Product miniaturization is a trend for facilitating product usage, enabling product functions to be implemented in microscale geometries, and aimed at reducing product weight, volume, cost and pollution. Driven by ongoing miniaturization in diverse areas including medical devices, precision equipment, communication devices, micro-electromechanical systems (MEMS) and microsystems technology (MST), the demands for micro metallic products have increased tremendously. Such a trend requires development of advanced micromanufacturing technology of metallic materials for producing high-quality micro metallic products that possess excellent dimensional tolerances, required mechanical properties and improved surface quality. Micromanufacturing differs from conventional manufacturing technology in terms of materials, processes, tools, and machines and equipment, due to the miniaturization nature of the whole micromanufacturing system, which challenges the rapid development of micromanufacturing technology. Against such a background, the Special Issue “Micromanufacturing of Metallic Materials” was proposed to present the recent developments of micromanufacturing technologies of metallic materials. The papers collected in the Special Issue include research articles, literature review and technical notes, which have been highlighted in this editorial.micromanufacturing; metallic materials; miniaturization; micro products Full article

In this paper, we test and evaluate policy gradient reinforcement learning for automated blood glucose control in patients with Type 1 Diabetes Mellitus. Recent research has shown that reinforcement learning is a promising approach to accommodate the need for individualized blood glucose level control algorithms. The motivation for using policy gradient algorithms comes from the fact that adaptively administering insulin is an inherently continuous task. Policy gradient algorithms are known to be superior in continuous high-dimensional control tasks. Previously, most of the approaches for automated blood glucose control using reinforcement learning has used a finite set of actions. We use the Trust-Region Policy Optimization algorithm in this work. It represents the state of the art for deep policy gradient algorithms. The experiments are carried out in-silico using the Hovorka model, and stochastic behavior is modeled through simulated carbohydrate counting errors to illustrate the full potential of the framework. Furthermore, we use a model-free approach where no prior information about the patient is given to the algorithm. Our experiments show that the reinforcement learning agent is able to compete with and sometimes outperform state-of-the-art model predictive control in blood glucose regulation. Full article

Ambient noise carries abundant subsurface structure information and attracts ever-increasing attention in the past decades. However, there are lots of interference factors in the ambient noise in the real world, making the noise difficult to be utilized in seismic interferometry. The paper performs shear-wave tomography on a very short recording of ocean ambient noise with interference. An adapted eigenvalue-based filter is adopted as a pre-processing method to deal with the strong, directional interference problem. Beamforming and the noise crosscorrelation analyses show that the filter works well on the noise recorded by the array. Directional energy is significantly suppressed and the background diffuse component of the noise is relatively enhanced. The shear-wave tomography shows a 4-layer subsurface structure of the area covered by the array, with relatively homogeneous distribution of the shear-wave velocity values in the top three layers and a complicated structure in the bottom layer. Moreover, 3 high-velocity zones can be recognized in the bottom layer. The result is compared with several other tomography results using different methods and data. It demonstrates that, although the ambient noise used in this paper is very short and severely contaminated, a reasonable tomography result can be obtained by applying the adapted eigenvalue-based filter. Since it is the first application of the adapted eigenvalue-based filter in seismic tomography using ambient noise, the paper proves the effectiveness of this technique and shows the potential of the technique in ambient noise processing and passive seismic interferometry. Full article

Accumulation of biologically active metabolites is a specific feature of plant biochemistry, directing the use of plants in numerous applications in the pharmaceutical and food industries. Among these substances, the plethora of phenolic compounds has attracted particular interest among researchers. Here, we report on new findings in phlorotannin research, a large group of multifunctional phenolic substances, produced in brown algae. Comprehensive LC-MS profiling of three algal species allowed us to depict the complex pattern of this structurally diverse compound group across different tissues and subcellular compartments. We compiled more than 30 different phlorotannin series in one sample and used accurate mass spectrometry to assign tentative structures to the observed ions based on the confirmed sum formulas. From that, we found that acetylation, hydroxylation, and oxidation are likely to be the most common in vivo modifications to phlorotannins. Using an alternative data mining strategy to cope with extensive coelution and structural isomers, we quantitatively compared the intensity of different phlorotannin series in species, tissues, and subcellular compartments to learn more about their physiological functions. The structure and intra-thallus profiles of cell wall-bound phlorotannins were studied here for the first time. We suggest that one of the major dibenzodioxin-type phlorotannin series may exclusively target integration into the cell wall of fucoid algae. Full article

Background and objectives: Recommendations for the control of stable patients with coronary artery disease (CAD) related to an adequate level of physical activity (PA). Practical experience shows that the PA level in most people with CAD is definitely too low in relation to the guidelines. The cause may be psychological factors and among them the fear of movement—kinesiophobia. The aim of this project was to examine the evaluation of psychometric features of the Polish version of the Tampa Scale for Kinesiophobia Heart (TSK Heart), used in people with CAD. Materials and methods: The study involved 287 patients with stable CAD: 112 women and 175 men. Age: 63.50 (SD = 11.49) years. Kinesiophobia was assessed using TSK Heart, physical activity (PA)—using the International Physical Activity Questionnaire (IPAQ), and anxiety and depression was examined using the Hospital Anxiety and Depression Scale (HADS). The structure of TSK was examined using principal component analysis (PCA), internal cohesion (Cronbach’s alpha, AC), and content validity was calculated by linear regression. Results: PCA showed a three-factor TSK structure. One-dimensionality and satisfactory reliability were found: TSK Heart: AC = 0.878. Kinesiophobia as a predictor of PA: R2 = 0.162 (p = 0.000000). Anxiety and depression—TSK: R2 = 0.093 (p = 0.00000). Conclusions: The Polish version of TSK Heart for cardiac patients is characterized by good psychometric features. The use of it can improve the cooperation of rehabilitation teams for patients with CAD. Full article

The β-thalassemias are an increasing challenge to health systems worldwide, caused by absent or reduced β-globin (HBB) production. Of particular frequency in many Western countries is HBB^{IVSI−110(G > A)} β-thalassemia (HGVS name: HBB:c.93-21G > A). Its underlying mutation creates an abnormal splice acceptor site in the HBB gene, and while partially retaining normal splicing of HBB, it severely reduces HBB protein expression from the mutant locus and HBB loci in trans. For the assessment of the underlying mechanisms and of therapies targeting β-thalassemia, accurate quantification of aberrant and normal HBB mRNA is essential, but to date, has only been performed by approximate methods. To address this shortcoming, we have developed an accurate, duplex reverse-transcription quantitative PCR assay for the assessment of the ratio and absolute quantities of normal and aberrant mRNA species as a tool for basic and translational research of HBB^{IVSI−110(G > A)} β-thalassemia. The method was employed here to determine mRNA ratios and quantities in blood and primary cell culture samples and correlate them with HBB protein levels. Moreover, with its immediate utility for β-thalassemia and the mutation in hand, the approach can readily be adopted for analysis of alternative splicing or for quantitative assays of any disease-causing mutation that interferes with normal splicing. Full article

Although aging is considered a normal process, there are cellular and molecular changes that occur with aging that may be detrimental to health. Osteoporosis is one of the most common age-related degenerative diseases, and its progression correlates with aging and decreased capacity for stem cell differentiation and proliferation in both men and women. Tryptophan metabolism through the kynurenine pathway appears to be a key factor in promoting bone-aging phenotypes, promoting bone breakdown and interfering with stem cell function and osteogenesis; however, little data is available on the impact of tryptophan metabolites downstream of kynurenine. Here we review available data on the impact of these tryptophan breakdown products on the body in general and, when available, the existing evidence of their impact on bone. A number of tryptophan metabolites (e.g., 3-hydroxykynurenine (3HKYN), kynurenic acid (KYNA) and anthranilic acid (AA)) have a detrimental effect on bone, decreasing bone mineral density (BMD) and increasing fracture risk. Other metabolites (e.g., 3-hydroxyAA, xanthurenic acid (XA), picolinic acid (PIA), quinolinic acid (QA), and NAD+) promote an increase in bone mineral density and are associated with lower fracture risk. Furthermore, the effects of other tryptophan breakdown products (e.g., serotonin) are complex, with either anabolic or catabolic actions on bone depending on their source. The mechanisms involved in the cellular actions of these tryptophan metabolites on bone are not yet fully known and will require further research as they are potential therapeutic targets. The current review is meant as a brief overview of existing English language literature on tryptophan and its metabolites and their effects on stem cells and musculoskeletal systems. The search terms used for a Medline database search were: kynurenine, mesenchymal stem cells, bone loss, tryptophan metabolism, aging, and oxidative stress. Full article

The activity of microsomal cytochromes P450 (CYP) is strictly dependent on the supply of electrons provided by NADPH cytochrome P450 oxidoreductase (CPR). The variant nature of the isoform-specific proximal interface of microsomal CYPs implies that the interacting interface between the two proteins is degenerated. Recently, we demonstrated that specific CPR mutations in the FMN-domain (FD) may induce a gain in activity for a specific CYP isoform. In the current report, we confirm the CYP isoform dependence of CPR’s degenerated binding by demonstrating that the effect of four of the formerly studied FD mutants are indeed exclusive of a specific CYP isoform, as verified by cytochrome c inhibition studies. Moreover, the nature of CYP’s substrate seems to have a modulating role in the CPR:CYP interaction. In silico molecular dynamics simulations of the FD evidence that mutations induces very subtle structural alterations, influencing the characteristics of residues formerly implicated in the CPR:CYP interaction or in positioning of the FMN moiety. CPR seems therefore to be able to form effective interaction complexes with its structural diverse partners via a combination of specific structural features of the FD, which are functional in a CYP isoform dependent manner, and dependent on the substrate bound. Full article

Accurate diagnosis of urogenital schistosomiasis is crucial for disease surveillance and control. Routine diagnostic methods, however, lack sensitivity when assessing patients with low levels of infection still able to maintain pathogen transmission. Therefore, there is a need for highly sensitive diagnostic tools that can be used at the point-of-care in endemic areas. Recombinase polymerase amplification (RPA) is a rapid and sensitive diagnostic tool that has been used to diagnose several pathogens at the point-of-care. Here, the analytical performance of a previously developed RPA assay (RT-ShDra1-RPA) targeting the Schistosoma haematobium Dra1 genomic region was assessed using commercially synthesised S. haematobium Dra1 copies and laboratory-prepared samples spiked with S. haematobium eggs. Clinical performance was also assessed by comparing diagnostic outcomes with that of a reference diagnostic standard, urine-egg microscopy. The RT-ShDra1-RPA was able to detect 1x10¹ copies of commercially synthesised Dra1 DNA as well as one S. haematobium egg within laboratory-spiked ddH₂O samples. When compared with urine-egg microscopy, the overall sensitivity and specificity of the RT-ShDra1-RPA assay was 93.7% (±88.7–96.9) and 100% (±69.1–100), respectively. Positive and negative predictive values were 100% (±97.5–100) and 50% (±27.2–72.8), respectively. The RT-ShDra1-RPA therefore shows promise as a rapid and highly sensitive diagnostic tool able to diagnose urogenital schistosomiasis at the point-of-care. Full article

Dry eye syndrome (DES) is characterized by decreased tear production and stability, leading to desiccating stress, inflammation and corneal damage. DES treatment may involve targeting the contributing inflammatory pathways mediated by polyunsaturated fatty acids and their derivatives, oxylipins. Here, using an animal model of general anesthesia-induced DES, we addressed these pathways by characterizing inflammatory changes in tear lipidome, in correlation with pathophysiological and biochemical signs of the disease. The decline in tear production was associated with the infiltration of inflammatory cells in the corneal stroma, which manifested one to three days after anesthesia, accompanied by changes in tear antioxidants and cytokines, resulting in persistent damage to the corneal epithelium. The inflammatory response manifested in the tear fluid as a short-term increase in linoleic and alpha-linolenic acid-derived oxylipins, followed by elevation in arachidonic acid and its derivatives, leukotriene B4 (5-lipoxigenase product), 12-hydroxyeicosatetraenoic acid (12-lipoxigeanse product) and prostaglandins, D2, E2 and F2α (cyclooxygenase products) that was observed for up to 7 days. Given these data, DES was treated by a novel ophthalmic formulation containing a dimethyl sulfoxide-based solution of zileuton, an inhibitor of 5-lipoxigenase and arachidonic acid release. The therapy markedly improved the corneal state in DES by attenuating cytokine- and oxylipin-mediated inflammatory responses, without affecting tear production rates. Interestingly, the high efficacy of the proposed therapy resulted from the synergetic action of its components, namely, the general healing activity of dimethyl sulfoxide, suppressing prostaglandins and the more specific effect of zileuton, downregulating leukotriene B4 (inhibition of T-cell recruitment), as well as upregulating docosahexaenoic acid (activation of resolution pathways). Full article

Plants and natural products have played a significant role in curing and preventing a variety of ailments occurring in humans and animals, and continue to provide new bioactive leads for researchers in therapeutic discovery. This study was conducted with the aim to identify and document local healers’ practices of treating human diseases and quantitatively document indigenous knowledge of medicinal plants, as well as to highlight the species of public interest for bioprospecting potential. A total of 17 field tours were carried out in 12 regions of Jasrota hill and its adjoining areas of Himalaya. Informants (113) were interviewed using semi-structured interviews and discussions and local guided collections. The results were analyzed using ethnobotanical indices—use-reports (URs) and the informant consensus factor (ICF)—and the data were statistically analyzed. The ethnopharmacological uses of 121 plant species belonging to 105 genera and 53 families were reported for use as medicine for treating 93 types of ailments. A total of 4987 URs were mentioned by 113 informants. Fabaceae (90.09%) and Asteraceae (6.62%) were the most represented families. Herbs (46.28%) were the primary sources of medicine, decoction (33.88%) was the most common use method for utilization, and leaves (43.80%) were the most frequently used plant parts. The ICF values ranged from 0.667 to 0.974, with the highest number of species (1314UR, 55 species) being used for the treatment of gastrointestinal ailments (GIA), followed by dermatological disorders (38 species). This result showed that the exchange of knowledge could be evident among the different communities, and their medicinal uses and practices could be correlated. Full article

: Volatile compounds from oils extracted from cactus seeds (Opuntia ficus-indica) of five regions of Morocco were analyzed by dynamic headspace-GC/MS. Aroma active compounds were characterized by olfactometry. A total of 18 compounds was detected with hexanal, 2-methyl propanal, acetaldehyde, acetic acid, acetoin and 2,3-butanedione as most abundant. Olfactometric analysis showed that those compounds are aroma active; therefore, cactus seed oil flavor can be attributed to those compounds. Moreover, the effect of roasting of cactus seeds on the composition of volatile compounds in the oil was investigated. Especially the concentration of compounds known as products from the Maillard reaction increased significantly with roasting time such as furfural, furan, 3-methyl furan, 2-butanone, thiophene, 2, 3- dithiabutane, methyl pyrazine, 2-methyl pyrimidine, 2-metoxy phenol, dimethyl trisulfide and 5-methyl furfural. Full article

In this paper, the impact of the back contact barrier on the performance of Cu (In, Ga) Se₂ solar cells is addressed. This effect is clearly visible at lower temperatures, but it also influences the fundamental parameters of a solar cell, such as open-circuit voltage, fill factor and the efficiency at normal operation conditions. A phototransistor model was proposed in previous works and could satisfactorily explain specific effects associated with the back contact barrier, such as the dependence of the saturated current in the forward bias on the illumination level. The effect of this contribution is also studied in this research in the context of metastable parameter drift, typical for Cu (In, Ga) Se₂ thin-film solar cells, as a consequence of different bias or light soaking treatments under high-temperature conditions. The impact of the back contact barrier on Cu (In, Ga) Se₂ thin-film solar cells is analyzed based on experimental measurements as well as numerical simulations with Technology Computer-Aided Design (TCAD). A barrier-lowering model for the molybdenum/Cu (In, Ga) Se₂ Schottky interface was proposed to reach a better agreement between the simulations and the experimental results. Thus, in this work, the phototransistor behavior is discussed further in the context of metastabilities supported by numerical simulations. Full article

The unsatisfactory response of colorectal cancer (CRC) to pharmacological treatment contributes to the substantial global health burden caused by this disease. Over the last few decades, CRC has become the cause of more than 800,000 deaths per year. The reason is a combination of two factors: i) the late cancer detection, which is being partially solved by the implementation of mass screening of adults over age 50, permitting earlier diagnosis and treatment; ii) the inadequate response of advanced unresectable tumors (i.e., stages III and IV) to pharmacological therapy. The latter is due to the existence of complex mechanisms of chemoresistance (MOCs) that interact and synergize with each other, rendering CRC cells strongly refractory to the available pharmacological regimens based on conventional chemotherapy, such as pyrimidine analogs (5-fluorouracil, capecitabine, trifluridine, and tipiracil), oxaliplatin, and irinotecan, as well as drugs targeted toward tyrosine kinase receptors (regorafenib, aflibercept, bevacizumab, cetuximab, panitumumab, and ramucirumab), and, more recently, immune checkpoint inhibitors (nivolumab, ipilimumab, and pembrolizumab). In the present review, we have inventoried the genes involved in the lack of CRC response to pharmacological treatment, classifying them into seven groups (from MOC-1 to MOC-7) according to functional criteria to identify cancer cell weaknesses. This classification will be useful to pave the way for developing sensitizing tools consisting of i) new agents to be co-administered with the active drug; ii) pharmacological approaches, such as drug encapsulation (e.g., into labeled liposomes or exosomes); iii) gene therapy interventions aimed at restoring the impaired function of some proteins (e.g., uptake transporters and tumor suppressors) or abolishing that of others (such as export pumps and oncogenes). Full article

Preventing the medium voltage (MV) transformer fault by protecting transformers against indirect lightning strikes plays a crucial role in enhancing the continuous service to electricity consumers. Surge arresters, if selected properly, are efficient devices in providing adequate protection for MV transformers against transient overvoltage impulses while preventing unwanted service interruptions. However, compared to other protective devices such as the spark gap, their prices are relatively high. The higher the surge arrester rating and energy absorption capacity are, the higher the prices go. This paper proposes an inductor-based filter to limit the energy pushed into the surge arrester, and consequently to prevent any unwanted failure. An energy-controlled switch is proposed to simulate the fault of the surge arrester. Surge arresters with different ratings, e.g., 12 kV, 18 kV, 24 kV, 30 kV, 36 kV, and 42 kV with two different classes of energy, namely, type a and type b, are tested under different indirect lightning impulses such as 100 kV, 125 kV, 150 kV, 175 kV, 200 kV, 250 kV, 300 kV, and 500 kV. Furthermore, these surge arresters are equipped with different filter sizes of 100 μH, 250 μH, 500 μH, and 1 mH. Results prove that equipping a surge arrester with a proper filter size enhances the performance of the surge arrester significantly such that a high rating and somewhat expensive surge arrester can be replaced by a low rating and cheap surge arrester while providing similar or even better protective performance for MV transformers. Therefore, such configurations not only enhance the protective capability of surge arrester, but also reduce the planning and operating costs of MV networks. Full article

It is proposed a novel instantaneous frequency estimation technology, multi-generalized demodulation transform, for non-stationary signals, whose true time variations of instantaneous frequencies are unknown and difficult to extract from the time-frequency representation due to essentially noisy environment. Theoretical bases of the novel instantaneous frequency estimation technology are created. The main innovations are summarized as: (a) novel instantaneous frequency estimation technology, multi-generalized demodulation transform, is proposed, (b) novel instantaneous frequency estimation results, obtained by simulation, for four types of amplitude and frequency modulated non-stationary single and multicomponent signals under strong background noise (signal to noise ratio is −5 dB), and (c) novel experimental instantaneous frequency estimation results for defect frequency of rolling bearings for multiple defect frequency harmonics, using the proposed technology in non-stationary conditions and in conditions of different levels of noise interference, including a strong noise interference. Quantitative instantaneous frequency estimation errors are employed to evaluate performance of the proposed IF estimation technology. Simulation and experimental estimation results show high effectiveness of the proposed estimation technology. Full article

The presented article describes the phase transformations in solid bodies based on fluid fly ash (FFA) over eight years from the initial to the final phases. FFA has been selected as a type of industrial waste whose amount has been growing in recent years. This type of ash has self-hardening properties when watered because of the conditions of its origin. The specific temperature of fluid burning and the addition of calcium carbonate into the burning zone create a mixture of phases which are, even when solidified, ready to form new crystal phases, especially alumina-silicates, relicts of coal clay minerals. For experiments, bricks from the mixture of FFA and quartz sand were industrially produced and left outside. Subsequent mineralogical analyses of samples of various ages confirmed differences in phase compositions. It is supposed that the main role in the presented changes is played by the content of the roentgen-amorphous part of alumina-silicates because they are likely to be transformed into a stable form of feldspar. In addition to that, this article presents the hypothesis of a moving agent, which could explain the transformations in the final bodies. Full article