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Aromatase, a cytochrome P450 member, is a key enzyme involved in estrogen biosynthesis and is dysregulated in the majority of breast cancers. Studies have shown that lysine deacetylase inhibitors (KDI) decrease aromatase expression in cancer cells, yet many unknowns remain regarding the mechanism by which this occurs. However, advances have been made to clarify factors involved in the transcriptional regulation of the aromatase gene (CYP19A1). Yet, despite aromatase being a primary target for breast cancer therapy, its posttranslational regulation has been virtually unexplored. Acetylation is a posttranslational modification (PTM) known to alter the activity and stability of many oncoproteins, and given the role of KDIs in regulating aromatase expression, we postulate that aromatase acetylation acts as a novel posttranslational regulatory mechanism that impacts aromatase expression and/or activity in breast cancer. Liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis revealed that aromatase is basally acetylated on several lysine residues (108, 169, 242, 262, 334, 352, and 354) in MCF-7 cells, and treatment with a SIRT-1 inhibitor induced additional acetylation (376, 390, 440, and 448). These acetylated lysine residues are in regions critical for aromatase activity. Site-directed mutagenesis and overexpression studies demonstrated that K108R/Q or K440R/Q mutations significantly altered aromatase activity in breast cancer cells without altering its subcellular localization.Implications: These findings demonstrate a novel posttranslational regulation of aromatase and uncover novel anticancer effects of deacetylase inhibitors, thus providing new insight for ongoing development of deacetylase inhibitors as cancer therapeutics. Mol Cancer Res; 16(10); 1530–42. ©2018 AACR.

Supplementary Table 2: siGENOME SMARTpool, Human SIRT1 siRNA sequence and exon location in the gene.

V5-tagged aromatase protein colocalizes with endoplasmic reticulum marker calnexin in stably transfected HEK293 cells.

Supplementary Table 3: Primer sets used in the generation of aromatase mutants during site directed mutagenesis.

Supplementary Table 1: Primer sets used in cloning of aromatase into pcDNA3.1+ and those used to amplify V5-tagged aromatase in a pool of RNA and their expected DNA product size.

Supplementary Table 4: Detailed LC-MS/MS data of acetylated aromatase protein. Table showing the location of basally (clear) and SIRT-1 inhibitor IV induced (highlighted) acetylation of aromatase peptides from MCF-7 cells under conventional (20% O2) and physiological oxygen (2.5% O2) conditions.

Breast cancer (BC) is primarily triggered by estrogens, especially 17β-estradiol (E2), which are synthesized by the aromatase enzyme. While all steroid hormones are derived from cholesterol, the rate-limiting step in steroid biosynthesis is mediated by the steroidogenic acute regulatory (StAR) protein. Herein, we demonstrate that StAR mRNA expression was aberrantly high in human hormone-dependent BC (MCF7, MDA-MB-361, and T-47D), modest in hormone-independent triple negative BC (TNBC; MDA-MB-468, BT-549, and MDA-MB-231), and had little to none in non-cancerous mammary epithelial (HMEC, MCF10A, and MCF12F) cells. In contrast, these cell lines showed abundant expression of aromatase (CYP19A1) mRNA. Immunofluorescence displayed qualitatively similar patterns of both StAR and aromatase expression in various breast cells. Additionally, three different transgenic (Tg) mouse models of spontaneous breast tumors, i.e., MMTV-Neu, MMTV-HRAS, and MMTV-PyMT, demonstrated markedly higher expression of StAR mRNA/protein in breast tumors than in normal mammary tissue. While breast tumors in these mouse models exhibited higher expression of ERα, ERβ, and PR mRNAs, their levels were undetected in TNBC tumors. Accumulation of E2 in plasma and breast tissues, from MMTV-PyMT and non-cancerous Tg mice, correlated with StAR, but not with aromatase, signifying the importance of StAR in governing E2 biosynthesis in mammary tissue. Treatment with a variety of histone deacetylase inhibitors (HDACIs) in primary cultures of enriched breast tumor epithelial cells, from MMTV-PyMT mice, resulted in suppression of StAR and E2 levels. Importantly, inhibition of StAR, concomitant with E2 synthesis, by various HDACIs, at clinical and preclinical doses, in MCF7 cells, indicated therapeutic relevance of StAR in hormone-dependent BCs. These findings provide insights into the molecular events underlying the differential expression of StAR in human and mouse cancerous and non-cancerous breast cells/tissues, highlighting StAR could serve not only as a novel diagnostic maker but also as a therapeutic target for the most prevalent hormone-sensitive BCs.

Novel steel of Fe-0.81C-1.9Mn-1.48Si-0.27Mo-0.95Ni-1.43Co-0.79Al composition was austenitized at 930 °C and isothermally treated at 240 °C for different intervals of time to produce carbide-free nanostructured bainite. The metastable austenite transformed to nanostructured bainite without any carbide precipitation. The transformation was slow but isothermal in nature, i.e., volume fraction of transformed product was increasing with time. The stability of phases was investigated under electropulsing at a high peak current density of 8.3 kA/mm2 and a low total pulse duration of 265 μs. Electropulsing drove cementite precipitation kinetics in both austenite and bainite even in the presence of high silicon content of 1.48 mass%. Thereby major part of metastable carbon lean austenite transformed to bainite in a few microseconds. As a result, the remaining austenite changed its morphology from a blocky form toward a desirable filmy form. Precipitation in bainite restricted its growth and nanostructure was maintained. The overall hardness of the steel was decreased due to reduction in residual strain, dislocation density although austenite was transformed to bainite, and precipitation of cementite, but hardness was much higher than that of coarse-grained ferrite. Electropulsing of nanostructured bainite increases the elastic modulus by the combined effect of transformation of retained austenite to bainite and cementite precipitation in austenite/bainite.

Composite powders of pre-alloyed 316 L austenitic stainless steel with yttria (Y2O3) powder in various compositions (0.3, 1.0, 1.5 and 2 wt%) were synthesized by mechanical alloying using a high energy ball mill. The 25-h milled powder has shown no changes other than exhibiting an austenite phase of FCC (a = 3.54 A) structure. Milled powders were found to contain nano-yttria dispersed in the austenitic stainless steel matrix of nano-crystallite size and with high lattice strain. Milled powders were cold pressed and sintered at 1100 °C (1373 K) in a controlled atmosphere. It can be inferred that nano-yttria dispersion restricts grain growth of matrix even during conventional sintering. The present yittria dispersed austenitic alloy showed the low physical density and increase in compressive strength (194–374 MPa) and hardness (477–528 HV). The compressive strength and hardness enhancement can be attributed primarily to the dispersoids of nano-yttria in the austenitic matrix by dispersion strengthening/hardening mechanisms.

Workpieces of a low carbon steel (LCS) are deformed by equal-channel angular pressing (ECAP) up to an equivalent strain of 6 in their as-received, coarse-grained condition. ECAP of LCS produces an ultrafine-grained (UFG) banded structure of 0.6 μm in width, with a high dislocation density and lattice strain. Though the refinement improves strength significantly, the material suffers from a detrimental low ductility. ECAPed samples are therefore electropulsed to recover the ductility to a large extent. A mechanism, by which a unique microstructure that fecilitates the regainment of ductility, is proposed in this study. Electropulsing (EP) creates additional low angle grain boundaries (LAGBs) by electromigration of dislocations within the grain and leads to the migration of high angle grain boundaries (HAGBs) under high electron wind force. Groups of subgrain boundaries move towards high angle grain boundaries and coalesce, producing a region of relatively lower defect density, i.e., the formation of recrystallized nuclei. On further pulsing, the HAGBs of the recrystallized nuclei continue to migrate and eventually impinge on each other. As a result, a bimodal grain size distribution consisting of micron-sized, near-equiaxed grains that are favorably interspersed with UFG grains occurs, and has a low defect density. The microstructure is clear of any residual strain. Upon electropulsing the strength of ECAPed LCS is marginally traded off for a larger gain in ductility. The micron-sized grains of the bimodal distribution are understood to accommodate larger deformations and enhance the ductility.

Tribological characteristics of low carbon steel (LCS) have been investigated on as-received coarse grains of 67 μm size and ultrafine-grained (UFG) microstructure of 0.2 μm size, which was prepared by equal-channel angular pressing (ECAP). Two-body abrasion tests have been carried out against silicon carbide abrasive papers at various loads. Furthermore, solid particle (silica sand) erosion tests were also conducted at normal particle impingement angles at various impact velocities. The ECAP process improved the resistance to abrasive and erosion wear of UFG LCS as compared to that of as-received coarse-grained steel. The abrasive and erosion wear resistances of UFG LCS were improved under severe conditions. The abrasive wear mechanism of as-received coarse-grained LCS was governed by micro-cutting, whereas it was microploughing in UFG LCS. The mechanism of material removal in erosive wear was brittle in as-received material in contrast to ductile in UFG steel.

Microstructure evolution and their effects on mechanical behaviors of the AA7075T7352 aluminum alloy are reported. Phase analysis was done by X-ray diffraction and transmission electron microscope. The presence of the GP-Zones, ɳ', and ɳ, along with Al2Cu, Al2CuMg, and Al3Zr, was noticed. Mechanical characterizations were done with the help of a tensile test and Vickers microhardness. Flow behaviors were studied to evaluate the impact of second-phase particles in the properties. Strain hardening exponents along with UTS/YS ratio have been calculated. Flow curve fitting follows Ludwigson relationship with two distinct slopes. Dislocation loops and forest dislocation were noticed in the low strain range, while dense dislocation walls in the high strain range. Variation in flow parameters is due to the random spread of precipitate particles in the matrix. The material fails by mixed mode of ductile and brittle fractures.

A newly designed composition of non-equiatomic Fe40Cr25Ni15Al15Co5 medium-entropy alloy (MEA) was produced by induction melting (IM). The as-cast alloy was found to consist of a two-phase microstructure of BCC (2.87 ± 0.01 A) and ordered B2 (2.88 ± 0.02 A) type phases. The structures of these phases were confirmed through X-ray diffraction (XRD) and transmission electron microscopy (TEM) techniques. It was observed that the Ni-Al-enriched ordered B2 phase of cuboidal shapes (~ 100 to 200 nm) is homogeneously distributed in Fe-Cr-rich BCC matrix with a cube-on-cube orientation relationship. The formation of the columnar dendrites (width 50 to 100 μm) was identified through optical microscopy (OM). The structural and microstructural stability of the alloy was investigated by heat-treating the alloy through different schedules. Heat-treated samples at different temperatures (< 1273 K) exhibit a similar type of two-phase microstructure with columnar dendrites. However, compositional rearrangement takes place during long time exposure to develop polymorphically related phases. The alloy was observed to possess a high compressive yield strength and hardness, i.e., ~ 1047 MPa and 391 ± 9 HV, respectively, at room temperature. Heat-treated samples at 600 °C and 900 °C (873 K and 1173 K) showed an increase in yield strength and ultimate strength with a significant increase in plasticity due to the increase in volume fraction of B2 phase and softening of the BCC matrix phase. The thermal stability and high strength of this alloy may open new avenues for high-temperature applications.

Ferritic stainless steel (FSS 430) has been deformed by equal-channel angular pressing (ECAP) at room temperature at an equivalent strain (evm) of 1.2 by adopting the route Bc. Microstructural developments were studied by optical microscopy, transmission electron microscopy, and microtexture by electron backscattered diffraction. Typical ultrafine-grains of less 0.2 µm could be identified. The XRD patterns confirm the presence of a BCC phase alone. An increase in peak broadening is attributed to the reduction of crystallite size and increase of lattice strain arising from deformation during ECAP. The grain refinement takes place through simple shear deformation by elongation of grains, splitting of grains into bands, the subdivision of bands into subgrains by dynamic recovery, and conversion of subgrains into grains by progressive lattice rotation (PLR). Weakly textured rolled ferritic stainless steel is strongly textured at an imposed equivalent strain of 0.6 with the development of ideal shear components of D2θ and $$\bar{E}_{\theta }$$ for bcc materials. On the second pass of ECAP texture is partially randomized and the intensity of components was decreased and new components of D1θ and Fθ are developed due to subdivision of grains into bands, bands into subgrains, and conversion of subgrains into grains of high angle of misorientation by PLR. The yield strength, tensile strength, and hardness are increased almost 1.5 times that of as-received coarse-grained material due to a high degree of grain refinement and an increase in defect density or strain. The yield strength of 687 MPa of as-received material was enhanced to 1093 MPa of ECAPed ferritic stainless steel. However, the material has lost its ductility significantly due to high defect density and a significant amount of non-equilibrium nature of grain boundaries.

Estrogen promotes the development and survival of the majority of breast cancers (BCs). Aromatase is the rate-limiting enzyme in estrogen biosynthesis, and it is immensely expressed in both cancerous and non-cancerous breast tissues. Endocrine therapy based on estrogen blockade, by aromatase inhibitors, has been the mainstay of BC treatment in post-menopausal women; however, resistance to hormone therapy is the leading cause of cancer death. An improved understanding of the molecular underpinnings is the key to develop therapeutic strategies for countering the most prevalent hormone receptor positive BCs. Of note, cholesterol is the precursor of all steroid hormones that are synthesized in a variety of tissues and play crucial roles in diverse processes, ranging from organogenesis to homeostasis to carcinogenesis. The rate-limiting step in steroid biosynthesis is the transport of cholesterol from the outer to the inner mitochondrial membrane, a process that is primarily mediated by the steroidogenic acute regulatory (StAR) protein. Advances in genomic and proteomic technologies have revealed a dynamic link between histone deacetylases (HDACs) and StAR, aromatase, and estrogen regulation. We were the first to report that StAR is abundantly expressed, along with large amounts of 17β-estradiol (E2), in hormone-dependent, but not hormone-independent, BCs, in which StAR was also identified as a novel acetylated protein. Our in-silico analyses of The Cancer Genome Atlas (TCGA) datasets, for StAR and steroidogenic enzyme genes, revealed an inverse correlation between the amplification of the StAR gene and the poor survival of BC patients. Additionally, we reported that a number of HDAC inhibitors, by altering StAR acetylation patterns, repress E2 synthesis in hormone-sensitive BC cells. This review highlights the current understanding of molecular pathogenesis of BCs, especially for luminal subtypes, and their therapeutics, underlining that StAR could serve not only as a prognostic marker, but also as a therapeutic candidate, in the prevention and treatment of this life-threatening disease.

Funding Acknowledgements Type of funding sources: None. Background Coronary microvascular dysfunction (CMD) occurs before left ventricular hypertrophy (LVH) in Anderson Fabry Disease (AFD). Few data exist about the role of CMD in Fabry cardiomyopathy, when overt LVH has already established. Purpose Aim of our study was to assess the relationship between CMD and clinical and echocardiographic features in a cohort of Fabry cardiomyopathy patients. Methods We performed coronary CT scan to exclude epicardial coronary artery disease (CAD) in 27 AFD cardiomyopathy patients with angina and/or evidence of silent ischemia at treadmill stress test. All consenting patients with no CAD (n = 17) were submitted to resting and stress 13N-Ammonia myocardial perfusion PET/CT to assess the presence of CMD. All patients also underwent complete echocardiography. Patients were followed-up for 17.3 ± 12.5 months. Results Global coronary flow reserve (CFR) resulted Conclusions In Fabry cardiomyopathy patients with angina and/or evidence of silent ischemia, the prevalence of CMD is high and it is associated to a more severe cardiac phenotype, including cardiac biomarker and functional capacity. We are not able to draw any conclusion on the possible prognostic role of CMD in Fabry cardiomyopathy.

Retinoids (vitamin A and its derivatives) play pivotal roles in diverse processes, ranging from homeostasis to neurodegeneration, which are also influenced by steroid hormones. The rate-limiting step in steroid biosynthesis is mediated by the steroidogenic acute regulatory (StAR) protein. In the present study, we demonstrate that retinoids enhanced StAR expression and pregnenolone biosynthesis, and these parameters were markedly augmented by activation of the PKA pathway in mouse hippocampal neuronal HT22 cells. Deletion and mutational analyses of the 5'-flanking regions of the StAR gene revealed the importance of a retinoic acid receptor (RAR)/retinoid X receptor (RXR)-liver X receptor (LXR) heterodimeric motif at -200/-185 bp region in retinoid responsiveness. The RAR/RXR-LXR sequence motif can bind RARα and RXRα, and retinoid regulated transcription of the StAR gene was found to be influenced by the LXR pathway, representing signaling cross-talk in hippocampal neurosteroid biosynthesis. Steroidogenesis decreases during senescence due to declines in the central nervous system and the endocrine system, and results in hormone deficiencies, inferring the need for hormonal balance for healthy aging. Loss of neuronal cells, involving accumulation of amyloid beta (Aβ) and/or phosphorylated Tau within the brain, is the pathological hallmark of Alzheimer's disease (AD). HT22 cells overexpressing either mutant APP (mAPP) or mutant Tau (mTau), conditions mimetic to AD, enhanced toxicities, and resulted in attenuation of both basal and retinoid-responsive StAR and pregnenolone levels. Co-expression of StAR with either mAPP or mTau diminished cytotoxicity, and concomitantly elevated neurosteroid biosynthesis, pointing to a protective role of StAR in AD. These findings provide insights into the molecular events by which retinoid signaling upregulates StAR and steroid levels in hippocampal neuronal cells, and StAR, by rescuing mAPP and/or mTau-induced toxicities, modulates neurosteroidogenesis and restores hormonal balance, which may have important implications in protecting AD and age-related complications and diseases.

Glucocorticoid synthesis is a complex, multistep process that starts with cholesterol being delivered to the inner membrane of mitochondria by StAR and StAR-related proteins. Here its side chain is cleaved by CYP11A1 producing pregnenolone. Pregnenolone is converted to cortisol by the enzymes 3-βHSD, CYP17A1, CYP21A2, and CYP11B1. Glucocorticoids play a critical role in the regulation of the immune system and exert their action through the glucocorticoid receptor (GR). Although corticosteroids are primarily produced in the adrenal gland, they can also be produced in a number of extra-adrenal tissue including the immune system, skin, brain, and intestine. Glucocorticoid production is regulated by ACTH, CRH, and cytokines such as IL-1, IL-6, and TNFα. The bioavailability of cortisol is also dependent on its interconversion to cortisone, which is inactive, by 11βHSD1/2. Local and systemic glucocorticoid biosynthesis can be stimulated by ultraviolet B, explaining its immunosuppressive activity. In this review, we want to emphasize that dysregulation of extra-adrenal glucocorticoid production can play a key role in a variety of autoimmune diseases including multiple sclerosis (MS), lupus erythematosus (LE), rheumatoid arthritis (RA), and skin inflammatory disorders such as psoriasis and atopic dermatitis (AD). Further research on local glucocorticoid production and its bioavailability may open doors into new therapies for autoimmune diseases.

The low carbon steel (LCS) rods were plastically deformed at room temperature up to a very high strain level by equal channel angular pressing (ECAP). ECAPed samples were further cryo-rolled at subzero temperature up to 94% area reduction. After plastic deformation, samples were annealed for short period at 475–675 °C temperature range. Optical microscopy and transmission electron microscopy are used to characterize primary microstructure and fine microstructural details respectively. Hardness of the deformed and annealed samples is measured by Vickers hardness testing. Results show that the grains are refined from 65 µm to 200 nm by ECAP at equivalent strain of 16.8, further grains are refined to

Developments of microstructures and texture are investigated for a low-carbon steel deformed by equal-channel angular pressing (ECAP) at room temperature for equivalent strain (evm) of 16.8. ECAP at evm = 0.6 reduces grain size by two orders of magnitude. With increasing strain, grain size reduces further and high-angle grain boundary (HAGB) fraction improves by grain subdivision and its change in orientation. ECAP of low-carbon steel up to evm = 16.8 can produce ultrafine grains of 0.2 µm size with HAGB fraction of 82%. The as-received steel has low texture index. Microstructural changes strongly influence texture development. It increases with equivalent strain as grain subdivision continues. Texture index fluctuates at intermediate strain range due to randomization of initial texture. Texture index reaches saturation at the high equivalent strain. On ECAP at low to intermediate strain evm = 0.6-6, components of both α (Fθ, Jθ, and $$ \overline{J} $$ θ) and γ (D1θ, D2θ, and Eθ) fibers are developed though all of them deviate from their ideal positions. At higher strain (evm = 9-16.8), the γ fiber components (D1θ, D2θ, Eθ) are strengthened, and the Eθ component reaches the highest intensity of ≈ 17 at evm = 12. There is no texture symmetry at low to high strain level. The presence of pearlite in low-carbon steel enhances strongly the deviation of texture components from their ideal positions in Euler’s space as well as it increases the intensities of the components more than that of IF steel for a similar equivalent strain.

Anderson-Fabry disease (FD) is a rare genetic, progressive, and multi-systemic condition, with X-linked inheritance. This is caused by pathogenic variants in the GLA gene, coding for the lysosomal enzyme called alpha-galactosidase A (aGLA), responsible for the cleavage of globotriaosylceramide (Gb3). The reduced or absent activity of aGLA causes the intracellular accumulation of Gb3, particularly in smooth and endothelial muscle cells, which causes cellular dysfunction. The main organs involved are the central nervous system, heart, and kidneys. However, being a ubiquitous enzyme, FD disease must be considered a systemic disease involving the peripheral nervous system, ocular and audio-vestibular systems. Also, the vascular district is damaged but the pathophysiology of vasculopathy in FD is not yet entirely understood. In literature, many vascular diagnostic tests were used to evaluate this specific involvement in FD, i.e., carotid intima media thickness (cIMT), arterial stiffness (AS), flow-mediated dilation (FMD) and atherosclerotic plaques; evaluation of vascular calcifications in FD patients is not presently available. In this review, we examined the current available literature on vascular aspects in FD. Moreover, we presented our global vascular evaluation, based on Radio Frequency Duplex Ultrasound (RF-DU), plaques, and vascular calcifications, to apply to FD patients.

RFID is a technology that continues to evolve, improve, and grow. The number of ways the technology can be used to help companies stay efficient increases in a highly competitive environment. For companies that are still looking for ways to improve their supply chain and their warehouse operations, RFID technology is something worth exploring. It can save companies time and money and can be an especially great technology to adopt for companies that are growing at a rapid pace. Case studies comparing large health care systems provider in Pittsburgh, PA with a large manufacturing company, Boeing, located Everett, WA were cited to highlight best business practices of RFID applications to the warehousing function.

Aromatase, a cytochrome P450 member, is a key enzyme involved in estrogen biosynthesis and is dysregulated in the majority of breast cancers. Studies have shown that lysine deacetylase inhibitors (KDI) decrease aromatase expression in cancer cells, yet many unknowns remain regarding the mechanism by which this occurs. However, advances have been made to clarify factors involved in the transcriptional regulation of the aromatase gene (CYP19A1). Yet, despite aromatase being a primary target for breast cancer therapy, its posttranslational regulation has been virtually unexplored. Acetylation is a posttranslational modification (PTM) known to alter the activity and stability of many oncoproteins, and given the role of KDIs in regulating aromatase expression, we postulate that aromatase acetylation acts as a novel posttranslational regulatory mechanism that impacts aromatase expression and/or activity in breast cancer. Liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis revealed that aromatase is basally acetylated on several lysine residues (108, 169, 242, 262, 334, 352, and 354) in MCF-7 cells, and treatment with a SIRT-1 inhibitor induced additional acetylation (376, 390, 440, and 448). These acetylated lysine residues are in regions critical for aromatase activity. Site-directed mutagenesis and overexpression studies demonstrated that K108R/Q or K440R/Q mutations significantly altered aromatase activity in breast cancer cells without altering its subcellular localization. Implications: These findings demonstrate a novel posttranslational regulation of aromatase and uncover novel anticancer effects of deacetylase inhibitors, thus providing new insight for ongoing development of deacetylase inhibitors as cancer therapeutics. Mol Cancer Res; 16(10); 1530–42. ©2018 AACR.

Immunomodulation is influenced by the consumption of nutrients, and healthy immunity is pivotal to defending an individual from a variety of pathogens. The immune system is a network of intricately regulated biological processes that is comprised of many organs, cellular structures, and signaling molecules. A balanced diet, rich in vitamins, minerals, and antioxidants, is key to a strengthened immune system and, thus, crucial to proper functioning of various physiological activities. Conversely, deficiencies of these micronutrients, involving impaired immunity, are linked to numerous health complications, along with a host of pathologies. Coronavirus disease 2019 (COVID-19) is a dangerous infectious disease caused by a β-form of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its genomic variants, which enter host cells upon binding to the angiotensin converting enzyme 2 receptors, and is associated with substantial morbidities and mortalities globally. Patients afflicted with COVID-19 display asymptomatic to severe symptoms, occurrences of which are multifactorial and include diverse immune responses, sex and gender differences, aging, and underlying medical conditions. Geriatric populations, especially men in comparison to women, regardless of their states, are most vulnerable to severe COVID-19-associated infections and complications, with fatal outcomes. Advances in genomic and proteomic technologies help one understand molecular events, including host–pathogen interactions and pathogenesis of COVID-19 and, subsequently, have developed a variety of preventive measures urgently, ranging from mask wearing to vaccination to medication. Despite these approaches, no unique strategy is available today that can effectively prevent and/or treat this hostile disease. As a consequence, the maintenance of a boosted immune system could be considered a high priority of preventive medicine for combating COVID-19. Herein, we discuss the current level of understanding underlining the contribution of healthy immunity and its relevance to COVID-19 molecular pathogenesis, and potential therapeutic strategies, in the management of this devastating disease.

Mesophilic and thermophilic sulfide-producing microorganisms can thrive in underground environments and cause hydrocarbon reservoir souring during energy recovery operations, and the temperature regime underground can affect the efficacy of biological control programs. In this study, we evaluated the efficacy of selected biocides using a thermophilic and a mesophilic sulfide-producing bacteria. A commonly used oilfield biocide, glutaraldehyde (Glut), and three non-traditional oil&gas field biocides, cis-1-(3-chloroallyl)-3,5,7-triaza-1-azoniaadamantane chloride (CTAC), 4,4-dimethyloxazolidine (DMO), and tris (hydroxymethyl) nitromethane (THNM), were used for the investigation. It was found that Glut was very effective against both mesophilic and thermophilic sulfide-producing bacteria. However, its efficacy persisted for shorter periods at 75° C compared to 35° C. Higher doses of Glut were required for complete bacterial kill over an extended period of time. As traditional preservative biocides, CTAC, DMO and THNM acted slower as compared to Glut. However, their efficacy was enhanced at elevated temperature. CTAC, DMO and THNM all showed improved performance at 75° C versus 35° C, and their efficacy persisted longer than Glut. This study highlights the potential of non-traditional oil&gas field biocides for microbial and souring control in reservoirs with challenging temperature conditions.

Low carbon steel (LCS) workpieces have been deformed by equal-channel angular pressing (ECAP) at a large equivalent strain of 16.8 at room temperature. The mechanisms of microstructural refinement, strengthening, hardening, and fracture behavior are investigated. LCS becomes refined by a sequence of mechanisms of elongation of grains, splitting of elongated grains to bands at low strain, subdivision of bands to cells at intermediate strain, elongation of bands to ribbon grains, and breaking of ribbons to near-equiaxed grains at a high strain level. ECAP of LCS at e vm = 16.8 refines the material to near-equiaxed grains of size 0.2 µm having a high-angle grain boundary fraction of 82.4 pct and average misorientation angle of 40.8 deg. The ultrafine-grained (UFG) LCS contains a dislocation density of 1.7 × 1015 m2. In the initial passes of ECAP, the yield and tensile strengths increase rapidly due to rapid grain refinement, reduction in domain size, and increase in dislocation density. At high strain levels, strengthening can be attributed to a combination of grain refinement, dissolution of cementite in the ferrite matrix, and increase in misorientation angle. At e vm = 16.8, the ultimate tensile strength (UTS) reaches >1000 MPa with a consequent drop in ductility to ≈10.6 pct. Reduction in ductility is found to be due to high dislocation density, high stored energy in the matrix, and occurrence of nonequilibrium grain boundaries. The LCS at low equivalent strain fails by ductile fracture. The dimple size and its volume fraction decrease, but their number density and stored energy increase with increasing equivalent strain. Beyond a critical equivalent strain of 9, the material fails by ductile-brittle fracture. At e vm = 16.8, equal-channel angular pressed UFG LCS fails mainly by cleavage fracture.

Background Right ventricular hypertrophy (RVH) is a common finding in Anderson Fabry disease (AFD). In other infiltrative and storage cardiomyopathies right ventricular (RV) involvement may influence prognostic stratification. Nevertheless, the prognostic implications of right ventricle involvement in AFD have never been assessed. Purpose Evaluation of the prognostic significance of RVH and RV systolic function in AFD cardiomyopathy. Methods Forty-five AFD patients (56% male) with extensive baseline evaluation, including assessment of RVH and RV systolic function, were followed-up for an average of 44.9 ± 8.5 months. RV systolic function was assessed by standard and tissue Doppler echocardiography and quantified using RV fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE) and Systolic tissue Doppler velocity of the tricuspid annulus (RV Sa). Cardiovascular events were defined as new-onset atrial fibrillation, heart failure or pace-maker implantation; renal events were defined as progression to dialysis and/or renal transplantation or significant worsening of glomerular filtration rate; cerebrovascular events were defined as stroke or transient ischemic attack. The outcome was defined as the time to death or the first event in any of the above predefined categories. Results Fourteen patients (31.1%) presented RVH, while RV systolic function was normal in all cases. During the follow-up period, 13 patients (28.8%, 11 male) experienced major events including two deaths. Pace-maker implantation (6 cases) was the most common type of event. At univariate analysis several variables were associated with the occurrence of events, including RVH and indexes of RV systolic function. However, at multivariate analysis only proteinuria (HR:8.3, 95% CI: 2.88 to 23.87, p ˂0.001) and LV mass indexed (HR: 1.01, 95% CI: 1.00 to 1.03, p = 0.03) were independent predictors of outcome. Conclusions The presence and extension of RVH is not associated with outcome in AFD. Our study confirms that at variance with other infiltrative or storage cardiomyopathies, RV involvement in AFD is an innocent bystander and does not influence prognosis.

Idiopathic recurrent serositis (IRS) is the most frequent serositis encountered in real-life medical sceneries, and its management represents a therapeutic challenge. There are few epidemiologic data related to IRS, though most studies have focused on recurrent pericarditis, revealing that 70% of all forms of pericarditis are idiopathic and caused by innate immunity abnormalities. The aim of this study was to evaluate outcome and recurrence rates of patients with IRS, assessing management modalities used in our Periodic Fever Centre of the Gemelli Hospital, Rome, Italy, in comparison with previous treatments in other centres.Retrospectively, we analyzed the medical charts of 57 unselected patients with history of IRS managed during the period 1998-2017.A strong heterogeneity emerged by evaluating treatments of this cohort. In particular, in our Centre there was a larger use of combined therapies: 14 patients out of 27 (52%) were treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine, compared to only 2 patients (7.4%) previously treated with combined treatments. We used corticosteroid monotherapy only in 1 case, against 7 from other centres. The mean duration of NSAID treatment in other hospitals was 43.8 days (SD ±27.40) and 191.25 days (SD ±42.23) in our Centre; the mean duration of corticosteroid treatment in other hospitals was 101.5 days (SD ±56.40) and 180.7 days (SD ±84.87) in our Centre. Colchicine was administered in other hospitals for the same duration of NSAIDs, and corticosteroids with an average duration of 111 days (SD ±30); conversely, we administered colchicine for an average duration of 250.12 days (SD ±80.7). Relapses of IRS were reported in 1/3 of cases who had discontinued therapies.The overall duration of treatments to manage IRS has a weight in terms of patients' outcome. A reduced duration of therapy with corticosteroids and a longer duration of therapy with NSAIDs determine a longer disease-free interval. A significant discriminating effect in terms of risk of IRS recurrence relies in an earlier combination therapy with colchicine independently from the start with either NSAIDs or corticosteroids. Finally, the evaluation of genes causing autoinflammatory diseases has not revealed any pathogenetic variants in a subcohort of 20/57 patients with IRS.

The low-carbon steel workpieces are deformed by equal-channel angular pressing at 293 K (20 °C) up to an equivalent strain of ~12 using route B c, which results in the bulk ultrafine-grained (UFG) structure with high dislocation density and partial dissolution of cementite. The yield strength (YS) is enhanced from 208 (as-received) to 872 MPa and the tensile strength is increased from 362 to 996 MPa, but the material loses total elongation (TE) from 36.2 to 2.9 pct. Cold rolling of equal-channel angular pressed steel produces the refined structure of grain size 0.11 μm. The YS increases further to 924 MPa with a marginal gain in ductility due to the reappearance of the γ fiber component. Flash annealing the samples, which were equal-channel angular pressed followed by cold rolling, at 873 K (600 °C) results in 27 pct of micron-sized (9 µm) ferrite grains in submicron-sized (

The head morphology and feeding habits of pairs of characin species (family Characidae) that coexist in four different coastal rainforest streams were analysed. Coexisting species differed in size, but were very similar in eco-morphological attributes. Gut analyses revealed differences in feeding preferences for each coexisting species, indicating resource partitioning. A pattern of organization in species pairs that was repeated in the four studied streams was noticed. The pattern consisted of one slightly larger species with a feeding preference for items of allochthonous origin and another smaller species with a preference for autochthonous items. The hypothesis that small morphological differences enable the current coexistence of those species pairs was proposed. Furthermore, the results show ecological equivalence among different species in the studied streams.