bimetallic plastic injection mold with hard casing (P20 tool steel) and soft core (mild steel) along with CCCs have been built as a case study. The mechanical and microstructural characterization leads to the fine-tuning of the process parameters. The plastic injection mold with CCCs is designed through heat flow analysis using a commercial software.

Purpose Electron beam-based additive manufacturing (EBAM) is an emerging technology to produce metal parts layer-by-layer. The purpose of this paper is to systematically address the research and development carried out for this technology, up till now. Design/methodology/approach This paper identifies several aspects of research and development in EBAM. Findings Electron beam has several unique advantages such as high scanning speed, energy efficiency, versatility for several materials and better part integrity because of a vacuum working environment. Originality/value This paper provides information on different aspects of EBAM with the current status and future scope.

We aimed to evaluate the efficacy and safety of low-dose atropine compared to placebo in the Indian population and also to study the impact of various modifiable and non-modifiable factors on myopia progression (MP) and drug efficacy (DE). It was a single-centre prospective placebo-controlled interventional study. 43 participants aged 6–16 years with progressive myopia received 0.01% atropine in the right eyes (treatment) and placebo in the left eyes (control) for 1-year. The main outcome measures were annual MP and axial length elongation (ALE) in treatment and control eyes and their percentage difference between two eyes (drug efficacy). Secondary outcome measures were the occurrence of any adverse events and the correlation of MP, ALE, and DE with various factors. 40 participants (80 eyes) completed the follow-up. After 1-year, MP was 0.25 D (IQR 0.13–0.44) and 0.69 D (IQR 0.50–1.0) (p

In this chapter, the authors study a weighted-((f / (r, s)), k)/ (m, n): G system. The system consists of mn components arranged in a matrix form and the system works if all the sub matrices of order (r, s), the total weight of the working components is greater than f and the total weight of the working components in the system is at least k. This chapter deals with the evaluation of fuzzy reliability and fuzzy mean time to failure of the considered system with the application of fuzzy universal generating function and fuzzy Rayleigh distribution. In this study, the authors formed some prepositions to understand the behaviour of the considered system with respect to different varying parameters and also present an illustrative example to understand them.

Anisotropy and omnidirectionality are the two most significant impediments to the growth of additive manufacturing (AM). While anisotropy is a property of the part, omnidirectionality is a characteristic of the machine tool. Omnidirectionality, implying invariance in AM processes with the goal of minimizing variations in material and geometric properties of the as-built parts, is often ignored during systems and process design. Disregard to directional sensitivity, which in some cases are inherent to the process (and/ or system), inadvertently changes the process parameter in-situ consequently, producing parts with non-uniform and often erratic properties. AM, attributing to its sheer number of processing variables, is especially susceptible to this subtle, yet significant system property. While some AM platforms, due to their nature of part production, are inherently omnidirectional, others require additional setup to ensure the same. Having an omnidirectional AM platform ensures that the parts are fabricated with process variables that are equally sensitive in all directions. In most AM systems, given a fixed set of process parameters, the spatial orientation of fusion (or joining) source vector, feedstock-delivery vector, and travel direction vector relative to each other governs omnidirectionality. Inconsistency or change in orientation of these three vectors results in non-uniform part properties and variations in geometric dimensions. Therefore, AM systems have to be omnidirectional to improve part performance and promote industrial acceptance. This paper, through a formal definition of omnidirectionality, analyses these three vectors individually along with their interplay with other process parameters and design variables.

Metal inert gas (MIG), Tungsten INERT GAs (TIG), laser and Electron beam (EB) cladding processes are used in cladding-based Additive manufacturing (AM). Only in the case of MIG, the raw-stock is fe...

Background: Obesity is described as a build-up of abnormal or excessive fat that risks life. A body mass index (BMI) is a screening tool for overweight and obesity. For a long time, BMI has been used as a marker to measure obesity. However, a significant limitation of using BMI is its failure to differentiate between a high body fat content and preserved or increased lean mass, especially in patients or subjects with a BMI

MIG can deposit with a very high deposition rate but fails in realizing the fine features. The precise deposition of the laser cladding process makes it different from the others. Therefore, in future, MIG, TIG or laser cladding will be used as per the requirement. In this paper, retrofitment of an omnidirectional laser cladding system with a 4-axis CNC machine has been presented. This retrofitment is a challenging task as laser cladding system consists of several subsystems such as optical cladding head, laser power source, wire feeder, and external cooling unit. These subsystems need to be mechanically as well as electrically integrated with the CNC machine and its controller. Mechanical integration was achieved by mounting the cladding head on a retractable fixture, and electrical integration was achieved by providing extra relays in the CNC controller. The preliminary experiments were conducted to demonstrate the retrofitment and capability of the omnidirectional cladding.

Rapid casting gives the opportunity to develop a new casting in days, not in weeks or months. Evaporative Pattern Casting (EPC) process gives flexibility to produce complex geometries by integrating several parts in single casting. The lead-time and cost involved in designing and fabricating the metal tooling for Expanded Polystyrene (EPS) pattern making can be overcome by using the Segmented Object Manufacturing (SOM) machine. This hybrid system of pattern making is explored with all sub-systems and a complicated EPS pattern is produced by this Rapid Prototyping system. Conventional EPC process is more complicated due to coating development, vacuum assisted metal pouring and vibration system for filling the cavities by unbounded sand. In the present work, different mold-making processes are explored to avoid complications of conventional process. The Green sand, No-bake sand, and Plaster of Paris molds are prepared using Rapid Prototyped EPS pattern to produce the castings. The castings are characterized by comparing the surface roughness, dimensional accuracy, hardness, and surface morphology.

As there are no cutting forces in High Energy Density (HED) beams like lasers and Electron Beam (EB), their speeds are limited only by their positioning systems. On the other hand, as the entire matrix of the 3D printed part has to be addressed by the thin beam in multiple passes in multiple layers, they have to travel several kilometers in tiny motions. Therefore, the acceleration of the motion system becomes the limiting factor than velocity or precision. The authors have proposed an area-filling strategy for EB to fill the layer with optimal squares to exploit analog and hardware computing. 3D printing requires uniform intensity slanged as flat hat shape whereas the default is Gaussian. The authors have proposed an optimal algorithm that takes into account the maximum velocity and acceleration for achieving a flat hat without any compromise on productivity.

Pregnane & Xenobiotic Receptor (PXR) is one of the 48 members of the ligand-modulated transcription factors belonging to nuclear receptor superfamily. Though PXR is now well-established as a ‘xenosensor’, regulating the central detoxification and drug metabolizing machinery, it has also emerged as a key player in several metabolic disorders. This makes PXR attractive to both, researchers and pharmaceutical industry since clinical success of small drug molecules can be pre-evaluated on PXR platform. At the early stages of drug discovery, cell-based assays are used for high-throughput screening of small molecules. The future success or failure of a drug can be predicted by this approach saving expensive resources and time. In view of this, we have developed human liver cell line-based, dual-level screening and validation protocol on PXR platform having application to assess small molecules. We have generated two different stably transfected cell lines, (i) a stable promoter-reporter cell line (HepXREM) expressing PXR and a commonly used CYP3A4 promoter-reporter i.e. XREM-luciferase; and (ii) two stable cell lines integrated with proximal PXR-promoter-reporter (Hepx−1096/+43 and Hepx−497/+43). Employing HepXREM, Hepx-1096/+43 and Hepx-497/+43 stable cell lines > 25 anti-cancer herbal drug ingredients were screened for examining their modulatory effects on a) PXR transcriptional activity and, b) PXR-promoter activity. In conclusion, the present report provides a convenient and economical, dual-level screening system to facilitate the identification of superior therapeutic small molecules.

In this paper we deal with the study of non-repairable complex system which consists of two subsystems say A and B, connected in series. The subsystems A and B are weighted k-out-of-n: G and weighted l-out-of-m: G configurations respectively. The subsystem A consists of n type-L components of linear (v, f, e): G configuration whereas the subsystem B consists of m type- S component of circular (v, f, e): G configuration. All the components of the subsystems A and B are arranged in parallel. In this study evaluation of the reliability characteristics such as reliability, mean time to failure and sensitivity of the considered system with the application of universal generating function is presented. To demonstrate the model a numerical example have been taken at last in which probability of success of the components of the component of the subsystems A and B follows exponential distribution. Reliability of the system after imposing some conditions on weight has also been compared.

Purpose The support structures of sacrificial material are built in deposition-based additive manufacturing (AM), which are later removed either by breaking or dissolving. Such a sacrificial material is not feasible in metal AM. The purpose of this study is to find a suitable method for eliminating the need of support mechanism. In this work, the authors use the tilting of the substrate to alleviate the need for the support mechanism altogether. Design/methodology/approach As in the traditional AM, the object is grown in horizontal layers. However, wherever undercuts are encountered, the substrate is tilted appropriately to capture the droplets. Such a tilt involves two rotary axes invariably. To conform to the slice geometry, these two tilts are accompanied by the three linear movements. Thus, the object with undercuts is grown in planar layers using five-axis deposition without any support structure. Each pair of the corresponding top and bottom contours of any slice defines a ruled surface. The axis of the deposition head will be aligned with the rules of this surface. Findings The need for the support mechanism was eliminated using five-axis deposition. This was experimentally demonstrated by building an aluminum impeller using a metal inert gas cladding head. Research limitations/implications In the proposed methodology, the objects with an abrupt change in the geometry are not possible to realize. Originality/value This manuscript proposed a novel method of eliminating the support mechanism through continuous five-axis deposition.

This paper deals with the introduction and study of fuzzy reliability measures of a linear m-consecutive weighted-k-out-of-r-from-n: F system. The paper provides an algorithm for the evaluation of fuzzy reliability of the proposed system based on application of universal generating function and fuzzy exponential distribution. It is assumed in the study that failure rate follows generalised symmetric trapezoidal fuzzy number in fuzzy exponential distribution. Further, generalised symmetric trapezoidal fuzzy number and its arithmetic operations are defined. Fuzzy mean time to failure and Brinbaum system fuzzy reliability importance is also calculated. A numerical example is also presented to illustrate the proposed approach.

A systematic comparison of the impact of some potential endocrine disruptors (EDs) on modulation of androgen receptor (AR) and pregnane and xenobiotic receptor (PXR) function was conducted in a multi-step analysis. Promoter-reporter-based transcription assays were performed in conjunction with receptor dynamic studies in living cells that helped implicating the suspected EDs for their deleterious effects. We demonstrate that most of the selected EDs not only inhibit AR transcriptional activity, but also alter its subcellular dynamics. Conversely, some of these anti-androgenic compounds were potent activator of xeno-sensing nuclear receptor, PXR. Interestingly, agonist-activated AR that associates with the mitotic chromatin fails to achieve this association when bound to anti-androgenic EDs. Conclusively, most EDs (except BCH) behaved like pure antagonist for AR while as agonist for PXR. Subsequent experiments with DDT treatment in mice model indicated that in testis AR and its regulated genes PEM and ODC levels are down-regulated, whereas in liver of same mice PEM is up-regulated while AR and ODC remain unchanged. On the contrary, PXR and its regulated genes CYP3A11 and MDR1 levels in mice liver were up-regulated while in testis PXR remained unchanged, CYP3A11 up-regulated and MDR1 were down-regulated. Based on a novel "Biopit" concept it is speculated that long-term exposure to endocrine disrupting chemicals may influence the epigenetic profile of target cells via transcription factors thereby making them vulnerable to onset of chemically induced endocrine-related malignancies or metabolic disorders.

In this study reliability analysis of non-repairable weighted k-out-of-n: G (F) systems by incorporating uncertainties namely aleatory and epistemic have been considered. To remove these uncertainties the combination of mass distribution, fuzzy exponential distribution and belief universal generating function have been used. The failure rate (λ) of each component is taken as trapezoidal fuzzy number. Using the proposed method fuzzy reliability function of each component have been calculated and then distributed masses among the components. With the help of these masses reliability and MTTF of the proposed system have been obtained. Lastly, a numerical example is taken to understand the proposed method.

The androgen receptor (AR) is a member of nuclear receptor superfamily (NRs) and plays a critical role in prostate cancer development and progression. Therefore, anti-androgens that repress AR activity remain a critical mainstay for prostate cancer therapy. However, molecular mechanisms by which anti-androgens exert their therapeutic effects are not clearly elucidated and hence are a major area of scientific pursuit. Here, we demonstrate that another member of NRs, pregnane and xenobiotic receptor (PXR), not only acts as a molecular sensor of anti-androgens but also influences the outcome of therapeutic regimen with anti-androgenic drugs via a novel AR–PXR cross-talk. Using ‘gain- and loss-of-function’ studies, we identified a distinct role of PXR as a potent repressor of AR-regulated transcription. Our study implicates PXR as a key determinant of anti-androgen action since down-regulation of PXR diminishes the potency of the anti-androgenic drugs and enhances transcriptional actions of androgens. In addition, our subcellular localization studies revealed that ligand-activated AR induces nuclear localization of PXR and the two receptors colocalize at discrete sites in nucleus and mitotic chromatin. Finally, we report a distinct antagonist-induced interaction between AR and PXR defining a hitherto unidentified mode of action of AR antagonist. In this perspective, the study may help in designing and development of novel AR antagonists offering improved avenues in prostate cancer therapy.