Dysregulation of the angiotensin-II Type-I receptor (AT1R) and its pathway was reported to associate with poor-prognosis in several malignancies, including colorectal-cancer (CRC). We have explored the therapeutic-potential of targeting AT1R using valsartan, and its pharmacological-interaction with Fluorouracil (5-FU) in CRC. Anti-proliferative function was evaluated in 2-/3-dimensional cells and in vivo models. Anti-proliferative, anti-migratory, apoptotic function and effect on cell-cycle was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), wound-healing test, and Fluorescence-activated cell sorting (FACS), respectively, while gene-expression was determined at mRNA/protein levels. By histogical analysis and measuring of oxidative/antioxidant markers, we evaluated the anti-inflammatory properties of valsartan. Valsartan suppressed cell-growth and impacted the anti-tumor-activities of 5-FU by apoptosis-induction. Valsartan inhibited the cells migration by perturbation of Matrix metalloproteinase (MMP1). Furthermore, valsartan inhibited tumor-growth and metastasis, and this was more notable in valsartan/5-FU combination-treated-group. The mechanism was plausible to be via the induction of Reactive-oxygen-species (ROS) and down-regulation of Superoxide-dismutase (SOD), thiol/catalase (CAT) as well as Vascular endothelial growth factor (VEGF) and Transforming growth factor beta (TGF-β). Valsartan may protect cells against intestinal fibrosis by modulation of pro-fibrotic and pro-inflammatory components include fibronectin, Interleukin) IL-1β (, Tumor necrosis factor alpha) TNF-α (, Interferon gamma) INF-γ (, and Monocyte Chemotactic Protein 1 (MCP-1). Our findings demonstrated that targeting the AT1R receptor may inhibit tumor-growth and ameliorate fibrosis and inflammation associated with CRC via modulation of AT1 and TGF-β pathways.

Our recent study detected the expression of a tissue Renin-Angiotensin System (tRAS) in human intervertebral discs (IVDs). The present study sought to investigate the impact of angiotensin II receptor type 1 (AGTR1) antagonist losartan on human nucleus pulposus (NP) cell inflammation and degeneration induced by tumor necrosis factor-α (TNF-α). Human NP cells (4 donors, Pfirrmann grade 2-3, 30-37 years old, male) were isolated and expanded. TNF-α (10 ng/mL) was used to induce inflammation and degeneration. We examined the impact of losartan supplementation and measured gene expression of tRAS, anabolic, catabolic, and inflammatory markers in NP cells after 24 h and 72 h of exposure, respectively. T0070907, a PPAR-gamma antagonist, was applied to examine the regulatory pathway of losartan. Losartan (1 mM) significantly impaired TNF-α induced increase of pro-inflammatory (nitric oxide and TNF-α), catabolic (matrix metalloproteinases), and tRAS (AGTR1a and Angiotensin Converting Enzyme) markers. Further, losartan maintained the NP cell phenotype by upregulating aggrecan and downregulating collagen type I expression. In summary, losartan showed anti-inflammatory, anti-catabolic, and positive phenotype modulating effects on human NP cells. These results indicate that tRAS signaling plays an important role in IVD degeneration, and tRAS modulation with losartan could represent a novel therapeutic approach.

The involvement of the angiotensin II type 1 receptor in the Frank-Starling Law of the Heart, where the various activations are very limited, allows simple analysis of the kinase systems involved and thence extrapolation of the mechanism to that of angiotensin control of activation of cardiac and skeletal muscle contraction. The involvement of phosphorylation of the myosin light chain in the control of contraction is accepted but not fully understood. The involvement of troponin-I phosphorylation is also indicated but of unknown mechanism. There is no known signal for activation of myosin light chain kinase or Protein Kinase C-βII other than Ca²⁺/calmodulin but the former is constitutively active and thus has to be under control of a regulated inhibitor, the latter kinase may also be the same. Ca²⁺/calmodulin is not activated in Frank-Starling, i.e. there are no diastolic or systolic [Ca²⁺] changes. I suggest here that that the regulated inhibition is by myosin light chain phosphatase and/or β-arrestin. Angiotensin activation is by translocation of the β-arrestin from the sarcoplasm to the PM thus reducing its kinase inhibition action in the sarcoplasm, this reduced inhibition has been wrongly attributed to a mythical downstream agonist property of β-arrestin.

Lettuce is a salt-sensitive crop and has a threshold electrical conductivity of 1.3–2.0 mS cm-1 and above that is considered detrimental. As there has been very little information on the physio-logical response of different critical stages of lettuce under different salt stress (SS), the current study is focused on investigating the effects of SS on the critical physiological traits influencing the carbon assimilation in different growth stages of lettuce. The experiment was conducted in deep-water culture hydroponic system in a greenhouse condition. Four levels of sodium chloride salt treatments (EC: 20, 16, 8, and 1.8 mS cm-1) were applied. During both growth stages (day 11 (GS1) and day 19 (GS2) after salt treatment), the leaf transpiration rate, stomatal conductance, and intercellular CO2 were severely decreased. However, the carbon assimilation rate remained unchanged under SS. Similarly, the water use efficiency increased under the SS. It is concluded that the increasing SS increased stomatal and non-stomatal limiting factors during GS1 suggesting the enhanced limitation in photosynthetic activity while no such trend was observed during GS2. The decreased gm with increased SS at GS1 and GS2 suggested that SS induced the irreversible decrease of gm, which in turn can be responsible for the transient reduction in the Vcmax and Jmax during GS2. Taken together, the evidence from this research recommends that varying the SS levels can significantly affect the physiological performance of lettuce at both growth stages.

As the world grapples with a pandemic with various and expanding epicenters, a flurry of medical and scientific activity has gained speed and momentum in a race to halt COVID-19. A controversial topic has been the connection between COVID-19 and the Renin-Angiotensin system (RAS). COVID-19, like Sars before it, enters by way of the Angiotensin Converting Enzyme 2 (ACE2). ACE2 is ubiquitously expressed in many tissues in the body serving as the doorway by which the virus can enter and spread causing inflammatory havoc. Demographic evidence coming out of China and other locations make it clear that the elderly and those suffering cardiovascular complications such as hypertension etc are most at risk. The connection to RAS and the demographic nature of the data coming out has led many to advance hypothesis, recommendations and even therapies based on existing RAS inhibitors and other components of the renin-Angiotensin system. It is pertinent to review the literature in the context of our understanding of the renin-angiotesnin system to allow better judgements to be made as well as lines of research initiated advancing a quick resolution to COVID-19. Covid-19 appears invincible as if dipped in the river Styx, but even Achilles had a vulnerable heel. Understanding the homeostatic balance that the coronavirus disrupts, we can discover the arrow in corona’s heel.

SARS-CoV-2, the newly identified human coronavirus causing severe pneumonia epidemic, was probably originated from Chinese horseshoe bats. However, direct transmission of the virus from bats to humans is unlikely due to lack of direct contact, implying the existence of unknown intermediate hosts. Angiotensin converting enzyme 2 (ACE2) is the receptor of SARS-CoV-2, but only ACE2s of certain species can be utilized by SARS-CoV-2. Here, we evaluated and ranked the receptor-utilizing capability of ACE2s from various species by phylogenetic clustering and sequence alignment with the currently known ACE2s utilized by SARS-CoV-2, predicting potential intermediate hosts of SARS-CoV-2.

The endoplasmic reticulum (ER) plays a multifunctional role in lipid biosynthesis, calcium storage, protein folding, and processing. Thus, maintaining ER homeostasis in insulin-secreting beta-cells is essential. Several pathophysiological conditions and pharmacological agents disrupt the ER homeostasis, thereby causing ER stress. The cells react to ER stress by initiating an adaptive signaling process called the unfolded protein response (UPR). However, the ER initiates death signaling pathways whenever the ER stress persists. ER stress has been linked to several diseases, such as cancers, obesity, and diabetes. Thus, the regulation of ER stress may provide possible therapeutic targets for many diseases. Current evidence suggests that chronic hyperglycemia and hyperlipidemia linked to type II diabetes disrupt ER homeostasis, resulting in irreversible UPR activation and cells death. Despite much progress in understanding the pathophysiology of UPR and ER stress, to date, the mechanisms of ER stress in relation to type II diabetes remain unclear. This review provided up-to-date information regarding the current status of UPR, ER stress mechanisms, insulin dysfunction, oxidative stress, and the therapeutic potential of targeting specific ER stress pathways.

Aims: Angiotensin-converting enzyme 2 (ACE2) plays an important role in the entry of coronaviruses into host cells. This paper described how carnosine, a naturally occurring supplement, can be an effective drug candidate for coronavirus disease (COVID-19) on the basis of molecular docking and modeling to host ACE2 co-crystallized with COVID-19 spike protein. Methods: First, the starting point was ACE2 inhibitors and their structure-activity relationship (SAR). Next, chemical similarity (or diversity) and PubMed searches made it possible to repurpose and assess approved or experimental drugs for COVID-19. In parallel, at all stages, authors performed bioactivity scoring to assess potential repurposed inhibitors at ACE2. Finally, investigators performed molecular docking and modeling of the identified drug candidate to host ACE2 co-crystallized with COVID-19 spike protein. Results: Carnosine emerged as the best known drug candidate to match ACE2 inhibitor structure. Preliminary docking was more optimal to ACE2 than the known typical angiotensin-converting enzyme 1 (ACE1) inhibitor (enalapril) and quite comparable to known or presumed ACE2 inhibitors. Viral spike protein elements binding to ACE2 were retained in the best carnosine pose in SwissDock at 1.75 Angstroms. Out of the three main areas of attachment expected to the co-crystallized protein structure, carnosine bind with higher affinity to two compared to the known ACE2 active site. LibDock score was 92.40 for site 3, 90.88 for site 1, and inside the active site 85.49. Conclusion: Carnosine has promising inhibitory interactions with host ACE2 co-crystallized with COVID-19 spike protein and hence could offer potential mitigating effect against current COVID-19 pandemic.

The II law of thermodynamics is most often given in three supposedly equivalent formulations: two Clausius (I and II) and one Kelvin. The most general and indisputable entropy formulation belong to Clausius (II). The earlier Clausius I principle determines the natural direction heat flow between bodies at different temperatures. On the other hand, the Kelvin principle states that it is impossible to completely convert heat into work. The author argues that the Kelvin principle is a weaker statement (or more strictly non-equivalent) than Clausius I principle, and the latter is a weaker statement than Carnot principle, which is equivalent to Clausius II principle. As a result, the Kelvin principle and the Clausius I principle are not exhaustive formulations of the II law of thermodynamics. At the same time, it turns out that the Carnot principle becomes such a formulation. Apart from providing a complete set of proof and disproof, the author, indicates where the methodological errors were made in the alleged proof of the equivalence of the Kelvin principle and both Clausius principles.

Neuroinflammation, defined as inflammatory reactions mediated by cytokines, chemokines, reactive oxygen species, and secondary messengers in the central nervous system (CNS) including the brain and spinal cord is the basis of many neurological disorders. Recently, erythropoietin (EPO) has been considered and studied as a modulator of neuroinflammation. On this article minireview of pathophysiology of neuroinflammation and the neuroprotective effects of EPO is discussed and a case of subacute huge subdural hematoma with double mydriasis operated urgently, treated with low daily dose (vs high dose once or twice a month in the literature) of EPO and recovered fully and discharged home with good consciousness is reported. In addition, the probable unfavorable outcome of erythropoietin administration in patients with neuroinflammation in COVID-19 is considered.

The association between angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphisms and plasma ACE levels may allow for the optimization of a preventive intervention to reduce cardiovascular morbidity and mortality in the chronic kidney disease (CKD) population. In this study, we aimed to analyze the association between ACE I/D polymorphism and cardiovascular mortality risk among non-hemodialyzed chronic kidney disease patients. This cross-sectional study examined 70 patients of Javanese ethnic origin with stable CKD who did not receive hemodialysis. ACE I/D polymorphisms, plasma ACE levels, atherosclerotic cardiovascular disease (ASCVD) risk, and cardiovascular mortality risk were investigated. As per our findings, the I allele was found to be more frequent (78.6) than the D allele (21.4), and the DD genotype was less frequent than the II genotype (4.3 vs. 61.4). The ACE I/D polymorphism had a significant direct positive effect on plasma ACE levels (path coefficient = 0.302, p = 0.021). Similarly, plasma ACE levels had a direct and significant positive effect on the risk of atherosclerotic cardiovascular disease (path coefficient = 0.410, p = 0.000). Moreover, atherosclerotic cardiovascular disease risk had a significant positive effect on cardiovascular mortality risk (path coefficient = 0.918, p = 0.000). The ACE I/D polymorphism had no direct effect on ASCVD and cardiovascular mortality risk. However, our findings show that the indirect effects of high plasma ACE levels may be a factor in the increased risk of ASCVD and cardiovascular mortality in Javanese CKD patients.

A literature review was conducted to summarize the frequency of the D-allele of the angiotensin-converting enzyme-1 in all countries with available data. Using an ecological study design limited to high income countries, we found that the country-level frequency of the D-allele was associated with increased COVID-19 incidence and mortality.

Purpose: Acute kidney injury (AKI) is a severe symptom of the 2019 novel coronavirus disease (COVID-19), especially for patients in a critical condition.This study explored the potential mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on AKI at the single-cell level. Methods: 15 normal human kidney samples were collected and analyzed using single-cell RNA sequencing (scRNA-seq). Subsequently, we analyzed the components and proportions of kidney cells expressing the host cellular receptor ACE2 and the key protease TMPRSSs family, and analyzed the expression differences in Occidental and Asian populations. Results: We drafted the currently available world's largest human kidney cell atlas with 42,589 cells and identified 19 clusters through unsupervised hierarchical clustering analysis. ACE2 and TMPRSSs genes were significantly co-expressed in podocytes and proximal convoluted tubules as potential host cells targeted by SARS-CoV-2. Comparative analysis showed that ACE2 expression in kidney cells was no less than that in the lung, esophagus, small intestine and colon, suggesting that the kidney may be an important target organ for SARS-CoV-2. In addition, given the high expression of ACE2 and kidney disease-related genes in Occidental donors relative to Asian donors, Occidental populations with SARS-CoV-2 infection might be a higher risk of of kidney injury.

This paper presents results of the experiments performed on a nonconventional and extremely interesting in regard to evolution, creature, the European river lamprey Lampetra fluviatilis (Petromyzontiformes, Cyclostomata), one of the oldest taxa of vertebrates. We present detailed immunocytochemical and electron microscopy analyses of chromosome synapsis, the transcription process, and chromatin dynamics in lamprey prophase I, which is the first time for science. We found that not all chromosomes complete synapsis. Rounded structures were detected in chromatin and in some synaptonemal complexes but their nature could not be determined conclusively. An analysis of RNA polymerase II distribution led to the conclusion that transcriptional reactivation in lamprey prophase I is not associated with the completion of chromosome synapsis. Monomethylated histone H3K4 is localized to meiotic chromatin throughout prophase I, and this pattern has not been previously detected in the animals. Thus, the findings made it possible to identify synaptic and epigenetic patterns specific for this group, and to add new pieces of the puzzle to the discussions of the scientific issues under study. The research on lamprey meiotic chromatin and chromosomal dynamics raises many questions leading to new discoveries.

SARS-CoV-2 is a newly emerging, highly transmissible, and pathogenic coronavirus in humans, which has caused global public health emergency and economic crisis. To date, millions of infections and thousands of deaths have been reported worldwide, and the numbers continue to rise. Currently, there is no specific drug or vaccine against this deadly virus; therefore, there is a pressing need to understand the mechanism through which this virus enters the host cell. Viral entry into the host cell is a multistep process in which SARS-CoV-2 utilizes the receptor binding domain of the spike glycoprotein (S) to recognize ACE2 receptors on the human cells; this initiates host cell entry by promoting viral-host cell membrane fusion through large scale conformational changes in the S protein. Receptor recognition and fusion are critical and essential steps of viral infections and are key determinants of the viral host range and cross-species transmission. In this review, we summarize the current knowledge on the origin and evolution of SARS-CoV-2 and the roles of key viral factors. We discuss the RNA dependent RNA polymerase structure of SARS-CoV-2, its significance in drug discovery, and explain the receptor recognition mechanisms of coronaviruses. We provide a comparative analysis of the SARS-CoV and SARS-CoV-2 S proteins, receptor-binding specificity, and discuss the differences in their antigenicity based on biophysical and structural characteristics.

In aqueous solution planar bis(1,2-dithiooxalato)nickelates(II), [Ni(dto)2]2- react with lanthanide ions (Ln3+) to form pentanuclear, hetero-bimetallic complexes of the general composition [{Ln(H2O)n}2{Ni(dto)2}3] · x H2O (n = 4 or 5; x = 9 - 12). Two complexes of this series, [{Pr(H2O)5}2{Ni(dto)2}3] · 11 H2O, Pr2Ni3 1 and [{Gd(H2O)5}2{Ni(dto)2}3] · 11 H2O, Gd2Ni3 2 were synthesized and characterized by single crystal X-ray structure analysis, X-ray powder diffraction, and IR spectroscopy. All Ln2Ni3 complexes crystallize as monoclinic crystals in the space group P21/c.

The spike protein of SARS coronavirus (SARS-CoV) attaches the virus to its cellular receptor, angiotensin-converting enzyme 2 (ACE2), which is mediated by the receptor binding domain (RBD) of the spike protein. Recently, an analysis based on decade-long structural studies of SARS was reported to illustrate with atomic-level details receptor recognition by the novel coronavirus from Wuhan, i.e., 2019-nCoV. Here, this article reports a comprehensive set of structural electrostatic analysis of all SARS-CoV spike protein RBD-related structures as of February 13, 2020, aiming at identifying the electrostatic hot spots for SARS-CoV spike protein to be complexed with ACE2 and its neutralizing antibodies. First, this article identified a structural action mechanism of the F26G19 antibody (of SARS-CoV spike protein), where its Asp56 residue binds to the Arg426 of the SARS-CoV spike protein RBD against the formation of the interfacial Arg426-Glu329 salt bridges between ACE2 and the SARS-CoV spike protein RBD. Second, a hypothesis is reported that a pair of electrostatic clips exist at the interface between ACE2 and the SARS-CoV spike protein RBD, including both Arg426-Glu329 and His445-Glu23-Lys447 salt bridges. Last, this article reports a structurally identified interfacial Glu35-Arg479 salt bridge which helps stabilize the complex structure of ACE2 and the SARS-CoV spike protein RBD. Overall, the structurally identified electrostatic hot spots reported here may be useful for the design of SARS-CoV-neutralizing antibodies in future.

In the face of the newly emergent COVID-19 pandemic, researchers around the world are racing to identify efficacious drugs capable of preventing or treating its infection. They are doing that by testing already available and approved antimicrobials for their rapid repurposing against COVID-19. Using the data emerging on the comparable efficacy of various compounds having different mechanisms of action and indications, I suggest in this report, their potential mechanistic convergence. Specifically, I highlight the lysosome as a key possible therapeutic target for COVID-19, proposing one of the lysosomal storage disorders, Niemann-Pick type C disease (NPC), as a prototypical condition with inherent resistance or an “unfavorable” host cell environment for viral propagation. The included reasoning evolves from previously generated data in NPC, along with the emerging data on COVID-19. The aim of this report is to suggest that pharmacological induction of a “transient” NPC-like lysosomal dysfunction, could hold answers for targeting the ongoing COVID-19 pandemic.

Streptococcus mutans is well known for having virulence factors associated with its cariogenic role, such as glucosyltransferases, which have been used as targets for the virtual screening of molecules with inhibitory capacity. The Antigen I/II of S. mutans is involved in the adhesion to the surface of the tooth and the bacterial co-aggregation in the biofilm formation, despite that, this protein has not been used as a target in a virtual strategy search for inhibitors. In this study we identified in silico and evaluated in vitro molecules with adhesion inhibitory potential on S. mutans Ag I/II. A virtual screening of 883,551 molecules was conducted, cytotoxicity analysis on fibroblast cells, S. mutans adhesion studies, scanning electron microscopy analysis for bacterial integrity, and molecular dynamics simulation were also performed. We have found three molecules (ZI-187, ZI-939, ZI-906) that were not cytotoxic and inhibited the adhesion of S. mutans to polystyrene microplates. Molecular dynamic simulation by 300 nanoseconds showed stability of the interaction between ZI-187 and Ag I/II (PDB: 3IPK). This work provides three new molecules that targets Ag I/II and have the capacity to inhibit in vitro the S. mutans adhesion on polystyrene microplates and provides a new computational line for the search and selection of safe inhibitory molecules against different pathogens.

Dystrophin-deficient cardiomyopathy (DDC) is currently the leading cause of death in patients with dystrophinopathies. Targeting myocardial fibrosis (MF) has become a major therapeutic goal in order to prevent the occurrence of DDC. We aimed to review and summarize the current evidence about the role of the renin-angiotensin-aldosterone system (RAAS) in the development and perpetuation of MF in DCC. We conducted a comprehensive search of peer-reviewed English literature on PubMed about this subject. We found increasing preclinical evidence from studies in animal models during the last 20 years pointing out a central role of RAAS in the development of MF in DDC. Local tissue RAAS acts directly mainly through its main fibrotic component angiotensin II (ANG2) and its transducer receptor (AT1R) and downstream TGF-b pathway. Also, it modulates the actions of most of the remaining pro-fibrotic factors involved in DDC. Despite limited clinical evidence, RAAS blockade constitutes the most studied, available and promising therapeutic strategy against MF and DDC. Conclusion: Based on the evidence reviewed, it would be recommendable to start RAAS blockade therapy through angiotensin converter enzyme inhibitors (ACEI) or AT1R blockers (ARBs) alone or in combination with mineralocorticoid receptor antagonists (MRa) at the youngest age after the diagnosis of dystrophinopathies, in order to delay the occurrence or slow the progression of MF, even before the detection of any cardiovascular alteration.

G-protein-coupled receptors (GPCR) belong to a large family of molecules eliciting different responses to a variety of signaling molecules. These receptors participate in various physiologic pathways such as metabolism, growth, immune responses, inflammation, vision, taste, olfaction, neurotransmission and even and pathologic responses including chronic inflammatory and vascular diseases. Receptors contributing to the biological responses of renin-angiotensin system (RAS) are members of GPCR family. COVID-19-induced inflammatory cascade has been attributed to acute ACE2 downregulation and imbalance of proinflammatory ACE/AngII/AT1R and anti-inflammatory ACE2/angiotensin (1-7)/Mas axes in favor of the former. Some of the receptors contributing to activities of proteins in RAS including AT1R, AT2R and Mas receptors are members of GPCR family. It is notable that these receptors induce their effects both through G protein and β-arrestin pathway; the former exerts temporary and the latter more sustained effects. In addition to the imbalance of GPCR responses contributing to RAS activities, it has been suggested that SARS-CoV2 pathogenesis might be attributed to the activation of GPCRs or modulating G-proteins involved in adenosine-CFTR regulation system and epithelial Na channel function.This article includes a minireview about the physiological functions of GPCRs and their contribution to COVID-19.

Low back pain is a clinically highly relevant musculoskeletal burden and is associated with inflammatory as well as degenerative processes of the intervertebral disc. However, the pathophysiology and cellular pathways contributing to this devastating condition are still poorly understood. Based on previous evidence, we hypothesize that tissue renin-angiotensin system (tRAS) components, including the SARS-CoV-2 entry receptor angiotensin-converting enzyme 2 (ACE2), are present in human nucleus pulposus (NP) cells and associated with inflammatory and degenerative processes. Experiments were performed with NP cells from 4 human donors. The existence of angiotensin II, angiotensin II type 1 receptor (AGTR1), AGTR2, MAS-receptor (MasR), and ACE2 in human NP cells was validated with immunofluorescent staining and gene expression analysis. Hereafter the cell viability was assessed after adding agonists and antagonists of the target receptors as well as angiotensin II in different concentrations for up to 48 hours of exposure. A TNF-α-induced inflammatory in vitro model was employed to assess the impact of angiotensin II addition and the stimulation or inhibition of the tRAS receptors on inflammation, tissue remodeling, expression of tRAS markers, and the release of nitric oxide (NO) into the medium. Further, protein levels of IL-6, IL-8, IL-10, and intracellular as well as secreted angiotensin II were assessed after exposing the cells to the substances, and inducible nitric oxide synthase (iNOS) levels were evaluated utilizing Western Blot. The existence of tRAS receptors and angiotensin II were validated in human NP cells. Cell viability analysis revealed no cytotoxic effects of angiotensin II. The AGTR1 inhibitor Candesartan and the MAS receptors AVE0991 showed cytotoxic effects at high concentrations (100 µM). The addition of angiotensin II only showed a mild impact on gene expression markers. However, there was a significant increase in NO secreted by the cells. The gene expression ratios of pro-inflammatory/anti-inflammatory cytokines IL-6/IL--10, IL-8/IL-10, and TNF-α /IL-10 were positively correlated with the AGTR1/AGTR2 and AGTR1/MAS1 ratios, respectively. The stimulation of the AGTR2 MAS-receptor and the inhibition of the AGTR1 receptor revealed beneficial effects on the gene expression of inflammatory and tissue remodeling markers. This finding was also present at the protein level. We did not find alterations in iNOS protein concentrations after adding the drugs. The current data showed that tRAS components are expressed in human NP cells and are associated with inflammatory and degenerative processes. Further characterization of the associated pathways is warranted. The findings indicate that tRAS modulation might be a novel therapeutic approach to intervertebral disc disease.

Information taken from David A. Scott’s book “Copper and Bronze in Art” was crucial for research on copper corrosion products in Stuttgart. Examples discussed are the nature and variability of ‘Black Spots’ (aka ‘Brown Fuzzies’); cupric hydroxide by cleaning, patination, and pigment synthesis; the wondrous phenomenon of curly malachite; chalconatronite formed by contact to soda glass; the formation of copper formates by glass-induced metal corrosion; and synthesis and X-ray diffraction of basic copper acetates (‘verdigris’).

The role of the Renin-Angiotensin-Aldosterone System (RAAS) in Corona Virus Disease 2019 (COVID-19) infection has become a controversial topic of discussion. RAAS inhibitors, such as Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin II receptor blockers (ARBs), which are used to treat cardiovascular diseases, have been implicated in potentially increasing cell surface levels of ACE2. ACE2 is the host receptor for COVID-19 that was discovered in Wuhan, China in December 2019. Since December, COVID-19 has transmitted rapidly across the world and has become a global pandemic. COVID-19 is similar to the Middle East respiratory syndrome coronavirus (MERS-CoV) with the first case reported in Saudi Arabia in September 2012. COVID-19, also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is also similar to SARS-CoV, which first infected humans in the Guangdong province of southern China in 2002, and caused an epidemic between November 2002 and July 2003. Both SARS-CoV and COVID-19 use ACE2 to enter host cells. ACE2 is primarily expressed in the mouth, lung, heart, esophagus, kidney, bladder, and intestines, and is a component of RAAS, which serves to maintain vascular tone and blood volume. Inhibition or activation of other components of RAAS has been shown to directly increase or decrease the expression and/or activity of ACE2. Furthermore, RAAS-targeting therapeutics, such as ACE inhibitors and ARBs, have also been shown to regulate the expression and/or activity of ACE2, albeit in animal models. Although these changes in ACE2 have been demonstrated only in animal models, there is no evidence that administration of RAAS-targeting therapeutics to humans for the treatment of hypertension, diabetes, and other cardiovascular diseases (e.g., myocardial infarction and heart failure) causes changes in ACE2 expression. Nor is there clinical evidence that RAAS-targeting therapeutics augment COVID-19 infection, morbidity, or mortality. However, clinical evidence does suggest that ACE2 expression may protect against respiratory distress caused by a variety of noxious agents. This review attempts to provide a balanced overview of the potential role of RAAS in regulating ACE2, and the role of ACE2 during COVID-19 infection. Evidence is provided to show that the expression of ACE2 may mediate both positive and negative outcomes, depending on the timing of ACE2 expression.

Mercury is a toxic metal, thus, it is an element which has more and more restrictions in its uses, but despite the above, the removal of this metal, from whatever the form in which it is encountered (zero valent metal, inorganic or organic compounds), and from different sources, is of a widespread interest. In the case of Hg(II), or Hg²⁺, the investigations about the treatment of Hg(II)-bearing liquid effluents (real or in most cases synthetic solutions) appear not to end, and from the various separation technologies, adsorption is the most popular among researchers. In this topic, and in the 2019 year, more than 100 publications had been devote to this field: Hg(II)-removal-adsorption. This work examined all of them.

Background and Objective: In an experiment designed to explore the mechanisms of fludrocortisone-induced high blood pressure, we serendipitously observed aortic aneurysms in mice infused with fludrocortisone. The purpose of this study was to investigate whether fludrocortisone induces aortic pathologies in both normocholesterolemic and hypercholesterolemic mice. Methods and Results: Male adult C57BL/6J mice were infused with either vehicle (85% polyethylene glycol 400 (PEG-400) and 15% dimethyl sulfoxide (DMSO); N=5) or fludrocortisone (12 mg/kg/day dissolved in 85% PEG-400 and 15% DMSO; N=15) for 28 days. Fludrocortisone-infused mice had higher systolic blood pressure, compared to mice infused with vehicle. Fludrocortisone induced aortic pathologies in 4 of 15 mice with 3 having pathologies in the ascending and aortic arch regions and 1 having pathology in both the ascending and descending thoracic aorta. No pathologies were noted in abdominal aortas. Subsequently, we infused either vehicle (N=5/group) or fludrocortisone (N=15/group) into male ApoE -/- mice fed a normal laboratory diet or LDL receptor -/- mice fed either normal or Western diet. Fludrocortisone increased systolic blood pressure, irrespective of mouse strain or diet. In ApoE -/- mice infused with fludrocortisone, 2 of 15 mice had ascending aortic pathologies, but no mice had abdominal aortic pathologies. In LDL receptor -/- mice fed normal diet, 5 had ascending/arch pathologies, 1 had pathologies in the ascending, arch, and suprarenal aortic regions. In LDL receptor -/- mice fed Western diet, 2 died of aortic rupture in either the descending thoracic or abdominal region, and 2 of the 13 survived mice had ascending/arch aortic pathologies. Aortic pathologies included hemorrhage, wall thickening or thinning, or dilation. Given the low incidence, only ascending aortic diameter in LDLR -/- mice fed Western diet reached statistical significance, compared to their vehicle. Conclusion: Fludrocortisone induces aortic pathologies independent of hypercholesterolemia. The findings in mouse studies have the potential to provide caution to people who are taking or have taken fludrocortisone that could have an increased risk of aortic pathologies.

The misuse of antibiotics during the last decades led to the emergence of multidrug resistant pathogenic bacteria. This phenomenon constitutes a major public health issue. Consequently, the discovery of new antibacterials in the short term is crucial. Colicins, due to their antibacterial properties, thus constitute good candidates. These toxin proteins, produced by E. coli to kill enteric relative competitors, exhibit cytotoxicity through ionophoric activity or essential macromolecule degradation. Among the 25-colicin types known to date, colicin M (ColM) is the only one colicin interfering with peptidoglycan biosynthesis. Accordingly, ColM develops its lethal activity in E. coli periplasm by hydrolyzing the last peptidoglycan precursor, lipid II, into two dead-end products, thereby leading to cell lysis. Since the discovery of its unusual mode of action, several ColM orthologs have also been identified based on sequence alignments; all of the characterized ColM-like proteins display the same enzymatic activity of lipid II degradation and narrow antibacterial spectra. This publication aims at being an exhaustive review about what is currently known on this new family of antibacterial enzymes as well as on their potential use of food preservatives or therapeutic agents.

In this work, nanochitosan (NC) was prepared through ionic gelation using low-molecular-weight chitosan and maleic acid (MA). The synthesized NC was charac¬terized by means of Fourier Transform Infrared Spectroscopy (FTIR), Atomic Force Microscopy (AFM) and Scanning Electron Microscopy (SEM). In the course of preparation, the particle size of the material was strongly depended on the parameters such as chitosan concentration and pH of the solution. By controlling the above parameters, NC with the size of smaller than 100 nm was prepared. The chitosan and prepared NC were used for the adsorption of Pb (II) from aqueous solutions in a batch system. Among the sorption parameters, pH showed the strongest effect on the sorption process and maximum Pb (II) removal was obtained at pH value of 6. The pseudo-first-order and pseudo-second-order were used to track the kinetics of adsorption process. Langmuir and Freundlich isotherms were subjected to sorption data to estimate the sorption capacity. NC proved to be an excellent adsorbent with remarkable capacity to remove Pb (II) ions from the aqueous solutions at various concentrations. The NC also showed incredible performance with a comparatively easier preparation process than other reported work.

Using analytic approach we study the effect of HPA axis secretions to the emotional variation of bipolar II disorder patient. Modified Duffing – Van der Pol oscillator was used to model the emotional variation, that was solved analytically using multiple scale perturbation to obtain an asymptotic solution. The solution was graphed to understand the effect of the variation of the cortisol to the oscillator. It was observed that the increase or decrease of the HPA hormone from the basal level in the body system, affects the mood variation of bipolar II disorder patients.

Since the effects of renin–angiotensin–aldosterone system (RAAS) inhibitors on the clinical outcomes of coronavirus disease-19 (COVID-19) have been conflicting in different studies, we performed this meta-analysis. A systematic search of published articles was performed in PubMed and EMBASE from January-May 5, 2020. Studies that reported the clinical outcomes of patients with COVID-19, stratified by the class of concomitant antihypertensive drug therapy, were included. The Mantel-Haenszel random effects model was used to estimate pooled odds ratio (OR). A total of 6,997 hypertensive patients with COVID-19 were included. The overall risk of poor patient outcomes (severe COVID-19 or death) was lower in patients taking RAAS inhibitors (OR=0.84, 95% CI: [0.73, 0.96]; P=0.017) compared with those receiving non-RAAS inhibitor antihypertensives. Patients taking angiotensin-I-converting enzyme inhibitors (ACEIs) were less likely to experience poor clinical outcomes (OR=0.73, 95% CI: [0.58-0.92]; P=0.01) compared with those receiving angiotensin-II receptor blockers (ARBs). Compared to all other antihypertensives, ACEIs decreases the risk poor COVID-19 outcomes (OR=0.77, 95% CI: [0.63-0.93]) while ARBs did not (OR=1.13, 95% CI: [0.95-1.35]). The risk of poor patient outcomes from COVID-19 was lower in patients who received RAAS inhibitors compared with those who took non-RAAS inhibitors. Unlike ARBs, ACEIs might help in decreasing the severity and mortality of COVID-19.

Objectives Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has high infectivity in humans, attributed to the strong affinity of its spike (S) protein to human angiotensin-converting enzyme 2 (ACE2). Here, we analyzed the structural similarity of the S protein between SARS-CoV-2 and other SARS-related coronaviruses (CoVs). Methods We performed multiple alignment analysis of nine amino acid sequences of CoV S proteins from NCBI with MAFFT web-based software, followed by phylogeny analysis. Three-dimensional structure modeling was performed by SWISS-MODEL. We calculated the template modeling score between the S protein of SARS-CoV-2 and that of other SARS-related CoVs. Results The S1 domain of the unclassified CoV RaTG13 (the host of which is the intermediate horseshoe bat) was structurally very similar to that of SARS-CoV-2, implying that RaTG13 could be the origin of SARS-CoV-2. In addition, the folding property of the entire S protein was nearly the same between SARS-CoV-2 and RaTG13 after the PRRA amino acid insertion was removed from SARS-CoV-2. Conclusions RaTG13 could have a high binding affinity to ACE2, similar to SARS-CoV-2, and it is therefore highly likely to infect other animals. Therefore, massive research and monitoring of CoVs in animals is necessary to prevent future COVID-19-like disasters.

Patients with glioblastoma (GB), a highly aggressive brain tumor, have a median survival of 14.6 months following neurosurgical resection with adjuvant chemoradiotherapy. Quiescent GB cancer stem cells (CSCs) invariably cause local recurrence. These GB CSCs that can be identified by embryonic stem cell markers express components of the renin-angiotensin system and are associated with circulating CSCs. Despite the presence of circulating CSCs, GB rarely develops distant metastasis outside the central nervous system. This paper reviews the current literature on GB growth inhibition in relation to CSCs, circulating CSCs, the RAS and the novel therapeutic approach by repurposing drugs that target the renin-angiotensin system to improve overall symptom-free survival and maintain quality of life.

Clopidogrel is one of the thienopyridine antiplatelet drugs commonly used as a prophylactic medication to prevent coagulation in vessels and cardiovascular events. The molecule of clopidogrel is metabolized in the liver via phase-I and phase-II metabolism pathways. The sulfenic acid clopidogrel metabolite undergoes phase-II metabolism through conjugation with glutathione by the glutathione-s-transferase (GST) to form a glutathione conjugate of clopidogrel (inactive metabolite). A glutaredoxin enzyme removes the glutathione conjugated with clopidogrel to form cis-thiol-clopidogrel. This review focused on the polymorphisms of genes related to phase-II metabolism during the clopidogrel bioactivation process. Overall, no well-controlled studies were done about the relationship between the clopidogrel bioactivation process and genes related to phase-II metabolism’s enzymes. Nevertheless, some polymorphisms of G6PD, GCLC, GCLM, GSS, GST, GSR, HK, and GLRX genes could be responsible for clopidogrel resistance due to low glutathione conjugate or glutaredoxin plasma levels. Studies needed to be concerned with the relationship between clopidogrel resistance and phase-II metabolism issues in the near future.

The weight coefficients of the diaphragm spring depend on experiences in the traditional optimization. However, this method not only cannot guarantee the optimal solution but it is also not universal. Therefore, a new optimization target function is proposed. The new function takes the minimum of average compress force changing of the spring and the minimum force of the separation as total objectives. Based on the optimization function, the result of the clutch diaphragm spring in a car is analyzed by the non-dominated sorting genetic algorithm (NSGA-II) and the solution set of Pareto is obtained. The results show that the pressing force of the diaphragm spring is improved by 4.09%by the new algorithmand the steering separation force is improved by 6.55%, which has better stability and steering portability. The problem of the weight coefficient in the traditional empirical design is solved. The pressing force of the optimized diaphragm spring varied slightly during the abrasion range of the friction film, and the manipulation became remarkably light.

The Severe acute respiratory syndrome-Corona virus-2 (SARS-CoV-2) which is responsible for recurring pandemics takes advantage of host-cell processes including the glycosylation pathway. The heavily glycosylated spike protein assists viruses in attachment and penetration. The N-glycans of N-terminal domain N165 and N234 play a significant role in conformational dynamics of the receptor-binding domain (RBD) with angiotensin-converting enzyme 2 (ACE2). In addition, the deletion of N-glycan sites N331 and N334 have been associated with reduced infectivity. This signifies the importance of targeting the N-glycans making them unavailable for interacting with the ACE2 receptor, ultimately leading to reduced infectivity. These glycans can be specifically targeted and can be used for designing SARS specific drugs or neutralizing molecules. In the current study, lectins Griffithsin, Cyanovirin-N, Cyanovirin homolog, and BanLec H84T were used to target the spike protein's N-glycans. Molecular docking programs AutoDock Vina and HADDOCK were used to study lectin-glycan interactions. The interactions look convincible in accordance with the lowest interaction energies best-fit approach but the characteristic feature (scoring functions) of the docking programs are questionable concerning Lectin-Glycan interactions exist in nature. There is a high need of the hour for developing specific algorithms for docking glycans with a preferential selection of terminal residues.

The outbreak of a novel coronavirus (SARS-CoV2) associated with acute respiratory disease called COVID-19 marked the introduction of the third spillover of an animal CoV to humans in the last 2 decades. The SARS-CoV2 genome analysis with various bioinformatics tools revealed that it belongs to beta CoVs genera, with highly similar genome as bat coronavirus and receptor binding domain (RBD) of spike glycoprotein as Malayan pangolin coronavirus. Based on its genetic proximity, SARS-CoV2 is likely to be originated from bat derived CoV and transmitted to humans via an unknown intermediate mammalian host, probably Malayan pangolin. Further spike protein S1/S2 cleavage site of SARS-CoV2 has acquired polybasic furin cleavage site which is absent in bat and pangolin suggesting natural selection either in an animal host before zoonotic transfer or in humans following zoonotic transfer. In the current review, we recapitulate a preliminary opinion about the disease, origin and life cycle of SARS-CoV2, roles of virus proteins in pathogenesis, commonalities and differences between different corona viruses. We have also highlighted the evidences regarding the potential drugs and vaccine candidates with their modes of action to cope with this viral outbreak. Our review provides comprehensive up-dated information on molecular aspects of the SARS-CoV2.

We hypothesize that the reason severe COVID-19 is closely linked to a limited number of conditions such as obesity, hypertension, older age and diabetes is that these conditions are characterized by a pro-inflammatory state in general and an angiotensin converting enzyme-1-bias in particular. We review recent evidence that this pro-inflammatory state can be reversed via regular exercise and a healthy diet. Studies are suggested that could test this hypothesis.

Since the spread of the deadly virus SARS-CoV2 in late 2019, researchers have restlessly been seeking for unraveling how the virus factually enters the host cells. Some proteins on each side of the interaction between the virus and the host cells are involved as the major contributors to this process: 1- the nano-machine Spike protein on behalf of the virus, 2- angiotensin converting enzyme II, the mono-carboxypeptidase and the key component of renin angiotensin system on behalf of the host cell, 3- some host proteases and proteins exploited by SARS-CoV2, In this review, the complex process of SARS-CoV2 entrance into the host cells with the contribution of the involved host proteins as well as the sequential conformational changes in the Spike protein tending to increase the probability of complexification of the latter with angiotensin converting enzyme II, the receptor of the virus on the host cells, are discussed. Besides, the release of the catalytic ectodomain of angiotensin converting enzyme II as its soluble form in the extracellular space and its positive or negative impact on the infectivity of the virus are considered.

Background: A significant proportion of SARS-CoV-2-infected patients develops respiratory failure. Thromboembolism is also prevalent in coronavirus disease 2019 (Covid-19). Vitamin K plays a role in coagulation and possibly also in lung diseases. We therefore hypothesized that vitamin K is implicated in Covid-19 pathogenesis. Methods: 134 Covid-19 patients and 184 controls were included. Inactive vitamin K-dependent matrix Gla protein (i.e.dp-ucMGP) and prothrombin (i.e. PIVKA-II) were measured, which are inversely related to respectively extrahepatic and hepatic vitamin K status. Desmosine was measured to quantify elastic fiber degradation. Lung involvement and arterial calcifications severity were assessed by computed tomography. Results Dp-ucMGP was elevated in Covid-19 patients compared to controls (P=0.001). Higher dp-ucMGP was found in Covid-19 patients with poor compared to better outcomes (P=0.002). PIVKA-II was normal in 81.8%, mildly elevated in 14.0% and moderately elevated in 4.1% of Covid-19 patients not using vitamin K antagonists. Dp-ucMGP in Covid-19 patients was correlated with desmosine (P<0.001), thoracic aortic calcification (P<0.001) but not with pneumonia severity. Conclusions: Extrahepatic vitamin K status was severely reduced in Covid-19 patients, as reflected by elevated inactive MGP, and related to poor outcome. Procoagulant prothrombin activity remained preserved in the majority of Covid-19 patients, which is compatible with the increased thrombogenicity that is frequently observed in severe Covid-19. Impaired MGP activation was linked to accelerated elastic fiber degradation and premorbid vascular calcifications. A trial should assess whether increasing MGP and protein S activity by vitamin K administration improves Covid-19 outcomes.

The transport of iron(III) from Fe(III)-Mn(II)-HCl mixed solutions through a flat-sheet supported liquid membrane is investigated, being the carrier phase of Cyanex 923 (commercially available phosphine oxide extractant) dissolved in Solvesso 100 (commercially available diluent), as a function of hydrodynamic conditions, concentration of manganese and HCl in the feed phase, and carrier concentration in the membrane phase. A transport model is derived that describes the transport mechanism, consisting of diffusion through a feed aqueous diffusion layer, a fast interfacial chemical reaction, and diffusion of the Fe(III)-Cyanex 923 complex across the membrane phase. The membrane diffusional resistance (Δm) and feed diffusional resistance (Δf) are calculated from the model, and their values are 145 s/cm and 361 s/cm, respectively. It is apparent that the transport of iron(III) is mainly controlled by diffusion through the aqueous feed boundary layer, being the thickness of this layer calculated as 2.9x10-3 cm. Since Mn(II) is not transported through the membrane phase, the present system allows to the purification of this manganese-bearing solutions.

Cadmium(II) contamination in the environment is an emerging problem due to its acute toxicity and mobility, so it is very urgent to remove this species from industrial wastewater before it is discharged into the environment. Thus, a starch-based activated carbon (AC) with a specific surface area of 1600 m2g-1 is used as an adsorbent for the capturing of toxic cadmium(II) ions from synthetic solutions. The sorbent is characterized by BET, SEM, TEM, XRD, FT-IR, TGA, and zeta potential. The maximum uptake (284 mg g-1) of Cadmium(II) ion is obtained at pH 6. The thermodynamic parameters like ∆G, ∆H, ΔS are found to be -17.42 kJmol-1, 6.49 kJ mol-1, and 55.66 Jmol-1K-1 respectively, revealing that the adsorption mechanism is endothermic, spontaneous, and feasible. The experimental data follows the D-R and Langmuir models well. The mass transfer is controlled by pseudo 2nd order kinetics. Furthermore, the density functional theory simulations demonstrate that the activated carbon strongly interacted with the Cd(II) ion through its various active sites. The adsorption energy noted for all interactive sites is highly negative (-0.45 eV to -10.03 eV), which shows that the adsorption process is spontaneous and stable which is in agreement with the experimental thermodynamics analysis.

The photocatalysis process over N-doped TiO2 under visible light is examined for Pb(II) oxidation to form the less toxic and handleable PbO2 suggesting a new method for Pb(II) remediation. The doping TiO2 with N element was conducted by simple hydrothermal technique and using urea as the N source with various concentrations. The doped photocatalysts were characterized by DRUVS, XRD, FTIR and SEM-EDX instruments. Photocatalysis of Pb(II) through batch experiment was performed for evaluation of the doped TiO2 activity under visible light, with applying various fractions of N doped, photocatalyst weigh, irradiation time, and solution pH. The research results attributed that N doping has been successfully performed, that shifted TiO2 absorption into visible region, allowing it to be active under visible irradiation. The photocatalytic removal of Pb(II) under visible ligth over N-TiO2 showed more effective than that of over the un-doped photocatalyst. The removal of Pb(II) has notably taken place through oxidation, that may form PbO2. The highest photocatalytic oxidation of Pb(II) 15 mg/L in 25 mL of the solution could be reached by using TiO2 doped with 10%w of N, 15 mg of N-TiO2 weight, 30 minutes of time, and at pH 8, suggesting a feseable method for Pb(II) remediation.

Gold nanoparticles have been indicated for use in a diagnostic and/or therapeutic role in several cancer types. The use of gold nanorods (AuNRs) with a surface plasmon resonance (SPR) in the second Near-Infrared II (NIR-II) optical window promises deeper anatomical penetration through increased maximum permissible exposure and lower optical attenuation. In this study, the targeting efficiency of anti-epidermal growth factor receptor (EGFR) antibody functionalised AuNRs with an SPR at 1064 nm was evaluated in vitro. Four cell lines, KYSE-30, CAL-27, Hep-G2 and MCF-7 that either over or under expressed EGFR were used. This expression was confirmed by flow cytometry and immunofluorescence. Cytotoxicity assays showed no AuNRs toxicity to both EGFR positive and EGFR negative cell lines up to a concentrations of 19 µg/ml. Optical microscopy demonstrated a significant difference (p&lt;0.0001) between targeted AuNRs (tAuNRs) and untargeted AuNRs (uAuNRs) in all four cancer cell lines. This study demonstrates that anti-EGFR functionalisation significantly increased the number of tAuNRs associated with each EGFR positive cancer cell. This successful targeting highlights the use of tAuNRs for molecular photoacoustic imaging or tumour treatment through plasmonic photothermal therapy.

Longevity risk constitutes an important risk factor for life insurance companies and it can be managed through longevity-linked securities. The market of longevity-linked securities is at present far from being complete and does not allow to find a unique pricing measure. We propose a method to estimate the maximum market price of longevity risk depending on the risk margin implicit within the calculation of the technical provisions as defined by Solvency II. The maximum price of longevity risk is determined for a survivor forward (S-forward), an agreement between two counterparties to exchange at maturity a fixed survival-dependent payment for a payment depending on the realized survival of a given cohort of individuals. The maximum prices determined for the S-forwards can be used to price other longevity-linked securities, such as q-forwards. The Cairns-Blake-Dowd model is used to represent the evolution of mortality over time, that combined with the information on the risk margin, enables us to calculate upper limits for the risk-adjusted survival probabilities, the market price of longevity risk and the S-forward prices. Numerical results can be extended for the pricing of other longevity-linked securities.

We investigated whether a functional insertion/deletion (I/D) polymorphism of angiotensin-converting enzyme (ACE) influenced antipsychotic treatment. At baseline, and after 8 weeks of treatment with various antipsychotic medications, we assessed patients’ Positive and Negative Syndrome Scale (PANSS) scores, PANSS factors, and metabolic syndrome-related parameters (fasting plasma lipid and glucose levels, and body mass index). A total of 186 antipsychotic-naïve first-episode psychosis patients or nonadherent chronic psychosis individuals (99 males and 87 females) were genotyped by polymerase chain reaction analysis. The ACE-I/D polymorphism was significantly associated with changes in PANSS psychopathology only (p < 0.05). Compared to ACE-II homozygous males, ACE-DD homozygous and ACE-ID heterozygous males manifested significantly greater decreases in PANSS positive score, PANSS excitement factor, and PANSS cognitive factor. ACE-DD homozygous females manifested higher decreases in PANSS depression factor compared to ACE-II homozygous and ACE-ID heterozygous females. The polymorphism’s effect size was estimated as moderate to strong, while its contribution to the PANSS psychopathology ranged from ~5.4–8.7%, with the lowest contribution observed for PANSS positive score changes and the highest for PANSS depressive factor changes. Our results indicated that ACE-I/D polymorphism had a statistically significant but weak gender-specific impact on psychopathology data and showed no association between ACE-I/D polymorphism and metabolic syndrome-related parameters.

Abstract: SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection is associated, alongside with lung infection and respiratory disease, to cardiovascular dysfunction that occurs at any stage of the disease. This includes ischemic heart disease, arrhythmias, and cardiomyopathies. The common pathophysiological link between SARS-CoV-2 infection and the cardiovascular events is represented by coagulation abnormalities and disruption of factors released by endothelial cells which contribute in maintaining the blood vessels into an anti-thrombotic state. Thus, early alteration of the functionality of endothelial cells, which may be found soon after SARS-CoV-2 infection, seems to represent the major target of SARS CoV-2 disease state and accounts for the systemic vascular dysfunction that leads to detrimental effect in terms of hospitalization and death accompanying the disease. In particular, the molecular interaction of SARS-CoV-2 with ACE2 receptor located in endothelial cell surface, either at the pulmonary and systemic level, leads to early impairment of endothelial function which, in turn, is followed by vascular inflammation and thrombosis of peripheral blood vessels. This highlights systemic hypoxia and further aggravates the vicious circle that compromises the development of the disease leading to irreversible tissue damage and death of patients with SARS CoV-2 infection. The review aims to assess some recent advances to define the crucial role of endothelial dysfunction in the pathogenesis of vascular complications accompanying SARS-CoV-2 infection. In particular, the molecular mechanisms associated to the interaction of SARS CoV-2 with ACE2 receptor located on the endothelial cells are highlighted to support its role in compromising endothelial cell functionality. Finally, the consequences of endothelial dysfunction in enhancing pro-inflammatory and pro-thrombotic effects of SARS-CoV-2 infection are assessed in order to identify early therapeutic interventions able to reduce the impact of the disease in high-risk patients.

The angiotensin-converting enzyme (ACE) is a peptidase that is involved in the synthesis of Angiotensin II, the bioactive component of the renin-angiotensin system. A growing body of literature argues for a beneficial impact of ACE inhibitors (ACEi) on age-associated metabolic disorders, mediated by cellular changes in reactive oxygen species (ROS) that improve mitochondrial function. Yet, our understanding of the relationship between ACEi therapy and metabolic parameters is limited. Here, we used three genetically diverse strains of Drosophila melanogaster to show that Lisinopril treatment reduces thoracic ROS levels and mitochondrial respiration in young flies, and increases mitochondrial content in middle-aged flies. Using untargeted metabolomics analysis, we also showed that Lisinopril perturbs the thoracic metabolic network structure by affecting metabolic pathways involved in glycogen degradation, glycolysis, and mevalonate metabolism. The Lisinopril-induced effects on mitochondrial and metabolic parameters, however, are genotype-specific and likely reflect the drug’s impact on nutrient-dependent fitness traits. Accordingly, we found that Lisinopril negatively affects survival under nutrient starvation, an effect that can be blunted by genotype and age in a manner that partially mirrors the drug-induced changes in mitochondrial respiration. In conclusion, our results provide novel and important insights into the role of ACEi in cellular metabolism.

A method was developed to perform shape optimization of a tidal stream turbine hydrofoil using a multi-objective genetic algorithm. A bezier curve parameterized the refrence hydrofoil profoil NACA 63815. Shape optimization of this hydrofoil maximized its lift-to-darg ratio and minimized its pressure coefficient, thereby increasing the turbines power output power and improving its cavitation characteristics. The Elitist Non-dominated Sorting Genetic Algorithm (NSGA-II) was employed to perform the shape optimization. A comparative study of two-and three-dimensional optimizations was carried out. The effect of varing the angle of attack on the quality of optimized results was also studied. predictions based on two-dimensional panel method results was also studied. Preditions based on a two-dimensional panel method and on a computational fluid dynamics code were compared to experimental measurments.

Ferric uptake regulation protein is a repressor protein which binds an AT rich region of DNA (the iron box). Fur binds as a dimer in a helix turn helix mode and it is activated by iron(II) and other divalent transition metal ions at elevated concentrations in a process to regulate the ion uptake. Each transition metal ion induces certain conformational changes to aid the Fur binding, both the N-terminal and C-terminal domains take part in binding to DNA in addition to His 88 and His 86 residues. The process is discussed in view of experimental reports. Fe(II), Mn(II) and Co(II) activate Fur to bind DNA experimentally but Zinc plays a structural role and does not activate Fur to bind DNA.

Structural perturbations in the Mn4CaO5 cluster site, an oxygen-evolving complex of photosystem II, such as those induced by Ca2+/Sr2+ exchanges or Ca/Mn-removal have been known to induce long-range positive shifts (+30 mV to +150 mV) in the redox potential of the primary quinone electron acceptor plastoquinone A (QA) located 40 Å distant from the OEC. Here, we reanalyzed the crystal structure of Sr-PSII solved at 2.1 Å and compare it with the native Ca-PSII of 1.9 Å with focus on the acceptor site and report on the possible long-range interactions between the donor, Mn4Ca(Sr)O5 cluster, and acceptor sites.

One of the hallmarks of the SARS-CoV-2 infection has been the inflammatory process that played a role in its pathogenesis, resulting in mortality within susceptible individuals. This uncontrolled inflammatory process leads to severe systemic symptoms via multiple pathways, however, the role of endothelial dysfunction and thrombosis have not been truly explored. This review aims to highlight the pathogenic mechanisms of these inflammatory triggers leading to thrombogenic complications. There are direct and indirect pathogenic pathways of the infection that are examined in detail. We also describe the case of carotid artery thrombosis in a patient following the SARS-CoV-2 infection, while reviewing the literature on the role of ACE2, the endothelium, and the different mechanisms by which SARS-CoV-2 may manifest both acutely and chronically. We also highlight differences from the other coronaviruses that have made this infection pandemic with similarities to the influenza virus.

With the emergence of the novel corona virus SARS-CoV-2 since December 2019, more than 43 million cases have been reported worldwide. This virus has shown high infectivity and severe symptoms in some cases leading to over 1 million deaths globally. Despite the collaborative and concerted research efforts that has been made, no effective treatment for COVID-19 (corona virus disease-2019) is currently available. SARS-CoV-2 uses the angiotensin converting enzyme 2 (ACE2) as an initial mediator for viral attachment and host cell invasion. ACE2 is widely distributed in human tissues including the cell surface of lung cells which represent the primary site of the infection. Inhibiting or reducing cell surface availability of ACE2 represents a promising therapy for tackling COVID-19. In this context, most ACE2–based therapeutic strategies have aimed to achieve this through the use of angiotensin converting enzyme (ACE) inhibitors or neutralizing the virus by exogenous administration of ACE2. However, through this review, we present another perspective focusing on the subcellular localization and trafficking of ACE2. Membrane targeting of ACE2, shedding and its cellular trafficking pathways including internalization are not well elucidated. Therefore, hereby we present an overview on the fate of newly synthesized ACE2, its post translational modifications, what is known of its trafficking pathways. In addition, we highlight the possibility that some of the identified ACE2 missense variants might affect its trafficking efficiency and localization and hence may explain some of the observed variable severity of SARS-CoV-2 infections. Extensive understanding of these processes is necessary to evaluate the potential use of ACE2 as a credible therapeutic target.

Hypertension is a common and growing medical problem that leads to enormous cardiovascular and kidney disease worldwide. While many drugs exist to treat hypertension, there is large individual variation in how a given individual responds to different agents, which contributes to dismal rates of hypertension control. While demographic factors predict which drugs may work better in certain individuals, a great degree of this variation has a genetic basis. In recent years, genome wide association studies have begun to identify specific gene variants that predict drug response to particular agents. This review identifies the major genetic variants influencing antihypertensive response that have emerged from this growing body of work. For novel genetic variants without a previously known biologic basis in blood pressure, it is crucial to validate initial findings in subsequent studies. This information may eventually lead to a more personalized approach to hypertension management that will improve blood pressure control and patient outcomes. The integration of this large amount of data and its real world application will be highly challenging, but strategies to accomplish this are discussed.

Lanthanide-doped upconversion nanoparticles (UCNPs) are promising bioimaging nanoprobes due to their excellent photostability. As one of the most commonly-used lanthanide activators, Tm3+ ions have perfect ladder-type electron configuration and can be directly excited by bio-friendly near-infrared-II (NIR-II) wavelengths. Here, the emission characteristics of Tm3+-doped nanoparticles under laser excitations of different near-infrared-II wavelengths were systematically investigated. The 1064 nm, 1150 nm and 1208 nm lasers are proposed to be three excitation strategies with different response spectra of Tm3+ ions. Particularly we found that 1150 nm laser excitation enables intense three-photon 475 nm emission, which is nearly 100 times stronger than that excited by 1064 nm excitation. We further optimized the luminescence brightness after investigating the luminescence quenching mechanism of bare NaYF4:Tm (1.75%) core. After growing inert shell, ten-fold increase of emission intensity was achieved. Combining the advantages of NIR-II wavelength and the higher-order nonlinear excitation, a promising facile excitation strategy was developed for the application of thulium-doped upconversion nanoparticles in single nanoparticle imaging and cancer cell microscopic imaging.

The optimization of the production process of metal mines has been traditionally driven only by economic benefits while ignoring resource efficiency. However, it has become increasingly aware of the importance of resource efficiency since mineral resource reserves continue to decrease while the demand continues to grow. To better utilize the mineral resources for sustainable development, this paper proposes a multi-objective optimization model of the production process of metal mines considering both economic benefits and resource efficiency. Specifically, the goals of the proposed model are to maximize the profit and resource utilization rate. Then, the fast and elitist Non-Dominated Sorting Genetic Algorithm (NSGA-II) is used to optimize the multi-objective optimization model. The proposed model has been applied to the optimization of the production process of a stage in the Huogeqi Copper Mine. The optimization results provide a set of Pareto-optimal solutions that can meet varying needs of decision makers. Moreover, compared with those of the current production indicators, the profit and resource utilization rate of some points in the optimization results can increase respectively by 2.99% and 2.64%. Additionally, the effects of the decision variables (geological cut-off grade, minimum industrial grade and loss ratio) on objective functions (profit and resource utilization rate) were discussed using variance analysis. The sensitivities of the Pareto-optimal solutions to the unit copper concentrate price were studied. The results show that the Pareto-optimal solutions at higher profits (with lower resource utilization rates) are more sensitive to the unit copper concentrate prices than those obtained in regions with lower profits.

In the past, Unmanned Aerial Vehicles (UAVs) were mostly used in the military operations to prevent pilot losses. Nowadays, the fast technological evolution enables the production of a class of cost-effective UAVs which can service a plethora of public and civilian applications, specially when configured to work cooperatively to accomplish a task. However, designing a communication network among the UAVs is challenging task. In this article, we propose a centralized UAV placement strategy, where UAVs are used as flying access points forming a mesh network, providing connectivity to ground nodes deployed in a target area. The geographical placement of UAVs is optimized based on a Multi-Objective Evolutionary Algorithm (MOEA). The goal of the proposed scheme is to cover all ground nodes using a minimum number of UAVs, while maximizing the fulfillment of their data rate requirements. The UAVs can employ different data rates depending on the channel conditions, which are expressed by the Signal-to-Noise-Ratio (SNR). In this work, elitist Non-Dominated Sorting Genetic Algorithm II (NSGA-II) is used to find a set of optimal positions to place UAVs, given the positions of the ground nodes. We evaluate the trade-off between the number of UAVs used to cover the target area and the data rate requirement of the ground nodes. Simulation results show that the proposed algorithm can optimize the UAV placement given the requirement and the positions of the ground nodes in the geographical area.

Veratrum californicum is a rich source of steroidal alkaloids such as cyclopamine, a known inhibitor of the Hedgehog (Hh) signaling pathway. Here we provide a detailed analysis of the alkaloid composition of V. californicum by plant part through quantitative analysis of cyclopamine, veratramine, muldamine and isorubijervine in the leaf, stem and root/rhizome of the plant. To determine if additional alkaloids in the extracts contribute to Hh signaling inhibition, we replicated the concentrations of these alkaloids observed in extracts using commercially available standards and compared the inhibitory potential of the extracts to alkaloid standard mixtures using Shh-Light II cells. Alkaloid combinations enhanced Hh signaling pathway antagonism compared to cyclopamine alone, and significant differences were observed in the Hh pathway inhibition between the stem and root/rhizome extracts and their corresponding alkaloid standard mixtures, indicating that additional alkaloids present in these extracts contribute to Hh signaling inhibition.

Angiotensin converting enzyme 2 (ACE2) is a key entry point of SARS-CoV-2 virus known to induce COVID-19. We have recently outlined the concept to reduce ACE2 expression by the administration of glycyrrhizin, a component of Glycyrrhiza glabra extract, via its inhibitory activity on 11beta hydroxysteroid dehydrogenase type 2 (11betaHSD2) and resulting activation of mineralocorticoid receptor (MR). We hypothesized that in organs, such as the intestine, which co-express 11betaHSD2, MR and ACE2, the expression of ACE2 would be suppressed. We studied organ tissues from an experiment originally designed to address the effects of Glycyrrhiza glabra extract on the stress response. Male Sprague Dawley rats were left undisturbed or exposed to chronic mild stress for five weeks. For the last two weeks, animals continued with a placebo diet or received a diet containing extract of Glycyrrhiza glabra root at a dose of 150 mg/kg of body weight/day. Quantitative PCR measurements showed a significant decrease in gene expression of ACE2 in the small intestine of rats fed with diet containing Glycyrrhiza glabra extract. This effect was independent of the stress condition and failed to be observed in non-target tissues, namely the heart and the brain cortex. In the small intestine we confirmed the reduction of ACE2 also at the protein level. Present findings provide first evidence to support the hypothesis that Glycyrrhiza glabra extract may reduce an entry point of SARS-CoV-2. Whether this phenomenon, when confirmed in additional studies, is linked to the susceptibility of cells to the virus requires further studies.

SARS-CoV-2, the causal agent of the globally spreading COVID-19, is capable of infecting variable animals besides human being. We evaluated the potential susceptibility of important livestock, pets and aquatic mammals by performing a multi-species sequence analysis of ACE2 based on the reported affected and unaffected animals. We identified a triple amino acid pattern of ACE2, at position 30, 31 and 34, that might be associated with SARS-CoV-2 infection and H34 might be an indicator of the susceptibility to COVID-19.

Renal artery thrombosis is a sporadic serious clinical condition which potentially cause renal infarction. Diagnosis of renal infarction can be delayed or missed due to non specific clinical presentation and overlapping appearance of medical and surgical phenomena. Early diagnosis supported by biochemical and radiological findings while appropriate management potentially improve morbidity and mortality. Persistent abdominal or flank pain with raised LDH and proteinuria on background of thromboembolism risk factors supports the diagnosis. Despite the rarity of the disease rapid identification with prompt medical or endovascular intervention could prevent irreversible renal parenchymal damage.

Electronic structure calculations have been carried out to examine the effect of protonation and water molecules on the heme group of peroxidases in different redox (ferric, ferrous, compounds I and II) and spin states. Shared geometries, spectroscopic properties at Soret region, and thermodynamics of peroxidases are discussed. B3LYP and M06-2X density functionals with different basis sets were employed on a common molecular model of the active site (Fe-centred porphine and proximal imidazole). Computed Gibbs free energies indicate that the corresponding aquo complexes are not thermodynamically stable, supporting the five-coordinate Fe(III) centre in native ferric peroxidases, with a water molecule located at a non-bonding distance. Protonation of the ferryl oxygen of compound II is discussed in terms of thermodynamics, Fe–O bond distances, and redox properties. It is demonstrated that this protonation is necessary to account for the experimental data and computed Gibbs free energies that reveal pKa values of compound II about 8.5 – 9.0. Computation suggests that the origin of the general oxidative properties of peroxidase species, as well as their reactivity towards water and protons and Soret spectral properties, mostly resides on the iron porphyrin and its proximal ligand histidine.

Purpose: This research aims to model a police agency ordering problem based on criteria that measure the performance of operational and logistical variables, using a multicriteria method. Design/methodology/approach: The multicriteria method PROMETHEE II was used, which with the aid of the Visual PROMETHEE software, emulated the systematized data in the impact matrix and produced the final ordering of the most efficient police agencies in equalizing the operational, logistical, financial, and human resources applied in the combating crime and reducing criminal indices. Findings: The results confirmed that the resources made available to police agencies located in different municipalities in the metropolitan region of the state of Rio de Janeiro are better applied by managers compared to police units in the capital of Rio de Janeiro. Research limitations/implications: As implications of the research, it can be inferred that the use of multicriteria methods in modelling problems in ​​public security can contribute to the rationalization of the use of available resources to fight crime in large cities. Research has shown that it is possible to use the multicriteria methodology in ordering police agencies that best equalize the available resources. Practical implications: The practical impact of this research lies in optimizing the resources available to law enforcement agencies in the fight against crime in general. Social implications: The results can influence the decision making of the local government in the allocation of resources, as well as offering sectors of the economy information relevant to local development. Originality/value: The results of the MCDA analysis can be used to help police agencies in Rio de Janeiro, Brazil to be more efficient. In addition, the application of MCDA can be a new approach to measuring the efficiency of police services.

Mitochondria play key roles in cellular energy metabolism in eukaryotes. Mitochondria of most organisms contain their own genome and specific transcription and translation machineries. The expression of angiosperm mtDNA involves extensive RNA-processing steps, such as RNA trimming, editing, and the splicing of numerous group II-type introns. Pentatricopeptide repeat (PPR) proteins are key players of plant organelle gene expression and RNA metabolism. In the present analysis, we reveal the function of the MITOCHONDRIAL SPLICING FACTOR 2 gene (MISF2, AT3G22670) and show that it encodes a mitochondria-localized PPR protein that is crucial for early embryo-development in Arabidopsis. Molecular characterization of embryo-rescued misf2 plantlets indicates that the splicing of nad2 intron 1 and thus respiratory complex I biogenesis are strongly compromised. Moreover, the molecular function seems conserved between MISF2 protein in Arabidopsis and its orthologous gene (EMP10) in maize, suggesting that the ancestor of MISF2/EMP10 was recruited to function in nad2 processing before the monocot-dicot divergence, ~200 million years ago. These data provide new insights into the function of nuclear-encoded factors in mitochondrial gene expression and respiratory chain biogenesis during plant embryo development.

Copper is a heavy metal used in many industries and known for its negative impacts on the environment and human’s health. A novel structured metal organic framework (MOF) was used for copper adsorption for this work. SEM, EDAX, XRD and FTIR were done to confirm the structure of MOF prepared. MOF of 0.05 gm was used to examine its ability in Cu+ 2 removals with different initial concentrations of Cu+2 and pH values (5, 7 and 9). The prepared MOF was able to achieve Cu removal with 94.6%, 93%, 91.5%, and 92.5 % for the initial concentrations of 5, 10, 15, and 20 ppm respectively. It also performed very well for pH 5 and 7 with average removal ranging from 93.9%-95% for pH 5 and 7 for the initial concentrations of 5, 10, and 15 respectively which indicate that the prepared MOF is of high ability in Cu+ 2 removal.

This study presents a novel technique utilizing high frequency vibration to shorten treatment time and preserve alveolar bone in challenging orthodontic cases treated with Invisalign® clear aligners. Four non-growing orthodontic patients (age range 14-47 years old) with Class II skeletal patterns (convex profiles with retrognathic mandibles) who sought correction of their crowded teeth and non-surgical correction of their convex profiles were included in this study. These patients were treated using Invisalign clear aligners together with high frequency vibration (HFV) devices (120 Hz) (VPro5™) that were used by all patients for five minutes per day during active orthodontic treatment. Vertical control and forward rotation of the mandible for each patient was achieved through pre-programming the Invisalign to produce posterior teeth intrusion. Successful forward rotation of the mandibles achieved in all patients led to improvement of their facial convex profiles (ANB improved 2.1 + 0.5 degrees; FMA improved 1.2 +1.1 degrees). Dental decompensation was achieved by lingual tipping of the lower incisors and palatal root torque of upper incisors. The use of HFV together with Invisalign facilitated achieving these results within a 12+6 month period. In addition, more bone labial to the lower incisors after their lingual movement was noted. In conclusion, the use of HFV concurrent with SmartTrack Invisalign aligners allowed complex tooth movement and forward projection without surgery in non-growing patients with skeletal Class II relationships. The clinical impact and implications of this case series is that the use of HFV facilitates complex orthodontic tooth movement including posterior teeth intrusion and incisor decompensation in addition to increased bone formation labial to lower incisors that may minimize future gum recession due to their labial inclination.

Industry 4.0 is having a great impact in all smart efforts. This is not a single product, but is composed of several technologies, being one of them Industrial Internet of Things (IIoT). Currently, there are very varied implementation options offered by several companies, and this imposes a new challenge to companies that want to implement IoT in their processes. This challenge suggests to use multi-criteria analysis to make a repeatable and justified decision, requiring a set of alternatives and criteria. This paper proposes a new methodology and comprehensive criteria to help organizations to take an educated decision by applying multi-criteria analysis. Here, we suggest a new original use of PROMETHEE-II with full example from weight calculation up to IoT platform selection, showing this methodology as an effective study for other organizations interested to select an IoT platform. The criteria proposed outstands from previous work by including not only technical aspects, but economic and social criteria, providing a full view of the problem analyzed. A case of study was used to prove this proposed methodology.

Novel collector lead(II)-benzohydroxamic acid (Pb(II)-BHA) complexes in aqueous solution were characterized by using experimental approaches, including Ultraviolet-visible (UV-Vis) spectroscopy and electrospray ionization–mass spectrometry (ESI-MS), as well as first-principle density functional theory (DFT) calculations with consideration for solvation effects. The Job plot delineated that a single coordinated Pb(BHA)⁺ should be formed first, and the higher coordination number complexes can be formed subsequently. Moreover, the Pb(II)-BHA species can aggregate with each other to form complicated structures, such as Pb(BHA)₂ or highly complicated complexes. ESI-MS results validated the existence of Pb-(BHA)_n=1,2 under different solution pH values. Further, the first-principles calculations suggested that Pb(BHA)⁺ should be the most stable structure, and the Pb atom in Pb(BHA)⁺ will act as an active site to attack nucleophiles. These findings are meaningful to further illustrate the adsorption mechanism of Pb(II)-BHA complexes in mineral processing.

SARS-CoV-2 causes severe pneumonia epidemics and probably originated in horseshoe bats, but the intermediate host is unknown. The interaction of SARS-CoV-2 spike protein and its acceptor protein ACE2 is an important issue in determining viral host range and cross-species infection, while the binding capacity of Spike protein to ACE2 of different species is unknown. Here, we used the atomic structure model of SARS-CoV-2 and human ACE2 to assess the receptor utilization capacity of ACE2s from different species including cats, chimpanzees, dogs, cattles. Our results show, domestic cats (Felis catusc) and dogs (Canis lupus familiaris) are more susceptible to infection by SARS-CoV-2 and that they can efficiently transmit the virus to previously uninfected animals that are housed with them. Especially, cats could be a choice of animal model for screening antiviral drugs or vaccine candidates against SARS-CoV-2.

Background: Cardiomyopathy is commonly observed disease that may occurs due to mutations in either susceptible genes or modifier gene. People with broad age group are affected either attributable to spontaneous or inherited mutations of these genes. Various gene mutations are reported so far but only few of them were studied in detail. Methods: In the current study, we evaluated epidemiological variables like age, sex, familial status, parental consanguinity. We also described specific clinical symptoms associated with the cardiomyopathy condition in Indian population. Results: Our studies on mutation screening of phospholamban gene revealed two transitions (4880 C/T, 4887 T/G) in 5’ flanking region which might cause inherited dilated cardiomyopathy with refractory congestive heart failure are We further deliberated the gene polymorphism of renin angiotensin system gene angiotensin-1-converting enzyme as an associated marker/ modifier in cardiomyopathy patients and their family members. Conclusions: Information on epidemiological, clinical statistics, phospholamban gene mutation analysis and angiotensin-1-converting enzyme gene polymorphism is essential to guide the successful execution for future therapies and benefits us to identify those patients at risk for faster disease progression, congestive heart failure, and arrhythmia.

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the chief concern of the international community in almost no time. As of May 9th, 2021, more than 150 million cases and 3.2 million deaths have been recorded. Considering the early struggle in treating COVID-19 patients, the researchers and clinicians have decided to try the previously available drugs according to their mechanisms of action. Hence, many antivirals, antibiotics, antiparasitics, and antipyretics have been proposed. Pregnant women, fetuses, and infants are known high-risk populations that are threatened during disease outbreaks. Therefore, this article reviews the safety of potential drugs for COVID-19 patients during pregnancy and breastfeeding.

Using optical characterization, it is evident that the spin state of the spin crossover molecular complex [Fe{H2B(pz)2}2(bipy)] (pz = tris (pyrazol-1-1y)-borohydride, bipy = 2,2’-bipyridine) depends on the ferroelectric polarization of an adjacent thin film of the polymer ferroelectric polyvinylidene fluoride-hexafluoropropylene (PVDF-HFP). The UV-Vis spectroscopy reveals that room temperature switching of [Fe{H2B(pz)2}2(bipy)] molecules in bilayers of PVDF-HFP/[Fe{H2B(pz)2}2(bipy)] as a function of ferroelectric polar polarization. The electric polarity dependence of bilayers of PVDF-HFP/[Fe{H2B(pz)2}2(bipy)] shows a strong dependence on the thickness of the PVDF-HFP layer. The PVDF-HFP/[Fe{H2B(pz)2}2(bipy)] interface may affect polarization retention in the PVDF-HFP thin film limit.

Background: Comorbidities have been frequently reported in COVID-19 patients, which often lead to more severe outcomes. The underlying molecular mechanisms behind these clinical observations have not yet been explained. Herein, we investigated the disease-specific gene expression signatures that may induce susceptibility to SARS-CoV-2 infection. Methods: We studied 30 frequently occurring acute, chronic, or infectious diseases of recent times that have shown comorbidity in one or another respiratory disease(s) caused by pathogenic human infecting coronaviruses, especially SARS-CoV-2. We retrieved array-based gene expression data for each disease and control from relevant datasets. Subsequently, all the datasets were quantile normalized, and log-2 transformed data was used for analysis. Results The expression of ACE2 receptor and host proteases, namely FURIN and TMPRSS2 that are essential for cellular entry of SARS-CoV-2, was upregulated in all six studied subtypes of leukemia (hereafter, referred as leukemia). The expression of ACE2 was also increased in psoriasis, lung cancer, Non-alcoholic fatty liver disease (NAFLD), breast cancer, and pulmonary arterial hypertension patients. The expression of FURIN was higher in psoriasis, NAFLD, lung cancer, and in type II diabetic liver, whereas it was lowered in breast cancer. Similarly, the expression of TMPRSS2 was increased during lung cancer and type II diabetes; it was decreased during psoriasis, NAFLD, lung cancer, breast cancer, and cervical cancer.Furthermore, a heightened expression of genes that are involved in immune response was observed in leukemia patients, as shown by the higher expression of IFNA2, IFNA8, IFNA10, IFNA14, IFNA16, IFNA21, IFNB1, CXCL10, and IL6. The expression of JAK1, STAT1, IL6, and CXCL10 was higher in NAFLD. Besides, JAK1 and STAT1 were upregulated in type II diabetic muscles. In addition, most of the upregulated genes in COVID-19 patients showed a similar trend in leukemia, NAFLD, and psoriasis. Furthermore, SARS-CoV-2, SARS-CoV and MERS CoV, were found to commonly alter two genes, namely, CARBONIC ANHYDRASE 11 and CLUSTERIN.Conclusions: The genes that may confer susceptibility to SARS-CoV-2 infection are mostly upregulated in leukemia patients; hence, leukemia patients are relatively more susceptible to develop COVID-19, followed by other chronic disorders, such as, NAFLD, type II diabetes, psoriasis, and hypertension. This study identifies key genes that are altered in the studied diseases types, which may aid in the infection of SARS-CoV-2 and underlie COVID-19 associated comorbidities.

Breast cancer (BC) is among the leading causes of mortality from cancer in women. Many of the available anticancer drugs have various side effects. Therefore, researchers are seeking novel anticancer agents particularly from natural compounds and in this regard, snake venom is still one of the main sources of drug discovery. Previous studies showed potential anticancer effects of Cytotoxin II (CTII) from Naja naja oxiana against the different types of cancers. In this study, a pET-SUMO-CTII vector was transformed into SHuffle® T7 Express, an Escherichia coli strain, for recombinant protein expression (rCTII) and the cytotoxic effects of this protein was assessed in MCF-7 cells. The flow cytometry assay was applied to measure the apoptosis and cell cycle. Also, mRNA levels of the Bax, Bcl2, P53, caspase-3, caspase-8, caspase-9, caspase-10, matrix metalloproteinases (MMP)-3, and MMP-9 were analyzed by quantitative real-time PCR to determine the underlying cellular pathways affected by rCTII. The results of this study showed that treatment with 4 µg mL-1 of rCTII enhanced apoptosis through the intrinsic and extrinsic pathways. Also, the increase of the cells' proportion in the sub-G1 phase as well as a reduction in S phase was observed. In addition, the expression of MMP-3 and MMP-9 was decreased in the treated group in comparison to the control group that may contribute to the reduced migratory ability of tumor cells. These experimental results indicate that rCTII has anti-proliferative potential, and so this protein could be a potential drug for BC therapy in combination with other drugs.

Abstract: This study reviewed aspects of the biology of two members of the glucosinolate family, namely sinigrin and glucoraphanin and their anti-tumour and anti-microbial properties. Sinigrin and glucoraphanin are converted by the β-sulphoglucosidase myrosinase or the gut microbiota into their bioactive forms, allyl isothiocyanate (AITC) and sulphoraphanin (SFN) which constitute part of a sophisticated defence system plants developed over several hundred million years of evolution to protect them from parasitic attack from aphids, ticks, bacteria or nematodes. Delivery of these components from consumption of cruciferous vegetables rich in the glucosinolates also delivers many other members of the glucosinolate family so the dietary AITCs and SFN do not act in isolation. In-vitro experiments with purified AITC and SFN have demonstrated their therapeutic utility as antimicrobials against a range of clinically important bacteria and fungi. AITC and SFN are as potent as Vancomycin in the treatment of bacteria listed by the World Health Organisation as antibiotic-resistant "priority pathogens" and also act as anti- cancer agents through the induction of phase II antioxidant enzymes which inactivate potential carcinogens. Glucosinolates may be useful in the treatment of biofilms formed on medical implants and catheters by problematic pathogenic bacteria such as Pseudomonas aeruginosa and Staphylococcus aureus and are potent antimicrobials against a range of clinically important bacteria and fungi. The glucosinolates have also been applied in the prevention of bacterial and fungal spoilage of food products in advanced atmospheric packaging technology which improves the shelf-life of these products.

The bark of Rhus verniciflua Stokes (RVS) is used as a food additive and herbal medicine for various inflammatory disorders and cancer in Eastern Asia. RVS exerted anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, but whether this effect occurs in macrophages after oral administration has not been determined. We used a thioglycollate-induced peritonitis model to obtain macrophages from mice given RVS. We examined the systemic inflammatory response to intraperitoneal LPS. RVS-treated mice had an increased population of peritoneal exudate cells expressing CD11b and SRA. Increased uptake of Alexa Fluor 488-labeled acetylated lipoprotein was observed in monocyte-derived macrophages from RVS-treated mice. When these cells from the RVS group were stimulated with LPS, the levels of tumor necrosis factor (TNF)- and interleukin (IL)-6 in the supernatant decreased, but the level of IL-12 increased. The surface expression of CD86 was reduced, but surface expression of class II MHC molecules was increased. RVS suppressed the serum levels of LPS-induced TNF- and IL-6. RVS enhanced monocyte differentiation in thioglycollate-induced peritonitis by increasing scavenger receptor expression and activity. Macrophages isolated from mice given RVS responded differently to LPS. These findings demonstrate that RVS confers selective anti-inflammatory activity without causing the overall inhibitory effects on immune cells.

Prompt removal of misfolded membrane proteins and misassembled membrane protein complexes is essential for membrane homeostasis. However, the elimination of these toxic proteins from the hydrophobic membrane environment has high energetic barriers. Transmembrane FtsH is the only known ATP-dependent protease responsible for this task, unlike other well-studied soluble ATP-dependent proteases. The mechanisms by which FtsH recognizes, unfolds, translocates, and proteolyzes its substrates remain unclear. Here, we report the crystal structures of the Thermotoga maritima FtsH periplasmic domain (PD) in an associative trimeric state at a 1.5-1.95 Å resolution. We also describe the pH-dependent oligomerization states of the isolated PD using dynamic light scattering. These observations help us understand how FtsH recognizes membrane-anchored misfolded proteins.

Optimizing the NACA0015 airfoil which is widely applied in small-scale vertical axis wind turbine to make it has a better aerodynamic performance. In the optimization process, using CST parameterization method to perturb the airfoil geometry, the thickness and camber of the airfoil are selected as the constraint, and the value of the maximum tangential force coefficient is chosen as the objective function, the genetic algorithm based on non-dominated sorting (NSGA-II)is selected as an optimization method, calculates the aerodynamic performance of the airfoil by applying the approach of combining XFOIL program and Viterna-Corrigan post-stall mode ,and establishes the optimizing process by the optimization software modefrontier for NACA0015 airfoil’s muti-point optimization, validate the airfoil’s performance with CFD finally. The result illustrates that, by comparing with the NACA0015 airfoil, the optimized airfoil’s lift to drag ratio is improved over a wide range of attack angles, the stall performance is more gentle. The maximum lift coefficient, the maximum lift-drag ratio and the maximum tangential force coefficient are increased by 7.5%,9 and 8.87%, respectively. The optimized airfoil has a wide variable condition performance, more suitable for the operating conditions of a vertical axis wind turbine. Finally, predict the rotor efficiency with optimized airfoil and NACA0015 airfoil for different tip speed ratios and different solidities with multiple streamtube model, the result shows the rotor with optimized airfoil has a higher efficiency.

The article describes how atherosclerosis and coronavirus disease 19 (COVID-19) may affect each other. The features of this comorbid pathogenesis at various levels (vascular, cellular and molecular) are considered. A bidirectional influence of these conditions is described: the presence of cardiovascular diseases affects different individual susceptibility to viral infection. In turn, SARS-CoV-2 can have a negative effect on the endothelium and cardiomyocytes, causing blood clotting, secretion of pro-inflammatory cytokines, and thus exacerbating the development of atherosclerosis. In addition to the established entry into cells via ACE2 принимая во внимание его влияние на, other mechanisms of SARS-CoV-2 entry are currently under investigation, for example, through CD147. Pathogenesis of comorbidity can be determined by the influence of the virus on various links which are meaningful for atherogenesis: generation of oxidized forms of LDL, launch of a cytokine storm, damage to the endothelial glycocalyx, and mitochondrial injury. The transformation of a stable plaque into an unstable one plays an important role in the pathogenesis of atherosclerosis complications and can be triggered by COVID-19. The impact of SARS-CoV-2 on large vessels such as aorta is more complex than previously thought considering its impact on vasa vasorum. Current information on the mutual influence of the medicines used in the treatment of atherosclerosis and acute COVID-19 is briefly summarized

A growing number of studies suggest that SARS-CoV-2 could interfere with homeostatic mechanisms in the lung but the implications of this possible interference have not been fully explored in the literature. In this work, we examine the consequences that can be drawn from this hypothesis according to currently available knowledge. We suggest that one such consequence is the potential disruption of normal ventilation and perfusion of lung regions that may be distant from the infection sites. Loss of ventilation might result in local alveolar hypoxia and contribute to hypoxemia, which in turn could trigger homeostatic responses that enhance blood oxygenation by redistributing pulmonary blood circulation. Sudden changes in perfusion might then lead to the development of hydrostatic edema and eventually to vascular remodeling and inflammation. Therefore, the immune response might not be the only source of the substantial inflammation observed in lung tissues of patients with severe COVID-19, as is often assumed in the literature. The balance between the homeostatic and the immune reaction in each patient could account for the observed heterogeneity of the clinical manifestations of COVID-19.

The article concerns a relatively small but important fragment of John Paul II's pastoral activity, namely his pilgrimages to Poland: the nature of these pilgrimages, their historical background and teaching - especially to the extent that went beyond the immediate and Polish context. The text is the result not only of reading papal statements, but also of personal observation of the political and social atmosphere. The first two parts contain a concise description of the Pope's eight pilgrimages to Poland (before and after the political transformation). The third highlights out the main universal themes raised by the Pope: the dignity of the person, truth and freedom. During consecutive pilgrimages to Poland, he deepened and expanded the themes of his teaching. This collection of his sermons and speeches to Poles constitutes a comprehensive (devoid of redundant repetitions and omissions) treatment of important social, philosophical and theological issues. John Paul II, when speaking to Poles and about Poles, did not lose his universal perspective; he appealed both to Christians and to all people of good will. Papal pilgrimages to Poland are a significant part of modern Polish history, and their message is a valuable intellectual and spiritual gift.

Nitrogen and phosphorous support the ecosystem by supplying nutrients to algae and aquatic plants. Having them in excess results in the eutrophication of waters creating quality problems. In the past, nitrogen has been widely investigated for wells in the context of groundwater flow. However, a national-scale nitrogen assessment in rivers and streams has not received enough attention. In this research, the Wilcoxon rank sum test, as a non-parametric hypothesis testing method, has been applied to nitrogen concentration in the form of nitrate-nitrogen and nitrite-nitrogen in rivers and streams of the Contiguous United States. This approach was particularly selected because of the non-normal and positively skewed nitrogen levels occurring in the surface flow. This method was able to identify the impaired body of waters as well as quantify the confidence, significance, and errors involved. The Northern Appalachians (NAP), Northern Plains (NPL), and Xeric (XER) ecoregions were worsening in the nitrogen-nitrate condition with NAP, and XER needed immediate actions. The nitrite-nitrogen condition did not pose an immediate threat, so mitigation plans should focus more on nitrate-nitrogen remediation. It was shown that the method was superior to the two-sample t-test by yielding lower type II errors.

There is limited data on pregnancy outcomes in Pompe Disease (PD) resulting from deficiency of the lysosomal enzyme acid alpha-glucosidase. Late-onset PD is characterized by progressive proximal muscle weakness and decline of respiratory function secondary to the involvement of the respiratory muscles. In a cohort of twenty-five females, the effects of both PD on the course of pregnancy and the effects of pregnancy on PD were investigated. Reproductive history, course of pregnancy, use of Enzyme replacement therapy (ERT), PD symptoms, and outcomes of each pregnancy were obtained through a questionnaire. Among 20 subjects that reported one or more pregnancies, one subject conceived while on ERT and continued therapy through two normal pregnancies with worsening of weakness during pregnancy and improvement postpartum. While fertility was not affected, pregnancy may worsen symptoms, or cause initial symptoms to arise. Complications with pregnancy or birth were not higher, except for an increase in the rate of stillbirths (3.8% compared to the national average of 0.2-0.7%). Given small sample size and possible bias of respondents being only women who have been pregnant, further data may be needed to better analyze the effects of pregnancy on PD, and the effects of ERT on pregnancy outcomes.

The food distribution process is responsible for significant quality loss in perishable products. However, preserving quality is costly and consumes a tremendous amount of energy. To tackle the challenge of minimizing transportation costs and CO2 emissions while also maximizing product freshness, a novel multi-objective model is proposed. The model integrates a vehicle routing problem with temperature, shelf life, and energy consumption prediction models, thereby enhancing its accuracy. Non-dominated sorting genetic algorithm II is adapted to solve the proposed model for the set of Solomon test data. The conflicting nature of these objectives and the sensitivity of the model to shelf life and shipping container temperature settings are analyzed. The results show that optimizing freshness objective degrade the cost and the emission objectives, and the distribution of perishable foods are sensible to the shelf life of the perishable foods and temperature settings inside the container.

Post-translational modifications (PTMs) of histone residues shape the landscape of gene expression by modulating the dynamic process of RNAPII transcription. The contribution of particular histone modifications to the definition of distinct RNAPII transcription stages remains poorly characterized in plants. Chromatin Immuno-precipitation combined with next-generation sequencing (ChIP-seq) resolves the genomic distribution of histone modifications. Here, we review histone PTM ChIP-seq data in Arabidopsis thaliana and find support for a Genomic Positioning System (GPS) that guides RNAPII transcription. We review the roles of histone PTM “readers”, “writers” and “erasers”, with a focus on the regulation of gene expression and biological functions in plants. The distinct functions of RNAPII transcription during the plant transcription cycle may in part rely on the characteristic histone PTMs profiles that distinguish transcription stages.

The current report contributes to the understanding of the stereoselectivity of the chiral dirhodium(II) carboxylate catalysts derived from N-protected amino acid ligands. Investigating the possible effect of ligand stereo-purity on catalyst structure and enantioselectivity was carried out. This was justified through a new X-ray crystal structure for Rh2(S,S,S,R-PTTL)4 diastereomer.

The core of risk aggregation in the Solvency II Standard Formula is the so-called square root formula. We argue that it should be seen as a means for the aggregation of different risks to an overall risk rather than being associated with variance-covariance based risk analysis. Considering the Solvency II Standard Formula from the viewpoint of linear geometry, we immediately find that it defines a norm and therefore provides a homogeneous and sub-additive tool for risk aggregation. Hence Euler's Principle for the reallocation of risk capital applies and yields explicit formulas for capital allocation in the framework given by the Solvency II Standard Formula. This gives rise to the definition of diversification functions, which we define as monotone, subadditive, and homogeneous functions on a convex cone. Diversification functions constitute a class of models for the study of the aggregation of risk, and diversification. The aggregation of risk measures using a diversification function preserves the respective properties of these risk measures. Examples of diversification functions are given by seminorms, which are monotone on the convex cone of non-negative vectors. Each L^p norm has this property, and any scalar product given by a non-negative positive semidefinite matrix does as well. In particular, the Standard Formula is a diversification function and hence a risk measure that preserves homogeneity, subadditivity, and convexity.

A recent report from the American Heart Association in 2018 shows that over 103 million American adults have hypertension. The angiotensin-converting enzyme (ACE) (EC 3.4.15.1) is a dipeptidyl carboxylase that, when inhibited, can reduce blood pressure through the renin-angiotensin system. ACE inhibitors are used as a first-line medication to be prescribed to treat hypertension, chronic kidney disease, heart failure among others. It has been suggested that ACE inhibitors can reduce the symptoms in mouse models. Despite the benefits of ACE inhibitors, previous studies also have suggested that alterations in the ACE gene are risk factors for Alzheimer’s disease (AD) and other neurological diseases. In mice, overexpression of ACE in the brain reduces symptoms of the AD-model systems. Thus, we find opposing effects of ACE on health. To clarify the effects, we dissect the functions of ACE as follows: (1) angiotensin-converting enzyme that hydrolyzes angiotensin I to make angiotensin II in the renin-angiotensin system; (2) amyloid-degrading enzyme that can hydrolyze beta-amyloid and reduce amyloid toxicity. The efficacy of the ACE inhibitors is well established in humans, while the knowledge specific to AD remains to be open for further research. We provide an overview of ACE and inhibitors that link a wide variety of age-related comorbidities from hypertension to Alzheimer’s disease to aging. ACE also serves as an example of the middle-life crisis theory that assumes deleterious events during the midlife, leading to age-related later events.

Coronavirus disease (COVID-19) is a new discovered strain where WHO officially declares the disease as COVID-19 while the virus responsible for it called Severe Acute Respiratory Syndrome Coronavirus 2 or SARS-CoV-2. The incubation period of this disease is between 14 days. Ordinary clinical symptoms that reported around the world include fever, cough, fatigue, diarrhoea and vomiting as well as asymptomatic for certain people. Infection is spread mainly through broad droplets. In early March 2020, WHO again has announced that COVID-19 is a pandemic with currently no specific treatment. The potential use of SARS-COV-2 proteome as a vaccine candidate by analysing through B-cell and T-cell antigenicity by using a immunoinformatics approach as a vaccine development early stage. In this study, we used consensus sequence for SARS-COV-2 proteome that was retrieved from NCBI database. VaxiJen 2.0 was mainly used to identify the antigenic property of SARS-COV-2 proteins. IEDB then used to analyse the B-cell epitope, the presence of T cell immunogenic epitope in SARS-COV-2 proteins was obtained by using compromise method of MHC class I and II tools that accessible respectively using ProPred-1 server and MHC II Binding Prediction in IEDB database. The best epitopes of B and T-cell epitopes were predicted with high antigencity and the information is disseminated through web-based database resource (https://covid-19.omicstutorials.com/epitopes/). This study will be useful to find a new epitope-based candidate for SARS-COV-2. However, further study needs to be done for the next stages of vaccine development.

Aims: Spironolactone is a steroidal mineralocoricosteroid receptor antagonist (MRA) used for treatment of resistant hypertension, heart failure and edema. It exerts class specific adverse effects that are shared by other MRAs. Additionally, it exerts unique “off target” steroidal effects that include gynecomastia, impotence and loss of libido in males and menstrual irregularity in females. Together, these have led to a poor tolerability and limited use despite positive results in many randomized, controlled clinical trials. We review the off-target effects of spironolactone that may summate with its MRA action to provide an advantageous profile for prevention or treatment of patients with COVID-19. Methods: Literature review using PubMed Central. Results: The blockade by spironolactone of the androgen receptor should diminish the expression of transmembrane protease serine 2 (TMPRSS2) that has an androgen promoter while its MRA action should enhance the expression of protease nexin1 (PN1) that inhibits furin and plasmin. TMPRSS2, furin and plasmin cooperated to process the SARS-CoV-2 spike protein to increase its high affinity binding to the angiotensin converting enzyme 2 (ACE2) and thereby promote viral cell entry. Its actions as an MRA may reduce inflammation and preserve pulmonary, cardiac and vascular functions. Its anti-plasmin action may combat hemostatic dysfunction. Conclusion: The hypothesis that the off-target effects of spironolactone summate with its MRA actions to provide special benefits for COVID-19 is worthy of direct investigation and clinical trial.

Understanding how the coronaviruses invade our body is an essential point, and the expression profile of coronaviruses receptor may help us to find where the coronavirus infects our body. We found that the coronavirus receptors, including angiotensin-converting enzyme 2 (ACE2) for SARS-CoV and SARS-Cov-2, are digestion-related enzymes in human enterocytes. Coronaviruses are continually altering the binding receptor and binding modes during their evolution, but the potential target cell in the small intestine is constant when in the lung is inconstant. Enterocytes may act as a conserved cell reservoir for coronaviruses, which may be partially explained by the Red Queen hypothesis. We also found that coronaviruses receptors could be elevated in the presence of both invasive bacteria and their counterpart, probiotics. We demonstrated here that enterocytes act as a conserved cell reservoir for coronaviruses during their evolutions, which should not be ignored in the investigation of coronavirus diagnosis and treatment strategies.

Influenza virus transcription is catalyzed by the viral RNA-polymerase (FluPol) through a cap-snatching activity. The snatching of the cap of cellular mRNA by FluPol is preceded by its binding to the flexible C-terminal domain (CTD) of the RPB1 subunit of RNA-polymerase II (Pol II). To better understand how FluPol brings the 3’-end of the genomic RNAs in close proximity to the host-derived primer, we hypothesized that FluPol may recognize additional Pol II subunits/domains to ensure cap-snatching. Using binary complementation assays between the Pol II and FluPol subunits and their structural domains, we revealed an interaction between the N-third domain of PB2 and RPB4. This interaction was confirmed by a co-immunoprecipitation assay and found to occur with the homologous domains of influenza B and C FluPols. Residues [1-72] of RPB4 were found critical in this interaction. Numerous punctual mutants generated at conserved positions between influenza A, B and C FluPols in the N-third domain of PB2 exhibited strong transcriptional activity defect. These results suggest that FluPol interacts with several domains/subunits of Pol II, the CTD to bind Pol II initiating host transcription and a second on RPB4 to locate FluPol at the proximity of the 5’-end of nascent host mRNA.

In many practical applications, it is more convenient to characterize the quality of production processes or service operations throughout the count of nonconformities. In the context of SPC, nonconformities are usually assumed to appear according to the binomial probability model. The conventional way for monitoring nonconformities involves Shewhart-type control procedures based on both constant and time-varying sample sizes. In this article, an EWMA scheme is proposed for monitoring the fraction of nonconforming items with time-varying sample sizes. The proposed control chart is referred to as the EWMAG-B and can be easily adapted to work with a constant sample size by fixing it at a needed value. By means of simulation, it was found out that the EWMAG-B chart outperforms the conventional p control chart in Phase II while detecting changes in the process level is wanted.

The present work evaluates the food effect on the absorption of rivaroxaban (Riva), a BCS II drug, from the orally administered commercial immediate-release tablet (Xarelto IR) using physiologically based pharmacokinetic (PBPK) and conventional in vitro- in vivo correlation (IVIVC) models. The bioavailability of Riva upon oral administration of Xarelto IR tablet is reported to exhibit a positive food effect. The PBPK model for Riva was developed and verified using the previously reported in vivo data for oral solution (5 and 10 mg) and Xarelto IR tablet (5 and 10 mg dose strength). Once the PBPK model was established, the in vivo performance of the tablet formulation with the higher dose strength (Xarelto IR tablet 20 mg in fasted and fed state) was predicted using the experimentally obtained data of in vitro permeability, biorelevant solubility and in vitro dynamic dissolution data using United States Pharmacopeia (USP) IV flow-through cell apparatus. In addition, the mathematical IVIVC model was developed using the in vitro dissolution and in vivo profile of 20 mg strength Xarelto IR tablet in fasted condition. Using the developed IVIVC model, the pharmacokinetic (PK) profile of the Xarelto IR tablet in fed condition was predicted and compared with the PK parameters obtained via the PBPK model. A virtual in vivo PK study was designed using a single-dose, 3-treatment cross-over trial in 50 subjects to predict the PK profile of the Xarelto® IR tablet in the fed state. Overall, the results obtained from the IVIVC model were found to be comparable with that from the PBPK model. The outcome from both the model pointed to the positive food effect on the in vivo profile of the Riva. The developed models thus can be effectively extended to establish bioequivalence for the marketed and novel complex formulations of Riva such as amorphous solid dispersions.

Nonparametric assessments of police technical and scale efficiency is challenging because of the stochastic nature of criminal behavior and because of the subjective dependence on multiple decision criteria, which can lead to a more or less efficiency prospect depending on the regulation, necessity, or organizational objective. There is a trade-off between efficiency and effectiveness in many police performance assessments, i.e., efficient departments (producing more clear-ups with a given resource) are crime-specialized or cannot reproduce those good results effectively on more severe or complex occurrences. This study proposes a combined methodology for carrying out efficiency and effectiveness analysis of Police departments. A conditional non-parametric approach, which allows to include crime as an external factor in the analysis, is combined with a non-compensatory ranking based on the PROMETHEE II methodology for the approach illustrated on the multidimensional efficiency and effectiveness comparison of 145 Pernambuco (Brazil)'s police departments. The application results offer compelling perspectives for public administrations concerning the strategic prioritization of units for rewards or interventions.

1) Background: Climate change may subject forests to climate conditions to which they are not adapted. Elevated temperatures reduce net photosynthesis by increasing respiration rates and increasingly long droughts dramatically increase morbidity. CO₂ enrichment enhances productivity, but it is not clear to what extent CO₂ enrichment can offset the negative effects of elevated temperatures and longer droughts. 2) Methods: We used a mechanistic landscape model to conduct controlled simulation experiments manipulating CO₂ concentration, temperature, drought length and soil water capacity. 3) Results: We found that elevated CO₂ stimulates productivity such that it dwarfs the negative effect caused by elevated temperature. Energy reserves were not as strongly mitigated by elevated CO₂, and mortality of less competitive cohorts increased. Drought length had a surprisingly small effect on productivity measures, but had a marked negative effect on mortality risk. 4) Conclusions: Elevated CO₂ compensated for the negative effect of longer droughts in terms of productivity measures, but not survival measures.

Increasing global concern over COVID-19 has recently brought greater attention to studies due to the ease of person-to-person transmission and the current lack of effective antiviral therapy. Here, we proposed the application of the adverse outcome pathway (AOP) framework to support re-search on the pathogenesis of viral disease. We first constructed adverse outcome pathways (AOPs) applicable to COVID-19 management to understand whether the infection causes severe acute respiratory distress. Based on the AOP framework where mechanistic elucidation of the pathway from the interaction of chemicals (or viruses) to apical endpoints is represented, our COVID-19 AOP indicated that the molecular initiating event (MIE) was angiotensin-converting enzyme 2 (ACE2) interaction, and the key events (KEs) were the increased pro-inflammatory cytokines in immune cells, with increased mortality as an apical adverse outcome (AO). However, there is still limited information on the toxicity mechanisms of AOPs in COVID-19; therefore, detailed KEs and AOs on toxicity mechanisms will be required to fill these gaps in the data. This study demonstrated that the COVID-19 AOP framework is a suitable tool to design new drugs and to integrate crowded-sourced information for the battle against the COVID-19 pandemic.

Background: Multi-drug resistance organisms (MDRO) often cause increased morbidity, mortality, and length of stays (LOS). However, there is uncertainty whether the infection of MDRO increase the morbidity, mortality, and ICU-LOS. Objective: This study performed to determine the prevalence of MDRO in ICU, site of infection and the association of MDRO or site of infection with mortality. Secondary outcome was determined by ascertaining the association of MDRO or site of infection with (ICU-LOS). Methods: A retrospective cohort study was performed with adult sepsis patients in ICU. Univariate and multivariate (MVA) logistic regression with cox regression modeling were performed to compute the association of MDRO on ICU-mortality. MVA modelling was performed for ICU-LOS predictors. Results: Out of 228 patients, the isolated MDRO was 97 (42.5%) of which 78% were gram-negative bacteria. The mortality rate among those with MDRO was 85 (37.3%). The hospital acquired infection (HAI) was significantly predictor for ICU-LOS in univariate linear regression (R² = 0.034, P=0.005). In MVA linear regression, both Enterococcus faecalis infection and acinetobacter baumannii (AC) -MDRO were predictors for ICU-LOS with (R² = 0.478, P<0.05). In the univariate cox regression, only the infection with AC- MDRO was a risk factor for ICU-mortality with [ HR =1.802 (95% CI: 1.2 – 2.706; P = 0.005)]. Conclusions: Identifying risk factors for MDRO highlight the appropriate administration of empirical antibiotics and effectively control of source of infection which would reduce mortality and ICU-LOS. The usage of broad- spectrum antibiotics should be limited for those having substantial risk factors to acquire MDRO.

Abstract Antibacterial activities can be improved using mixed ligands. Mixed ligands involved in this research are sodium sulfadiazine (Na-sfz) and dithiocarbamate (ai-dtc). One-pot synthesis was used to synthesize ligand of aniline dithiocarbamate (ai-dtc) and the corresponding coordination compounds of [VO(sfz)(ai-dtc)] and [Zn(sfz)(ai-dtc)]. Crystals of ai-dtc, which grew from the solution when refrigerated after five days, were diffracted with technique of single crystal x-ray crystallography to reveal the structure. Other characterization techniques involving physicochemical parameters, FT-IR, UV-Vis and NMR (1H NMR and 13C NMR) were carried out on ligands of ai-dtc, sfz and corresponding coordination compounds. Differences in results of FT-IR, UV-Vis and NMR between ligands and their respective metal ions confirmed the coordination. The in vitro antibacterial studies showed that the ligands (not the metal complexes) had modest activity against Gram negative bacteria: Staphylococcus aureus, whereas, the coordination compounds had modest activities against the Gram negative bacteria: Escherichia coli and Pseudomonas aeruginosa.

The X-ray induced spin crossover transition of an Fe(II) molecular thin film in the presence and absence of a magnetic field has been investigated. The thermal activation energy barrier in the soft X-ray activation of the spin crossover transition for [Fe{H2B(pz)2}2(bipy)] molecular thin films is reduced in the presence of an applied magnetic field, as measured through X-ray absorption spectroscopy at various temperatures. The influence of a 1.8 T magnetic field is sufficient to cause deviations from the expected exponential spin state transition behavior that is measured in the field free case. We find that orbital moment diminishes with increasing temperature, relative to the spin moment in the vicinity of room temperature.

We developed two human induced pluripotent stem cell (hiPSC)/human embryonic stem cell-specific glycan-recognizing mouse antibodies, R-10G and R-17F, using the Tic (JCRB1331) hiPSC line as an antigen. R-10G recognizes a low-sulfate keratan sulfate, and R-17F recognizes lacto-N-fucopentaose-1. To evaluate the general characteristics of stem cell glycans, we used the hiPSC line 201B7 (HPS0063), a prototype iPSC line. Using an R-10G affinity column, an R-10G-binding protein was isolated. The protein yielded a single but very broad band from 480 to 1,236 kDa by blue native gel electrophoresis. After trypsin digestion, the protein was identified as podocalyxin by liquid chromatography/mass spectrometry. According to Western blotting, the protein reacted with R-10G and R-17F. The R-10G positive band was resistant to digestion with glycan-degrading enzymes, including peptide N-glycanase, but the intensity of the band was decreased significantly by digestion with keratanase, keratanase II, and endo-β-galactosidase, suggesting the R-10G epitope to be a keratan sulfate. These results suggest that keratan sulfate-type epitopes are shared by hiPSCs. However, the keratan sulfate from 201B7 cells contained a polylactosamine disaccharide unit (Galβ1-4GlcNAc) at a significant frequency, whereas that from Tic cells consisted mostly of keratan sulfate disaccharide units (Galβ1-4GlcNAc(6S)). In addition, the abundance of the R-10G epitope was significantly lower in 201B7 cells than in Tic cells.