bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction of Optimal Conditions of Hydrogenation Reaction Using the Likelihood Ranking Approach
Authors: Afonina Valentina A. , Mazitov Daniyar A. , Nurmukhametova Albina , Shevelev Maxim D. , Khasanova Dina A. , Nugmanov Ramil I. , Burilov Vladimir A. , Madzhidov Timur I. , Varnek Alexandre
Published: December 2021

The selection of experimental conditions leading to a reasonable yield is an important and essential element for the automated development of a synthesis plan and the subsequent synthesis of the target compound. The classical QSPR approach, requiring one-to-one correspondence between chemical structure and a target property, can be used for optimal reaction conditions prediction only on a limited scale when only one condition component (e.g., catalyst or solvent) is considered. However, a particular reaction can proceed under several different conditions. In this paper, we describe the Likelihood Ranking Model representing an artificial neural network that outputs a list of different conditions ranked according to their suitability to a given chemical transformation. Benchmarking calculations demonstrated that our model outperformed some popular approaches to the theoretical assessment of reaction conditions, such as k Nearest Neighbors, and a recurrent artificial neural network performance prediction of condition components (reagents, solvents, catalysts, and temperature). The ability of the Likelihood Ranking model trained on a hydrogenation reactions dataset, (~42,000 reactions) from Reaxys® database, to propose conditions that led to the desired product was validated experimentally on a set of three reactions with rich selectivity issues.
Pathogenesis of Penile Squamous Cell Carcinoma: Molecular Update and Systematic Review
Authors: Ribera-Cortada Inmaculada , Guerrero-Pineda José , Trias Isabel , Veloza Luis , Garcia Adriana , Marimon Lorena , Diaz-Mercedes Sherley , Alamo José Ramon , Rodrigo-Calvo Maria Teresa , Vega Naiara , López del Campo Ricardo , Parra-Medina Rafael , Ajami Tarek , Martínez Antonio , Reig Oscar , Ribal Maria J. , Corral-Molina Juan Manuel , Jares Pedro , Ordi Jaume , Rakislova Natalia
Published: December 2021

Penile squamous cell carcinoma (PSCC) is a rare but aggressive neoplasm with dual pathogenesis (human papillomavirus (HPV)-associated and HPV-independent). The development of targeted treatment is hindered by poor knowledge of the molecular landscape of PSCC. We performed a thorough review of genetic alterations of PSCC focused on somatic mutations and/or copy number alterations. A total of seven articles have been identified which, overall, include 268 PSCC. However, the series are heterogeneous regarding methodologies employed for DNA sequencing and HPV detection together with HPV prevalence, and include, in general, a limited number of cases, which results in markedly different findings. Reported top-ranked mutations involve TP53, CDKN2A, FAT1, NOTCH-1 and PIK3CA. Numerical alterations involve gains in MYC and EGFR, as well as amplifications in HPV integration loci. A few genes including TP53, CDKN2A, PIK3CA and CCND1 harbor both somatic mutations and copy number alterations. Notch, RTK-RAS and Hippo pathways are frequently deregulated. Nevertheless, the relevance of the identified alterations, their role in signaling pathways or their association with HPV status remain elusive. Combined targeting of different pathways might represent a valid therapeutic approach in PSCC. This work calls for large-scale sequencing studies with robust HPV testing to improve the genomic understanding of PSCC.
Histone Modifications and Their Targeting in Lymphoid Malignancies
Authors: Fernández-Serrano Miranda , Winkler René , Santos Juliana C. , Le Pannérer Marguerite-Marie , Buschbeck Marcus , Roué Gaël
Published: December 2021

In a wide range of lymphoid neoplasms, the process of malignant transformation is associated with somatic mutations in B cells that affect the epigenetic machinery. Consequential alterations in histone modifications contribute to disease-specific changes in the transcriptional program. Affected genes commonly play important roles in cell cycle regulation, apoptosis-inducing signal transduction, and DNA damage response, thus facilitating the emergence of malignant traits that impair immune surveillance and favor the emergence of different B-cell lymphoma subtypes. In the last two decades, the field has made a major effort to develop therapies that target these epigenetic alterations. In this review, we discuss which epigenetic alterations occur in B-cell non-Hodgkin lymphoma. Furthermore, we aim to present in a close to comprehensive manner the current state-of-the-art in the preclinical and clinical development of epigenetic drugs. We focus on therapeutic strategies interfering with histone methylation and acetylation as these are most advanced in being deployed from the bench-to-bedside and have the greatest potential to improve the prognosis of lymphoma patients.
Pros and Cons of Pharmacological Manipulation of cGMP-PDEs in the Prevention and Treatment of Breast Cancer
Authors: Di Iorio Patrizia , Ronci Maurizio , Giuliani Patricia , Caciagli Francesco , Ciccarelli Renata , Caruso Vanni , Beggiato Sarah , Zuccarini Mariachiara
Published: December 2021

The cyclic nucleotides, cAMP and cGMP, are ubiquitous second messengers responsible for translating extracellular signals to intracellular biological responses in both normal and tumor cells. When these signals are aberrant or missing, cells may undergo neoplastic transformation or become resistant to chemotherapy. cGMP-hydrolyzing phosphodiesterases (PDEs) are attracting tremendous interest as drug targets for many diseases, including cancer, where they regulate cell growth, apoptosis and sensitization to radio- and chemotherapy. In breast cancer, PDE5 inhibition is associated with increased intracellular cGMP levels, which is responsible for the phosphorylation of PKG and other downstream molecules involved in cell proliferation or apoptosis. In this review, we provide an overview of the most relevant studies regarding the controversial role of PDE inhibitors as off-label adjuvants in cancer therapy.
Relevance of AIF/CypA Lethal Pathway in SH-SY5Y Cells Treated with Staurosporine
Authors: Conte Mariarosaria , Palumbo Rosanna , Monti Alessandra , Fontana Elisabetta , Nebbioso Angela , Ruvo Menotti , Altucci Lucia , Doti Nunzianna
Published: December 2021

The AIF/CypA complex exerts a lethal activity in several rodent models of acute brain injury. Upon formation, it translocates into the nucleus of cells receiving apoptotic stimuli, inducing chromatin condensation, DNA fragmentation, and cell death by a caspase-independent mechanism. Inhibition of this complex in a model of glutamate-induced cell death in HT-22 neuronal cells by an AIF peptide (AIF(370-394)) mimicking the binding site on CypA, restores cell survival and prevents brain injury in neonatal mice undergoing hypoxia-ischemia without apparent toxicity. Here, we explore the effects of the peptide on SH-SY5Y neuroblastoma cells stimulated with staurosporine (STS), a cellular model widely used to study Parkinson’s disease (PD). This will pave the way to understanding the role of the complex and the potential therapeutic efficacy of inhibitors in PD. We find that AIF(370-394) confers resistance to STS-induced apoptosis in SH-SY5Y cells similar to that observed with CypA silencing and that the peptide works on the AIF/CypA translocation pathway and not on caspases activation. These findings suggest that the AIF/CypA complex is a promising target for developing novel therapeutic strategies against PD.
Changes in Polar Metabolites Content during Natural and Methyl-Jasmonate-Promoted Senescence of Ginkgo biloba Leaves
Authors: Horbowicz Marcin , Szablińska-Piernik Joanna , Góraj-Koniarska Justyna , Miyamoto Kensuke , Ueda Junichi , Saniewski Marian
Published: December 2021

The present study clarified changes in the contents of polar metabolites (amino acids, organic acids, saccharides, cyclitols, and phosphoric acid) in leaf senescence in Ginkgo biloba with or without the application of methyl jasmonate (JA-Me) in comparison with those in naturally senescent leaf blades and petioles. The contents of most amino acids and citric and malic acids were significantly higher in abaxially, and that of myo-inositol was lower in abaxially JA-Me-treated leaves than in adaxially JA-Me-treated and naturally senescent leaves. The levels of succinic and fumaric acids in leaves treated adaxially substantially high, but not in naturally senescent leaves. In contrast, sucrose, glucose, and fructose contents were much lower in leaf blades and petioles treated abaxially with JA-Me than those treated adaxially. The levels of these saccharides were also lower compared with those in naturally senescent leaves. Shikimic acid and quinic acid were present at high levels in leaf blades and petioles of G. biloba. In leaves naturally senescent, their levels were higher compared to green leaves. The shikimic acid content was also higher in the organs of naturally yellow leaves than in those treated with JA-Me. These results strongly suggest that JA-Me applied abaxially significantly enhanced processes of primary metabolism during senescence of G. biloba compared with those applied adaxially. The changes in polar metabolites in relation to natural senescence were also discussed.
Pheomelanin Effect on UVB Radiation-Induced Oxidation/Nitration of l-Tyrosine
Authors: Mariano Alessia , Bigioni Irene , Scotto d’Abusco Anna , Baseggio Conrado Alessia , Maina Simonetta , Francioso Antonio , Mosca Luciana , Fontana Mario
Published: December 2021

Pheomelanin is a natural yellow-reddish sulfur-containing pigment derived from tyrosinase-catalyzed oxidation of tyrosine in presence of cysteine. Generally, the formation of melanin pigments is a protective response against the damaging effects of UV radiation in skin. However, pheomelanin, like other photosensitizing substances, can trigger, following exposure to UV radiation, photochemical reactions capable of modifying and damaging cellular components. The photoproperties of this natural pigment have been studied by analyzing pheomelanin effect on oxidation/nitration of tyrosine induced by UVB radiation at different pH values and in presence of iron ions. Photoproperties of pheomelanin can be modulated by various experimental conditions, ranging from the photoprotection to the triggering of potentially damaging photochemical reactions. The study of the photomodification of l-Tyrosine in the presence of the natural pigment pheomelanin has a special relevance, since this tyrosine oxidation/nitration pathway can potentially occur in vivo in tissues exposed to sunlight and play a role in the mechanisms of tissue damage induced by UV radiation.
In Vitro and In Silico Kinetic Studies of Patented 1,7-diEthyl and 1,7-diMethyl Aminoalkanol Derivatives as New Inhibitors of Acetylcholinesterase
Authors: Grodner Błażej , Napiórkowska Mariola , Pisklak Dariusz Maciej
Published: December 2021

Two aminoalkanol derivatives of 1,7-diEthyl-8,9-diphenyl-4azatricyclo (5.2.1.02.6) dec-8-ene-3,5,10-trione and two derivatives of 1,7-diMethyl-8,9-diphenyl-4-azatricyclo (5.2.1.02.6) dec-8-ene-3,5,10-trione were evaluated in vitro for their inhibition efficacy of acetylcholinesterase. The Km, Vmax, slope angles of Lineweaver–Burk plots, Ki and IC50 values showed that all four aminoalkanol derivatives are competitive inhibitors of acetylcholinesterase whose inhibitory potency depends, to a varying extent, on the nature of the four different substituents present in the main compound structure. Studies have shown that the most potent acetylcholinesterase inhibitors are derivatives containing isopropylamine and/or methyl substituents in their structure. In contrast, dimethylamine and/or ethyl substituents seem to have a weaker, albeit visible, effect on the inhibitory potency of acetylcholinesterase. Additionally, docking studies suggest that studied compounds binds with the peripheral anionic site and not enter into the catalytic pocket due to the presence of the sterically extended substituent.
MicroRNA-30b Is Both Necessary and Sufficient for Interleukin-21 Receptor-Mediated Angiogenesis in Experimental Peripheral Arterial Disease
Authors: Wang Tao , Yang Liang , Yuan Mingjie , Farber Charles R. , Spolski Rosanne , Leonard Warren J. , Ganta Vijay C. , Annex Brian H.
Published: December 2021

The interleukin-21 receptor (IL-21R) can be upregulated in endothelial cells (EC) from ischemic muscles in mice following hind-limb ischemia (HLI), an experimental peripheral arterial disease (PAD) model, blocking this ligand–receptor pathway-impaired STAT3 activation, angiogenesis, and perfusion recovery. We sought to identify mRNA and microRNA transcripts that were differentially regulated following HLI, based on the ischemic muscle having intact, or reduced, IL-21/IL21R signaling. In this comparison, 200 mRNAs were differentially expressed but only six microRNA (miR)/miR clusters (and among these only miR-30b) were upregulated in EC isolated from ischemic muscle. Next, myoglobin-overexpressing transgenic (MgTG) C57BL/6 mice examined following HLI and IL-21 overexpression displayed greater angiogenesis, better perfusion recovery, and less tissue necrosis, with increased miR-30b expression. In EC cultured under hypoxia serum starvation, knock-down of miR-30b reduced, while overexpression of miR-30b increased IL-21-mediated EC survival and angiogenesis. In Il21r−/− mice following HLI, miR-30b overexpression vs. control improved perfusion recovery, with a reduction of suppressor of cytokine signaling 3, a miR-30b target and negative regulator of STAT3. Together, miR-30b appears both necessary and sufficient for IL21/IL-21R-mediated angiogenesis and may present a new therapeutic option to treat PAD if the IL21R is not available for activation.
Removal of Persistent Sulfamethoxazole and Carbamazepine from Water by Horseradish Peroxidase Encapsulated into Poly(Vinyl Chloride) Electrospun Fibers
Authors: Zdarta Jakub , Degórska Oliwia , Jankowska Katarzyna , Rybarczyk Agnieszka , Piasecki Adam , Ciesielczyk Filip , Jesionowski Teofil
Published: December 2021

Enzymatic conversion of pharmaceutically active ingredients (API), using immobilized enzymes should be considered as a promising industrial tool due to improved reusability and stability of the biocatalysts at harsh process conditions. Therefore, in this study horseradish peroxidase was immobilized into sodium alginate capsules and then trapped into poly(vinyl chloride) electrospun fibers to provide additional enzyme stabilization and protection against the negative effect of harsh process conditions. Due to encapsulation immobilization, 100% of immobilization yield was achieved leading to loading of 25 μg of enzyme in 1 mg of the support. Immobilized in such a way, enzyme showed over 80% activity retention. Further, only slight changes in kinetic parameters of free (Km = 1.54 mM) and immobilized horseradish peroxidase (Km = 1.83 mM) were noticed, indicating retention of high catalytic properties and high substrate affinity by encapsulated biocatalyst. Encapsulated horseradish peroxidase was tested in biodegradation of two frequently occurring in wastewater API, sulfamethoxazole (antibiotic) and carbamazepine (anticonvulsant). Over 80% of both pharmaceutics was removed by immobilized enzyme after 24 h of the process from the solution at a concentration of 1 mg/L, under optimal conditions, which were found to be pH 7, temperature 25 °C and 2 mM of H2O2. However, even from 10 mg/L solutions, it was possible to remove over 40% of both pharmaceuticals. Finally, the reusability and storage stability study of immobilized horseradish peroxidase showed retention of over 60% of initial activity after 20 days of storage at 4 °C and after 10 repeated catalytic cycles, indicating great practical application potential. By contrast, the free enzyme showed less than 20% of its initial activity after 20 days of storage and exhibited no recycling potential.
A Holistic Approach to Determining Stereochemistry of Potential Pharmaceuticals by Circular Dichroism with β-Lactams as Test Cases
Authors: Górecki Marcin , Frelek Jadwiga
Published: December 2021

This paper’s main objective is to show that many different factors must be considered when solving stereochemical problems to avoid misleading conclusions and obtain conclusive results from the analysis of spectroscopic properties. Particularly in determining the absolute configuration, the use of chiroptical methods is crucial, especially when other techniques, including X-ray crystallography, fail, are not applicable, or give inconclusive results. Based on various β-lactam derivatives as models, we show how to reliably determine their absolute configuration (AC) and preferred conformation from circular dichroism (CD) spectra. Comprehensive CD analysis, employing both approaches, i.e., traditional with their sector and helicity rules, and state-of-the-art supported by quantum chemistry (QC) calculations along with solvation models for both electronic (ECD) and vibrational (VCD) circular dichroism ranges, allows confident defining stereochemistry of the β-lactams studied. Based on an in-depth analysis of the results, we have shown that choosing a proper chiroptical method/s strictly depends on the specific case and certain structural features.
Role of Selenium in Viral Infections with a Major Focus on SARS-CoV-2
Authors: Martinez Sabrina Sales , Huang Yongjun , Acuna Leonardo , Laverde Eduardo , Trujillo David , Barbieri Manuel A. , Tamargo Javier , Campa Adriana , Baum Marianna K.
Published: December 2021

Viral infections have afflicted human health and despite great advancements in scientific knowledge and technologies, continue to affect our society today. The current coronavirus (COVID-19) pandemic has put a spotlight on the need to review the evidence on the impact of nutritional strategies to maintain a healthy immune system, particularly in instances where there are limited therapeutic treatments. Selenium, an essential trace element in humans, has a long history of lowering the occurrence and severity of viral infections. Much of the benefits derived from selenium are due to its incorporation into selenocysteine, an important component of proteins known as selenoproteins. Viral infections are associated with an increase in reactive oxygen species and may result in oxidative stress. Studies suggest that selenium deficiency alters immune response and viral infection by increasing oxidative stress and the rate of mutations in the viral genome, leading to an increase in pathogenicity and damage to the host. This review examines viral infections, including the novel SARS-CoV-2, in the context of selenium, in order to inform potential nutritional strategies to maintain a healthy immune system.
Fidelity of Cotranslational Protein Targeting to the Endoplasmic Reticulum
Authors: Hsieh Hao-Hsuan , Shan Shu-ou
Published: December 2021

Fidelity of protein targeting is essential for the proper biogenesis and functioning of organelles. Unlike replication, transcription and translation processes, in which multiple mechanisms to recognize and reject noncognate substrates are established in energetic and molecular detail, the mechanisms by which cells achieve a high fidelity in protein localization remain incompletely understood. Signal recognition particle (SRP), a conserved pathway to mediate the localization of membrane and secretory proteins to the appropriate cellular membrane, provides a paradigm to understand the molecular basis of protein localization in the cell. In this chapter, we review recent progress in deciphering the molecular mechanisms and substrate selection of the mammalian SRP pathway, with an emphasis on the key role of the cotranslational chaperone NAC in preventing protein mistargeting to the ER and in ensuring the organelle specificity of protein localization.
Targeting AhR as a Novel Therapeutic Modality against Inflammatory Diseases
Authors: Cannon Alkeiver S. , Nagarkatti Prakash S. , Nagarkatti Mitzi
Published: December 2021

For decades, activation of Aryl Hydrocarbon Receptor (AhR) was excluded from consideration as a therapeutic approach due to the potential toxic effects of AhR ligands and the induction of the cytochrome P450 enzyme, Cyp1a1, following AhR activation. However, it is now understood that AhR activation not only serves as an environmental sensor that regulates the effects of environmental toxins, but also as a key immunomodulator where ligands induce a variety of cellular and epigenetic mechanisms to attenuate inflammation. Thus, the emergence of further in-depth research into diverse groups of compounds capable of activating this receptor has prompted reconsideration of its use therapeutically. The aim of this review is to summarize the body of research surrounding AhR and its role in regulating inflammation. Specifically, evidence supporting the potential of targeting this receptor to modulate the immune response in inflammatory and autoimmune diseases will be highlighted. Additionally, the opportunities and challenges of developing AhR-based therapies to suppress inflammation will be discussed.
Implantation of Various Cell-Free Matrixes Does Not Contribute to the Restoration of Hyaline Cartilage within Full-Thickness Focal Defects
Authors: Ibragimova Shabnam I. , Medvedeva Ekaterina V. , Romanova Irina A. , Istranov Leonid P. , Istranova Elena V. , Lychagin Aleksey V. , Nedorubov Andrey A. , Timashev Peter S. , Telpukhov Vladimir I. , Chagin Andrei S.
Published: December 2021

Articular cartilage is a highly organized tissue that has a limited ability to heal. Tissue engineering is actively exploited for joint tissue reconstruction in numerous cases of articular cartilage degeneration associated with trauma, arthrosis, rheumatoid arthritis, and osteoarthritis. However, the optimal scaffolds for cartilage repair are not yet identified. Here we have directly compared five various scaffolds, namely collagen-I membrane, collagen-II membrane, decellularized cartilage, a cellulose-based implant, and commercially available Chondro-Gide® (Geistlich Pharma AG, Wolhusen, Switzerland) collagen membrane. The scaffolds were implanted in osteochondral full-thickness defects, formed on adult Wistar rats using a hand-held cutter with a diameter of 2.0 mm and a depth of up to the subchondral bone. The congruence of the articular surface was almost fully restored by decellularized cartilage and collagen type II-based scaffold. The most vivid restoration was observed 4 months after the implantation. The formation of hyaline cartilage was not detected in any of the groups. Despite cellular infiltration into scaffolds being observed in each group except cellulose, neither chondrocytes nor chondro-progenitors were detected. We concluded that for restoration of hyaline cartilage, scaffolds have to be combined either with cellular therapy or morphogens promoting chondrogenic differentiation.
A Novel Role of BIRC3 in Stemness Reprogramming of Glioblastoma
Authors: Wu Qiong , Berglund Anders E. , MacAulay Robert J. , Etame Arnold B.
Published: December 2021

Stemness reprogramming remains a largely unaddressed principal cause of lethality in glioblastoma (GBM). It is therefore of utmost importance to identify and target mechanisms that are essential for GBM stemness and self-renewal. Previously, we implicated BIRC3 as an essential mediator of therapeutic resistance and survival adaptation in GBM. In this study, we present novel evidence that BIRC3 has an essential noncanonical role in GBM self-renewal and stemness reprogramming. We demonstrate that BIRC3 drives stemness reprogramming of human GBM cell lines, mouse GBM cell lines and patient-derived GBM stem cells (GSCs) through regulation of BMP4 signaling axis. Specifically, BIRC3 induces stemness reprogramming in GBM through downstream inactivation of BMP4 signaling. RNA-Seq interrogation of the stemness reprogramming hypoxic (pseudopalisading necrosis and perinecrosis) niche in GBM patient tissues further validated the high BIRC3/low BMP4 expression correlation. BIRC3 knockout upregulated BMP4 expression and prevented stemness reprogramming of GBM models. Furthermore, siRNA silencing of BMP4 restored stemness reprogramming of BIRC3 knockout in GBM models. In vivo silencing of BIRC3 suppressed tumor initiation and progression in GBM orthotopic intracranial xenografts. The stemness reprograming of both GSCs and non-GSCs populations highlights the impact of BIRC3 on intra-tumoral cellular heterogeneity GBM. Our study has identified a novel function of BIRC3 that can be targeted to reverse stemness programming of GBM.
Biochemical and Cellular Characterization of New Radio-Resistant Cell Lines Reveals a Role of Natural Flavonoids to Bypass Senescence
Authors: Russo Maria , Spagnuolo Carmela , Moccia Stefania , Tedesco Idolo , Lauria Fabio , Russo Gian Luigi
Published: December 2021

Cancer is one of the main causes of death worldwide, and, among the most frequent cancer types, osteosarcoma accounts for 56% of bone neoplasms observed in children and colorectal cancer for 10.2% of tumors diagnosed in the adult population. A common and frequent hurdle in cancer treatment is the emergence of resistance to chemo- and radiotherapy whose biological causes are largely unknown. In the present work, human osteosarcoma (SAOS) and colorectal adenocarcinoma (HT29) cell lines were γ-irradiated at doses mimicking the sub-lethal irradiation in clinical settings to obtain two radio-resistant cellular sub-populations named SAOS400 and HT500, respectively. Since “therapy-induced senescence” (TIS) is often associated with tumor response to radiotherapy in cancer cells, we measured specific cellular and biochemical markers of senescence in SAOS400 and HT500 cells. In detail, both cell lines were characterized by a higher level of expression of cyclin-dependent kinase inhibitors p16INK4 and p21CIP1 and increased positivity to SAβ-gal (senescence-associated β-galactosidase) with respect to parental cells. Moreover, the intracellular levels of reactive oxygen species in the resistant cells were significantly lower compared to the parental counterparts. Subsequently, we demonstrated that senolytic agents were able to sensitize SAOS400 and HT500 to cell death induced by γ-irradiation. Employing two natural flavonoids, fisetin and quercetin, and a BH3-mimetic, ABT-263/navitoclax, we observed that their association with γ-irradiation significantly reduced the expression of p16INK4, p21CIP1 and synergistically (combination index < 1) increased cell death compared to radiation mono-alone treatments. The present results reinforce the potential role of senolytics as adjuvant agents in cancer therapy.
Blood Pressure Elevation of Tubular Specific (P)RR Transgenic Mice and Lethal Tubular Degeneration due to Possible Intracellular Interactions between (P)RR and Alternative Renin Products
Authors: Saigo Sae , Kino Tabito , Uchida Kotaro , Sugawara Takuya , Chen Lin , Sugiyama Michiko , Azushima Kengo , Wakui Hiromichi , Tamura Kouichi , Ishigami Tomoaki
Published: December 2021

The prorenin/renin receptor ((P)RR) is a multifunctional protein that is widely distributed in various organs. Despite intensive research for more than 20 years, this receptor has not been fully characterized. In this study, we generated mice overexpressing the tubular epithelial (P)RR gene ((P)RR-TG mice) to test the previously reported functional role of (P)RR by Ramkumar et al. in 2015 using tubular specific (P)RR KO mice. (P)RR-TG mice were maintained and analyzed in individual metabolic cages and were administered angiotensin II blocker (ARB), direct renin inhibitor (DRI), and bafilomycin, that is, vacuolar ATPase (V-ATPase) antagonist. (P)RR-TG mice were hypertensive and had alkalized urine with lower osmolality and Na+ excretion. ARB and DRI, but not bafilomycin, concurrently decreased blood pressure. Bafilomycin acidized urine of (P)RR-TG mice, or equivalently this phenomenon restored the effect of overexpressed transgene, suggesting that (P)RR functioned as a V-ATPase in renal tubules. Afterall, (P)RR-TG mice were mated with alternative renin transgenic mice (ARen2-TG), which we identified as intracellular renin previously, to generate double transgenic mice (DT-TG). Lethal renal tubular damage was observed in DT-TG mice, suggesting that intracellular renin may be a ligand for (P)RR in tubules. In summary, (P)RR did not substantially affect the tissue renin-angiotensin system (RAS) in our model of tubular specific (P)RR gene over-expression, but alternative intracellular renin may be involved in (P)RR signaling in addition to conventional V-ATPase function. Further investigations are warranted.
Macrophages and Epithelial Cells Mutually Interact through NLRP3 to Clear Infection and Enhance the Gastrointestinal Barrier
Authors: Bording-Jorgensen Michael , Armstrong Heather , Wickenberg Madison , LaPointe Paul , Wine Eytan
Published: December 2021

Activation of the nod-like receptor protein 3 (NLRP3) leads to the release of the proinflammatory cytokine IL-1β, which then facilitates pathogen control by macrophages. The role of NLRPs in controlling infection of epithelial cells is not well understood. Our hypothesis was that activation of the NLRP3 inflammasome in colonic epithelial cells would promote macrophage-mediated epithelial recovery after infection with the pathogen Citrobacter rodentium. We devised a co-culture model using mouse colonic epithelial cells (CMT-93) and macrophages (J774A.1) during infection with C. rodentium. Inflammasome was activated using LPS and ATP and inhibited by YVAD. We assessed cytokine secretion (ELISA), macrophage recruitment and pathogen penetration (immunofluorescence), and epithelial barrier integrity (transepithelial electrical resistance). Macrophages were recruited to the apical membrane of epithelial cells, associated with tight junctions, promoted epithelial barrier recovery, and displaced C. rodentium. While NLRP3 was expressed in infected epithelial cells, IL-18 or IL-1β secretion remained unchanged. Supernatants from infected epithelial cells promoted infection clearance by macrophage; while this was inflammasome-independent, ATP significantly improved epithelial barrier recovery. The inflammasome appears to promote epithelial barrier function, independent of IL-18 and IL-1β secretion. Inflammasome activation in macrophages plays a dual role of promoting pathogen clearance and improving epithelial barrier integrity.
Explorative Visual Analysis of Rap Music
Authors: Meinecke Christofer , Hakimi Ahmad Dawar , Jänicke Stefan
Published: December 2021

Detecting references and similarities in music lyrics can be a difficult task. Crowdsourced knowledge platforms such as Genius. can help in this process through user-annotated information about the artist and the song but fail to include visualizations to help users find similarities and structures on a higher and more abstract level. We propose a prototype to compute similarities between rap artists based on word embedding of their lyrics crawled from Genius. Furthermore, the artists and their lyrics can be analyzed using an explorative visualization system applying multiple visualization methods to support domain-specific tasks.
Factors Effecting Omnichannel Customer Experience: Evidence from Fashion Retail
Authors: Riaz Hadiqa , Baig Umair , Meidute-Kavaliauskiene Ieva , Ahmed Hassaan
Published: December 2021

This research work was designed to investigate the changing dynamics of the retail landscape driven by omnichannel retailing, and to determine the effects on the omnichannel customer’s experience. The role of omnichannel customer behavior in the relation between omnichannel retailing and customer experience was assessed through a survey of 265 omnichannel customers of different fashion retail brands in Pakistan. The results of partial least squares structural equation modeling (PLS-SEM) showed a strong mediating effect of omnichannel customer behavior in channeling the drivers of omnichannel retailing towards an enhanced customer experience. Omnichannel retailing helps to enhance the customer experience via determinants of omnichannel integration, order fulfilment, usability and seamlessness. The research findings underpin the positive significant effect of all factors of omnichannel retailing on the customer experience. Among the four omnichannel retailing constructs, seamlessness emerged as a major direct and indirect contributor, followed by omnichannel integration and usability dimensions. Notwithstanding the small sample size, this research contributes to the omnichannel retailing landscape of Pakistan’s fashion retail industry by suggesting a functional approach for creating a fully integrated shopping experience and omnichannel strategies for fashion brands. Furthermore, it will also provide brands an opportunity to strengthen their customers’ experience throughout the buying channel.
The Triadic Relationship of Sense-Making, Analytics, and Institutional Influences
Authors: Bani-Hani Imad , Chowdhury Soumitra , Kurti Arianit
Published: December 2021

The current business environment demands the enablement of organization-wide use of analytics to support a fact-based decision making. Such movement within the organization require employees to take advantage of the self-service business analytics tools to independently fulfil their needs. However, assuming independence in data analytics requires employees to make sense of several elements which collectively contribute to the generation of required insights. Building on sense-making, self-service business analytics, and institutions literature, this paper explores the relationship between sense-making and self-service business analytics and how institutions influence and shape such relationship. By adopting a qualitative perspective and using 22 interviews, we have empirically investigated a model developed through our literature review and provided more understanding of the sense-making concept in a self-service business analytics context.
Host Plant Availability and Nest-Site Selection of the Social Spider Stegodyphus dumicola Pocock, 1898 (Eresidae)
Authors: Rose Clémence , Schramm Andreas , Irish John , Bilde Trine , Bird Tharina L.
Published: December 2021

An animals’ habitat defines the resources that are available for its use, such as host plants or food sources, and the use of these resources are critical for optimizing fitness. Spiders are abundant in all terrestrial habitats and are often associated with vegetation, which may provide structure for anchoring capture webs, attract insect prey, or provide protective function. Social spiders construct sedentary communal silk nests on host plants, but we know little about whether and how they make nest-site decisions. We examined host plant use in relation to host plant availability in the social spider Stegodyphus dumicola Pocock, 1898 (Eresidae) across different arid biomes in Namibia and analysed the role of host plant characteristics (height, spines, scent, sturdiness) on nest occurrence. Host plant communities and densities differed between locations. Spider nests were relatively more abundant on Acacia spp., Boscia foetida, Combretum spp., Dichrostachys cinerea, Parkinsonia africana, Tarchonanthus camphoratus, and Ziziphus mucronatus, and nests survived longer on preferred plant genera Acacia, Boscia and Combretum. Spider nests were relatively more abundant on plants higher than 2 m, and on plants with thorns and with a rigid structure. Our results suggest that spiders display differential use of host plant species, and that characteristics such as rigidity and thorns confer benefits such as protection from browsing animals.
Usefulness of the MAGGIC Score in Predicting the Competing Risk of Non-Sudden Death in Heart Failure Patients Receiving an Implantable Cardioverter-Defibrillator: A Sub-Analysis of the OBSERVO-ICD Registry
Authors: Canepa Marco , Palmisano Pietro , Dell’Era Gabriele , Ziacchi Matteo , Ammendola Ernesto , Accogli Michele , Occhetta Eraldo , Biffi Mauro , Nigro Gerardo , Ameri Pietro , Stronati Giulia , Porto Italo , Dello Russo Antonio , Guerra Federico
Published: December 2021

The role of prognostic risk scores in predicting the competing risk of non-sudden death in heart failure patients with reduced ejection fraction (HFrEF) receiving an implantable cardioverter-defibrillator (ICD) is unclear. To this goal, we evaluated the accuracy and usefulness of the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score. The present analysis included 1089 HFrEF ICD recipients enrolled in the OBSERVO-ICD registry (NCT02735811). During a median follow-up of 36 months (1st–3rd IQR 25–48 months), 193 patients (17.7%) experienced at least one appropriate ICD therapy, and 133 patients died (12.2%) without experiencing any ICD therapy. The frequency of patients receiving ICD therapies was stable around 17–19% across increasing tertiles of 3-year MAGGIC probability of death, whereas non-sudden mortality increased (6.4% to 9.8% to 20.8%, p < 0.0001). Accuracy of MAGGIC score was 0.60 (95% CI, 0.56–0.64) for the overall outcome, 0.53 (95% CI, 0.49–0.57) for ICD therapies and 0.65 (95% CI, 0.60–0.70) for non-sudden death. In patients with higher 3-year MAGGIC probability of death, the increase in the competing risk of non-sudden death during follow-up was greater than that of receiving an appropriate ICD therapy. Results were unaffected when analysis was limited to ICD shocks only. The MAGGIC risk score proved accurate and useful in predicting the competing risk of non-sudden death in HFrEF ICD recipients. Estimation of mortality risk should be taken into greater consideration at the time of ICD implantation.
Long-Term Outcomes of Staged Revision Surgery for Chronic Periprosthetic Joint Infection of Total Hip Arthroplasty
Authors: Day Christopher W. , Costi Kerry , Pannach Susan , Atkins Gerald J. , Hofstaetter Jochen G. , Callary Stuart A. , Nelson Renjy , Howie Donald W. , Solomon Lucian B.
Published: December 2021

Periprosthetic joint infection (PJI) is a serious complication of total hip arthroplasty. Staged revision surgery is considered effective in eradicating PJI. We aimed to determine the rate of infection resolution after each stage of staged revision surgery (first stage, repeat first stage, second stage, excision arthroplasty, and reimplantation) and to assess functional outcomes and the mortality rate at ten years in a consecutive series of 30 chronic PJI of total hip arthroplasties. Infection resolution was defined as no clinical nor laboratory evidence of infection at 24 months after the last surgery and after a minimum of 12 months following cessation of antimicrobial treatment. Four patients died within 24 months of their final surgery. Nineteen patients, 73% (worst-case analysis (wca) 63%), were infection free after 1 surgery; 22 patients, 85% (wca 73%), were infection free after 2 surgeries; and 26 patients, 100% (wca 87%), were infection free after three and four surgeries. The median Harris Hip Score was 41 prior to first revision surgery and improved to 74 at twelve months and 76 at ten years after the final surgery. Thirteen patients died at a mean of 64 months from first revision, giving a mortality rate of 43% at ten years, which is approximately 25% higher than that of an age-matched general population. The results show that with repeated aggressive surgical treatment, most PJIs of the hip are curable. Ten years after successful treatment of PJI, functional outcomes and pain are improved and maintained compared to before initial surgery, but this must be balanced against the high 10-year mortality. Level of evidence: cohort studies.
The Role of Factor Xa-Independent Pathway and Anticoagulant Therapies in Cancer-Related Stroke
Authors: Kim Hyung Jun , Chung Jong-Won , Bang Oh Young , Cho Yeon Hee , Lim Yun Jeong , Hwang Jaechun , Seo Woo-Keun , Kim Gyeong-Moon , Kim Hee-Jin , Ahn Myung-Ju
Published: December 2021

Background: The optimal strategy for stroke prevention in cancer patients is unknown. We compared the underlying mechanisms of coagulopathy and the effects of anticoagulants in patients with active cancer and atrial fibrillation (AF). Methods: We retrospectively enrolled 46 consecutive patients with embolic stroke of unknown source and active cancer (cancer stroke). We consecutively screened patients with cancer patients without stroke (n = 29), AF stroke (n = 52), and healthy subjects (n = 28), which served as controls. Patients with cancer stroke were treated with either enoxaparin (a low-molecular-weight heparin) or a factor Xa inhibitor, and those with AF stroke were treated with factor Xa inhibitors. D-dimer, factor Xa, and circulating cell-free DNA (cfDNA), a marker of neutrophil extracellular traposis, were measured at both before and after anticoagulation. Results: In AF stroke, factor Xa activity and cfDNA and D-dimer levels were decreased by treatment with factor Xa inhibitors. In contrast, in cancer stroke, factor Xa activity was decreased, D-dimer levels were unchanged, and cfDNA levels were increased by treatment with factor Xa inhibitors. In cancer stroke patients treated with enoxaparin, D-dimer levels were decreased (p = 0.011) and cfDNA levels were unchanged. Conclusion: The anticoagulation effects of factor Xa inhibitors differed between cancer stroke and AF stroke.
Iron Deficiency in Heart Failure: Mechanisms and Pathophysiology
Authors: Alnuwaysir Ridha , Hoes Martijn , van Veldhuisen Dirk , van der Meer Peter , Grote Beverborg Niels
Published: December 2021

Iron is an essential micronutrient for a myriad of physiological processes in the body beyond erythropoiesis. Iron deficiency (ID) is a common comorbidity in patients with heart failure (HF), with a prevalence reaching up to 59% even in non-anaemic patients. ID impairs exercise capacity, reduces the quality of life, increases hospitalisation rate and mortality risk regardless of anaemia. Intravenously correcting ID has emerged as a promising treatment in HF as it has been shown to alleviate symptoms, improve quality of life and exercise capacity and reduce hospitalisations. However, the pathophysiology of ID in HF remains poorly characterised. Recognition of ID in HF triggered more research with the aim to explain how correcting ID improves HF status as well as the underlying causes of ID in the first place. In the past few years, significant progress has been made in understanding iron homeostasis by characterising the role of the iron-regulating hormone hepcidin, the effects of ID on skeletal and cardiac myocytes, kidneys and the immune system. In this review, we summarise the current knowledge and recent advances in the pathophysiology of ID in heart failure, the deleterious systemic and cellular consequences of ID.
How to Predict Outcomes from a Biofeedback and Pelvic Floor Muscle Electric Stimulation Program in Patients with Urinary Incontinence after Radical Prostatectomy
Authors: Salciccia Stefano , Sciarra Alessandro , Moriconi Martina , Maggi Martina , Viscuso Pietro , Rosati Davide , Frisenda Marco , Di Pierro Giovanni Battista , Canale Vittorio , Bevilacqua Giulio , Nesi Gianluca , Del Giudice Francesco , Gentilucci Alessandro , Cattarino Susanna , Mariotti Gianna
Published: December 2021

Objectives: The objective of this study was to analyze the pre-operative and intra-operative variables that can condition urinary incontinence (UI) after radical prostatectomy (RP), as well as continence rate recovery during a pelvic floor rehabilitation program. Materials and Methods: A total of 72 cases with UI after RP were prospectively examined. All cases were homogeneously treated by the same surgeon, using the same RP technique. A combination of biofeedback (BF) and pelvic floor electric stimulation (PFES) performed by the same clinician and using the same protocol was used. Clinical, pathologic and surgical variables were analyzed in terms of 24 h pad test results (pad weight and pad-free status). Results: Prostate volume (PV) strongly varied from 24 to 127 cc (mean ± SD 46.39 ± 18.65 cc), and the baseline pad weight varied from 10 to 1500 cc (mean ± SD 354.29 ± 404.15 cc). PV strongly and positively correlated with the baseline pad weight (r = 0.4215; p = 0.0269) and inversely with the three-month pad weight (r = − 0.4763; p = 0.0213) and pad-free status (r =− 0.3010; p = 0.0429). The risk of a residual pad weight >10 g after the rehabilitative program significantly increased according to PV (p = 0.001) and the baseline pad weight (p = 0.002 and < 0.0001). In particular, PV > 40 cc and a baseline pad weight >400 g significantly (p = 0.010 and p < 0.0001, respectively) and independently predicted a 5.7 and a 35.4 times increase in the risk of a residual pad weight at the three-month follow-up, respectively. Conclusion: This is the first prospective trial whose primary objective is to verify the possible predictors, such as PV, that are able to condition the response to a pelvic floor rehabilitation program for UI after RP.
Needleless Ablation of Osteoid Osteoma and Osteoblastoma: The Emergent Role of MRgFUS
Authors: Cobianchi Bellisari Flavia , Palumbo Pierpaolo , Masciocchi Carlo , Zoccali Carmine , Barile Antonio , Arrigoni Francesco
Published: December 2021

Osteoblastoma (OB) and osteoid osteoma (OO) are benign bone-forming tumors, with nearly identical basic microscopic features. The main difference is dimension (OO has usually a nidus measuring <2 cm in diameter). In addition, OB is biologically more active than OO, with a tendency to grow in size. Historically, treatments have included surgical resection and analgesics, although invasiveness and poor tolerance have led to the current standard of care moving toward interventional radiology, where radiofrequency ablation (RFA) represents the most diffuse technique. Magnetic resonance-guided focused ultrasound surgery (MRgFUS) has recently emerged as another innovative alternative treatment, providing tumor ablation through a needleless and ionizing radiation-free modality. In addition, this technique has the ability to guarantee a very precise and controlled increase in temperature, delivering small amounts of energy that can accurately destroy only the lesion, avoiding healthy surrounding tissues. The present review focuses on MRgFUS as the less invasive, safe, effective, and durable treatment option for the management of osteoid osteoma and osteoblastoma, including a description of technical details, indications and outcomes.
Real-Time Brain Monitoring by Near-Infrared Spectroscopy Predicts Neurological Outcome after Cardiac Arrest and Resuscitation in Rats: A Proof of Concept Study of a Novel Prognostic Measure after Cardiac Arrest
Authors: Takegawa Ryosuke , Hayashida Kei , Yin Tai , Choudhary Rishabh C. , Miyara Santiago J. , Khalili Houman , Shoaib Muhammad , Endo Yusuke , Molmenti Emesto P. , Becker Lance B.
Published: December 2021

Clinical studies have demonstrated that dynamic changes in regional cerebral oxygen saturation (rSO2) after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) have a role in predicting neurological outcomes after the return of spontaneous circulation (ROSC). Our study evaluated whether the timing of rSO2 decline shortly after CPR reflects the severity of brain injury in a rat model of CA. Rats were subjected to different durations of asphyxia to produce variable severities of brain injury, due to CA. Time from ROSC to achieving the initial minimum rSO2 was defined as Tnadir. A Tnadir cut-off of 24 min had optimal sensitivity and specificity for predicting good neurological outcomes at 72 h after ROSC (AUC, 0.88; sensitivity, 89%; specificity, 86%; p < 0.01). Immunohistochemistry at 72 h post-CA revealed that the number of Fluoro-Jade B positive degenerating neurons in the hippocampus CA1 sector were markedly higher in animals with Tnadir > 24 min than that in animals with Tnadir ≤ 24 min. There was no difference in the gene expressions of cytokines and mitochondrial fission proteins in the brain at 2 h after ROSC between rats with Tnadir > 24 min and with Tnadir ≤ 24 min. In conclusion, Tnadir can be a novel predictor of good neurological outcomes after CA/CPR.