bluuebunny/crossref_metadata_2025 huggingface dataset:
Tissue-Specific Metabolic Reprogramming during Wound-Induced Organ Formation in Tomato Hypocotyl Explants
Authors: Larriba Eduardo , Sánchez-García Ana Belén , Martínez-Andújar Cristina , Albacete Alfonso , Pérez-Pérez José Manuel
Published: September 2021

Plants have remarkable regenerative capacity, which allows them to survive tissue damage after exposure to biotic and abiotic stresses. Some of the key transcription factors and hormone crosstalk mechanisms involved in wound-induced organ regeneration have been extensively studied in the model plant Arabidopsis thaliana. However, little is known about the role of metabolism in wound-induced organ formation. Here, we performed detailed transcriptome analysis and used a targeted metabolomics approach to study de novo organ formation in tomato hypocotyl explants and found tissue-specific metabolic differences and divergent developmental pathways. Our results indicate that successful regeneration in the apical region of the hypocotyl depends on a specific metabolic switch involving the upregulation of photorespiratory pathway components and the differential regulation of photosynthesis-related gene expression and gluconeogenesis pathway activation. These findings provide a useful resource for further investigation of the molecular mechanisms involved in wound-induced organ formation in crop species such as tomato.
Ruthenium Complexes with 2-Pyridin-2-yl-1H-benzimidazole as Potential Antimicrobial Agents: Correlation between Chemical Properties and Anti-Biofilm Effects
Authors: Jabłońska-Wawrzycka Agnieszka , Rogala Patrycja , Czerwonka Grzegorz , Gałczyńska Katarzyna , Drabik Marcin , Dańczuk Magdalena
Published: September 2021

Antimicrobial resistance is a growing public health concern that requires urgent action. Biofilm-associated resistance to antimicrobials begins at the attachment phase and increases as the biofilms maturate. Hence, interrupting the initial binding process of bacteria to surfaces is essential to effectively prevent biofilm-associated problems. Herein, we have evaluated the antibacterial and anti-biofilm activities of three ruthenium complexes in different oxidation states with 2-pyridin-2-yl-1H-benzimidazole (L1 = 2,2′-PyBIm): [(η6-p-cymene)RuIIClL1]PF6 (Ru(II) complex), mer-[RuIIICl3(CH3CN)L1]·L1·3H2O (Ru(III) complex), (H2L1)2[RuIIICl4(CH3CN)2]2[RuIVCl4(CH3CN)2]·2Cl·6H2O (Ru(III/IV) complex). The biological activity of the compounds was screened against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa strains. The results indicated that the anti-biofilm activity of the Ru complexes at concentration of 1 mM was better than that of the ligand alone against the P. aeruginosa PAO1. It means that ligand, in combination with ruthenium ion, shows a synergistic effect. The effect of the Ru complexes on cell surface properties was determined by the contact angle and zeta potential values. The electric and physical properties of the microbial surface are useful tools for the examined aggregation phenomenon and disruption of the adhesion. Considering that intermolecular interactions are important and largely define the functions of compounds, we examined interactions in the crystals of the Ru complexes using the Hirshfeld surface analysis.
LncRNA-CR11538 Decoys Dif/Dorsal to Reduce Antimicrobial Peptide Products for Restoring Drosophila Toll Immunity Homeostasis
Authors: Zhou Hongjian , Li Shengjie , Wu Shanshan , Jin Ping , Ma Fei
Published: September 2021

Avoiding excessive or insufficient immune responses and maintaining homeostasis are critical for animal survival. Although many positive or negative modulators involved in immune responses have been identified, little has been reported to date concerning whether the long non-coding RNA (lncRNA) can regulate Drosophila immunity response. In this study, we firstly discover that the overexpression of lncRNA-CR11538 can inhibit the expressions of antimicrobial peptides Drosomycin (Drs) and Metchnikowin (Mtk) in vivo, thereby suppressing the Toll signaling pathway. Secondly, our results demonstrate that lncRNA-CR11538 can interact with transcription factors Dif/Dorsal in the nucleus based on both subcellular localization and RIP analyses. Thirdly, our findings reveal that lncRNA-CR11538 can decoy Dif/Dorsal away from the promoters of Drs and Mtk to repress their transcriptions by ChIP-qPCR and dual luciferase report experiments. Fourthly, the dynamic expression changes of Drs, Dif, Dorsal and lncRNA-CR11538 in wild-type flies (w1118) at different time points after M. luteus stimulation disclose that lncRNA-CR11538 can help Drosophila restore immune homeostasis in the later period of immune response. Overall, our study reveals a novel mechanism by which lncRNA-CR11538 serves as a Dif/Dorsal decoy to downregulate antimicrobial peptide expressions for restoring Drosophila Toll immunity homeostasis, and provides a new insight into further studying the complex regulatory mechanism of animal innate immunity.
Deciphering Structural Alterations Associated with Activity Reductions of Genetic Polymorphisms in Cytochrome P450 2A6 Using Molecular Dynamics Simulations
Authors: Kato Koichi , Nakayoshi Tomoki , Nokura Rika , Hosono Hiroki , Hiratsuka Masahiro , Ishikawa Yoshinobu , Kurimoto Eiji , Oda Akifumi
Published: September 2021

Cytochrome P450 (CYP) 2A6 is a monooxygenase involved in the metabolism of various endogenous and exogenous chemicals, such as nicotine and therapeutic drugs. The genetic polymorphisms in CYP2A6 are a cause of individual variation in smoking behavior and drug toxicities. The enzymatic activities of the allelic variants of CYP2A6 were analyzed in previous studies. However, the three-dimensional structures of the mutants were not investigated, and the mechanisms underlying activity reduction remain unknown. In this study, to investigate the structural changes involved in the reduction in enzymatic activities, we performed molecular dynamics simulations for ten allelic mutants of CYP2A6. For the calculated wild type structure, no significant structural changes were observed in comparison with the experimental structure. On the other hand, the mutations affected the interaction with heme, substrates, and the redox partner. In CYP2A6.44, a structural change in the substrate access channel was also observed. Those structural effects could explain the alteration of enzymatic activity caused by the mutations. The results of simulations provide useful information regarding the relationship between genotype and phenotype.
Stereo-Specific Modulation of the Extracellular Calcium-Sensing Receptor in Colon Cancer Cells
Authors: Schepelmann Martin , Kupper Nadja , Sladczyk Marta , Mansfield Bethan , Manhardt Teresa , Piatek Karina , Iamartino Luca , Riccardi Daniela , Kariuki Benson M. , Bassetto Marcella , Kallay Enikö
Published: September 2021

Pharmacological allosteric agonists (calcimimetics) of the extracellular calcium-sensing receptor (CaSR) have substantial gastro-intestinal side effects and induce the expression of inflammatory markers in colon cancer cells. Here, we compared the effects of both CaSR-specific (R enantiomers) and -unspecific (S enantiomers) enantiomers of a calcimimetic (NPS 568) and a calcilytic (allosteric CaSR antagonists; NPS 2143) to prove that these effects are indeed mediated via the CaSR, rather than via off-target effects, e.g., on β-adrenoceptors or calcium channels, of these drugs. The unspecific S enantiomer of NPS 2143 and NPS S-2143 was prepared using synthetic chemistry and characterized using crystallography. NPS S-2143 was then tested in HEK-293 cells stably transfected with the human CaSR (HEK-CaSR), where it did not inhibit CaSR-mediated intracellular Ca2+ signals, as expected. HT29 colon cancer cells transfected with the CaSR were treated with both enantiomers of NPS 568 and NPS 2143 alone or in combination, and the expression of CaSR and the pro-inflammatory cytokine interleukin 8 (IL-8) was measured by RT-qPCR and ELISA. Only the CaSR-selective enantiomers of the calcimimetic NPS 568 and NPS 2143 were able to modulate CaSR and IL-8 expression. We proved that pro-inflammatory effects in colon cancer cells are indeed mediated through CaSR activation. The non-CaSR selective enantiomer NPS S-2143 will be a valuable tool for investigations in CaSR-mediated processes.
Increased Indoleamine 2,3-Dioxygenase Levels at the Onset of Sjögren’s Syndrome in SATB1-Conditional Knockout Mice
Authors: Tanaka Yuriko , Onozato Mayu , Mikami Tetuo , Kohwi-Shigematsu Terumi , Fukushima Takeshi , Kondo Motonari
Published: September 2021

Sjögren’s syndrome (SS) is a chronic autoimmune disease characterized by dysfunction of salivary and lacrimal glands, resulting in xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). Autoantibodies, such as anti-SSA and anti-SSB antibodies, are hallmarks and important diagnostic factors for SS. In our previous study, we demonstrated that SS-like xerostomia was observed in SATB1 conditional knockout (SATB1cKO) mice, in which the floxed SATB1 gene was specifically deleted in hematopoietic cells as early as 4 weeks of age. In these mice, autoantibodies were not detected until 8 weeks of age in SATB1cKO mice, although exocrine gland function reached its lowest at this age. Therefore, other markers may be necessary for the diagnosis of SS in the early phase. Here, we found that mRNA expression of the interferonγ (IFN-γ) gene and the IFN-responsive indoleamine 2,3-dioxygenase (IDO) gene is upregulated in the salivary glands of SATB1cKO mice after 3 and 4 weeks of age, respectively. We detected l-kynurenine (l-KYN), an intermediate of l-tryptophan (l-Trp) metabolism mediated by IDO, in the serum of SATB1cKO mice after 4 weeks of age. In addition, the upregulation of IDO expression was significantly suppressed by the administration of IFN-γ neutralizing antibodies in SATB1cKO mice. These results suggest that the induction of IFN-dependent IDO expression is an initial event that occurs immediately after the onset of SS in SATB1cKO mice. These results also imply that serum l-KYN could be used as a marker for SS diagnosis in the early phases of the disease before autoantibodies are detectable.
Therapeutic Implications of Mesenchymal Stromal Cells and Their Extracellular Vesicles in Autoimmune Diseases: From Biology to Clinical Applications
Authors: Matheakakis Angelos , Batsali Aristea , Papadaki Helen A. , Pontikoglou Charalampos G.
Published: September 2021

Mesenchymal stromal cells (MSCs) are perivascular multipotent stem cells originally identified in the bone marrow (BM) stroma and subsequently in virtually all vascularized tissues. Because of their ability to differentiate into various mesodermal lineages, their trophic properties, homing capacity, and immunomodulatory functions, MSCs have emerged as attractive candidates in tissue repair and treatment of autoimmune disorders. Accumulating evidence suggests that the beneficial effects of MSCs may be primarily mediated via a number of paracrine-acting soluble factors and extracellular vesicles (EVs). EVs are membrane-coated vesicles that are increasingly being acknowledged as playing a key role in intercellular communication via their capacity to carry and deliver their cargo, consisting of proteins, nucleic acids, and lipids to recipient cells. MSC-EVs recapitulate the functions of the cells they originate, including immunoregulatory effects but do not seem to be associated with the limitations and concerns of cell-based therapies, thereby emerging as an appealing alternative therapeutic option in immune-mediated disorders. In the present review, the biology of MSCs will be outlined and an overview of their immunomodulatory functions will be provided. In addition, current knowledge on the features of MSC-EVs and their immunoregulatory potential will be summarized. Finally, therapeutic applications of MSCs and MSC-EVs in autoimmune disorders will be discussed.
Kynurenine Pathway of Tryptophan Metabolism in Migraine and Functional Gastrointestinal Disorders
Authors: Fila Michal , Chojnacki Jan , Pawlowska Elzbieta , Szczepanska Joanna , Chojnacki Cezary , Blasiak Janusz
Published: September 2021

Migraine, the leading cause of disability in the population aged below 50, is associated with functional gastrointestinal (GI) disorders (FGIDs) such as functional nausea, cyclic vomiting syndrome, and irritable bowel syndrome (IBS). Conversely, changes in intestinal GI transit may cause diarrhea or constipation and are a component of the autonomic symptoms associated with pre- and post-dorsal phases of migraine attack. These mutual relationships provoke a question on a common trigger in migraine and FGIDs. The kynurenine (l-kyn) pathway (KP) is the major route for l-tryptophan (l-Trp) metabolism and transforms l-Trp into several neuroactive compounds. Changes in KP were reported in both migraine and FGIDs. Migraine was largely untreatable, but several drugs approved lately by the FDA, including monoclonal antibodies for calcitonin gene-related peptide (CGRP) and its receptor, create a hope for a breakthrough in migraine treatment. Derivatives of l-kyn were efficient in pain relief with a mechanism including CGRP inhibition. KP products are important ligands to the aryl hydrocarbon receptor (AhR), whose activation is implicated in the pathogenesis of GI and migraine. Toll-like receptors (TLRs) may play a role in migraine and IBS pathogeneses, and KP metabolites detected downstream of TLR activation may be an IBS marker. The TLR4 signaling was observed in initiating and maintaining migraine-like behavior through myeloid differentiation primary response gene 88 (MyD88) in the mouse. The aim of this review is to justify the view that KP modulation may provide common triggers for migraine and FGIDs with the involvement of TLR, AhR, and MyD88 activation.
Inferred Ancestral Origin of Cancer Cell Lines Associates with Differential Drug Response
Authors: Nguyen Phong B. H. , Ohnmacht Alexander J. , Sharifli Samir , Garnett Mathew J. , Menden Michael P.
Published: September 2021

Disparities between risk, treatment outcomes and survival rates in cancer patients across the world may be attributed to socioeconomic factors. In addition, the role of ancestry is frequently discussed. In preclinical studies, high-throughput drug screens in cancer cell lines have empowered the identification of clinically relevant molecular biomarkers of drug sensitivity; however, the genetic ancestry from tissue donors has been largely neglected in this setting. In order to address this, here, we show that the inferred ancestry of cancer cell lines is conserved and may impact drug response in patients as a predictive covariate in high-throughput drug screens. We found that there are differential drug responses between European and East Asian ancestries, especially when treated with PI3K/mTOR inhibitors. Our finding emphasizes a new angle in precision medicine, as cancer intervention strategies should consider the germline landscape, thereby reducing the failure rate of clinical trials.
HPTE-Induced Embryonic Thymocyte Death and Alteration of Differentiation Is Not Rescued by ERα or GPER Inhibition but Is Exacerbated by Concurrent TCR Signaling
Authors: Avellaneda Eddie , Lim Atalie , Moeller Sara , Marquez Jacqueline , Escalante Cobb Priscilla , Zambrano Cristina , Patel Aaditya , Sanchez Victoria , Godde K. , Broussard Christine
Published: September 2021

Organochlorine pesticides, such as DDT, methoxychlor, and their metabolites, have been characterized as endocrine disrupting chemicals (EDCs); suggesting that their modes of action involve interaction with or abrogation of endogenous endocrine function. This study examined whether embryonic thymocyte death and alteration of differentiation induced by the primary metabolite of methoxychlor, HPTE, rely upon estrogen receptor binding and concurrent T cell receptor signaling. Estrogen receptor inhibition of ERα or GPER did not rescue embryonic thymocyte death induced by HPTE or the model estrogen diethylstilbestrol (DES). Moreover, adverse effects induced by HPTE or DES were worsened by concurrent TCR and CD2 differentiation signaling, compared with EDC exposure post-signaling. Together, these data suggest that HPTE- and DES-induced adverse effects on embryonic thymocytes do not rely solely on ER alpha or GPER but may require both. These results also provide evidence of a potential collaborative signaling mechanism between TCR and estrogen receptors to mediate adverse effects on embryonic thymocytes, as well as highlight a window of sensitivity that modulates EDC exposure severity.
The Interplay between Non-Esterified Fatty Acids and Plasma Zinc and Its Influence on Thrombotic Risk in Obesity and Type 2 Diabetes
Authors: Hierons Stephen J. , Marsh Jordan S. , Wu Dongmei , Blindauer Claudia A. , Stewart Alan J.
Published: September 2021

Thrombosis is a major comorbidity of obesity and type-2 diabetes mellitus (T2DM). Despite the development of numerous effective treatments and preventative strategies to address thrombotic disease in such individuals, the incidence of thrombotic complications remains high. This suggests that not all the pathophysiological mechanisms underlying these events have been identified or targeted. Non-esterified fatty acids (NEFAs) are increasingly regarded as a nexus between obesity, insulin resistance, and vascular disease. Notably, plasma NEFA levels are consistently elevated in obesity and T2DM and may impact hemostasis in several ways. A potentially unrecognized route of NEFA-mediated thrombotic activity is their ability to disturb Zn2+ speciation in the plasma. Zn2+ is a potent regulator of coagulation and its availability in the plasma is monitored carefully through buffering by human serum albumin (HSA). The binding of long-chain NEFAs such as palmitate and stearate, however, trigger a conformational change in HSA that reduces its ability to bind Zn2+, thus increasing the ion’s availability to bind and activate coagulation proteins. NEFA-mediated perturbation of HSA-Zn2+ binding is thus predicted to contribute to the prothrombotic milieu in obesity and T2DM, representing a novel targetable disease mechanism in these disorders.
Non-Canonical Roles of Tau and Their Contribution to Synaptic Dysfunction
Authors: Siano Giacomo , Falcicchia Chiara , Origlia Nicola , Cattaneo Antonino , Di Primio Cristina
Published: September 2021

Tau plays a central role in a group of neurodegenerative disorders collectively named tauopathies. Despite the wide range of diverse symptoms at the onset and during the progression of the pathology, all tauopathies share two common hallmarks, namely the misfolding and aggregation of Tau protein and progressive synaptic dysfunctions. Tau aggregation correlates with cognitive decline and behavioural impairment. The mechanistic link between Tau misfolding and the synaptic dysfunction is still unknown, but this correlation is well established in the human brain and also in tauopathy mouse models. At the onset of the pathology, Tau undergoes post-translational modifications (PTMs) inducing the detachment from the cytoskeleton and its release in the cytoplasm as a soluble monomer. In this condition, the physiological enrichment in the axon is definitely disrupted, resulting in Tau relocalization in the cell soma and in dendrites. Subsequently, Tau aggregates into toxic oligomers and amyloidogenic forms that disrupt synaptic homeostasis and function, resulting in neuronal degeneration. The involvement of Tau in synaptic transmission alteration in tauopathies has been extensively reviewed. Here, we will focus on non-canonical Tau functions mediating synapse dysfunction.
Impacts of Hypoxia on Osteoclast Formation and Activity: Systematic Review
Authors: Tan Jen Kit , Mohamad Hazir Nur Shukriyah , Alias Ekram
Published: September 2021

Hypoxia is evident in several bone diseases which are characterized by excessive bone resorption by osteoclasts, the bone-resorbing cells. The effects of hypoxia on osteoclast formation and activities are widely studied but remain inconclusive. This systematic review discusses the studies reporting the effect of hypoxia on osteoclast differentiation and activity. A literature search for relevant studies was conducted through SCOPUS and PUBMED MEDLINE search engines. The inclusion criteria were original research articles presenting data demonstrating the effect of hypoxia or low oxygen on osteoclast formation and activity. A total of 286 studies were identified from the search, whereby 20 studies were included in this review, consisting of four in vivo studies and 16 in vitro studies. In total, 12 out of 14 studies reporting the effect of hypoxia on osteoclast activity indicated higher bone resorption under hypoxic conditions, 14 studies reported that hypoxia resulted in more osteoclasts, one study found that the number remained unchanged, and five studies indicated that the number decreased. In summary, examination of the relevant literature suggests differences in findings between studies, hence the impact of hypoxia on osteoclasts remains debatable, even though there is more evidence to suggest it promotes osteoclast differentiation and activity.
Therapeutic Potential of Human Stem Cell Implantation in Alzheimer’s Disease
Authors: Chan Hau Jun , Yanshree  , Roy Jaydeep , Tipoe George Lim , Fung Man-Lung , Lim Lee Wei
Published: September 2021

Alzheimer’s disease (AD) is a progressive debilitating neurodegenerative disease and the most common form of dementia in the older population. At present, there is no definitive effective treatment for AD. Therefore, researchers are now looking at stem cell therapy as a possible treatment for AD, but whether stem cells are safe and effective in humans is still not clear. In this narrative review, we discuss both preclinical studies and clinical trials on the therapeutic potential of human stem cells in AD. Preclinical studies have successfully differentiated stem cells into neurons in vitro, indicating the potential viability of stem cell therapy in neurodegenerative diseases. Preclinical studies have also shown that stem cell therapy is safe and effective in improving cognitive performance in animal models, as demonstrated in the Morris water maze test and novel object recognition test. Although few clinical trials have been completed and many trials are still in phase I and II, the initial results confirm the outcomes of the preclinical studies. However, limitations like rejection, tumorigenicity, and ethical issues are still barriers to the advancement of stem cell therapy. In conclusion, the use of stem cells in the treatment of AD shows promise in terms of effectiveness and safety.
Uncovering miRNA-mRNA Regulatory Modules in Developing Xylem of Pinus massoniana via Small RNA and Degradome Sequencing
Authors: Shen Tengfei , Xu Mengxuan , Qi Haoran , Feng Yuanheng , Yang Zhangqi , Xu Meng
Published: September 2021

Xylem is required for the growth and development of higher plants to provide water and mineral elements. The thickening of the xylem secondary cell wall (SCW) not only improves plant survival, but also provides raw materials for industrial production. Numerous studies have found that transcription factors and non-coding RNAs regulate the process of SCW thickening. Pinus massoniana is an important woody tree species in China and is widely used to produce materials for construction, furniture, and packaging. However, the target genes of microRNAs (miRNAs) in the developing xylem of P. massoniana are not known. In this study, a total of 25 conserved miRNAs and 173 novel miRNAs were identified via small RNA sequencing, and 58 differentially expressed miRNAs were identified between the developing xylem (PM_X) and protoplasts isolated from the developing xylem (PM_XP); 26 of these miRNAs were significantly up-regulated in PM_XP compared with PM_X, and 32 were significantly down-regulated. A total of 153 target genes of 20 conserved miRNAs and 712 target genes of 113 novel miRNAs were verified by degradome sequencing. There may be conserved miRNA-mRNA modules (miRNA-MYB, miRNA-ARF, and miRNA-LAC) involved in softwood and hardwood formation. The results of qRT-PCR-based parallel validation were in relatively high agreement. This study explored the potential regulatory network of miRNAs in the developing xylem of P. massoniana and provides new insights into wood formation in coniferous species.
Elucidating the Neuroprotective Role of PPARs in Parkinson’s Disease: A Neoteric and Prospective Target
Authors: Behl Tapan , Madaan Piyush , Sehgal Aayush , Singh Sukhbir , Sharma Neelam , Bhatia Saurabh , Al-Harrasi Ahmed , Chigurupati Sridevi , Alrashdi Ibrahim , Bungau Simona Gabriela
Published: September 2021

One of the utmost frequently emerging neurodegenerative diseases, Parkinson’s disease (PD) must be comprehended through the forfeit of dopamine (DA)-generating nerve cells in the substantia nigra pars compacta (SN-PC). The etiology and pathogenesis underlying the emergence of PD is still obscure. However, expanding corroboration encourages the involvement of genetic and environmental factors in the etiology of PD. The destruction of numerous cellular components, namely oxidative stress, ubiquitin-proteasome system (UPS) dysfunction, autophagy-lysosome system dysfunction, neuroinflammation and programmed cell death, and mitochondrial dysfunction partake in the pathogenesis of PD. Present-day pharmacotherapy can alleviate the manifestations, but no therapy has been demonstrated to cease disease progression. Peroxisome proliferator-activated receptors (PPARs) are ligand-directed transcription factors pertaining to the class of nuclear hormone receptors (NHR), and are implicated in the modulation of mitochondrial operation, inflammation, wound healing, redox equilibrium, and metabolism of blood sugar and lipids. Numerous PPAR agonists have been recognized to safeguard nerve cells from oxidative destruction, inflammation, and programmed cell death in PD and other neurodegenerative diseases. Additionally, various investigations suggest that regular administration of PPAR-activating non-steroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, indomethacin), and leukotriene receptor antagonists (montelukast) were related to the de-escalated evolution of neurodegenerative diseases. The present review elucidates the emerging evidence enlightening the neuroprotective outcomes of PPAR agonists in in vivo and in vitro models experiencing PD. Existing articles up to the present were procured through PubMed, MEDLINE, etc., utilizing specific keywords spotlighted in this review. Furthermore, the authors aim to provide insight into the neuroprotective actions of PPAR agonists by outlining the pharmacological mechanism. As a conclusion, PPAR agonists exhibit neuroprotection through modulating the expression of a group of genes implicated in cellular survival pathways, and may be a propitious target in the therapy of incapacitating neurodegenerative diseases like PD.
The RhoGEF Trio: A Protein with a Wide Range of Functions in the Vascular Endothelium
Authors: Kempers Lanette , Driessen Amber J. M. , van Rijssel Jos , Nolte Martijn A. , van Buul Jaap D.
Published: September 2021

Many cellular processes are controlled by small GTPases, which can be activated by guanine nucleotide exchange factors (GEFs). The RhoGEF Trio contains two GEF domains that differentially activate the small GTPases such as Rac1/RhoG and RhoA. These small RhoGTPases are mainly involved in the remodeling of the actin cytoskeleton. In the endothelium, they regulate junctional stabilization and play a crucial role in angiogenesis and endothelial barrier integrity. Multiple extracellular signals originating from different vascular processes can influence the activity of Trio and thereby the regulation of the forementioned small GTPases and actin cytoskeleton. This review elucidates how various signals regulate Trio in a distinct manner, resulting in different functional outcomes that are crucial for endothelial cell function in response to inflammation.
Editorial for Special Issue Detecting Attack and Incident Zone System
Authors: Ntantogian Christoforos
Published: September 2021

Attackers who have a strong motivation to succeed in their nefarious goals are often able to breach the security of their targets and cause havoc [...]
Integrating Comprehensive Human Oversight in Drone Deployment: A Conceptual Framework Applied to the Case of Military Surveillance Drones
Authors: Verdiesen Ilse , Aler Tubella Andrea , Dignum Virginia
Published: September 2021

Accountability is a value often mentioned in the debate on intelligent systems and their increased pervasiveness in our society. When focusing specifically on autonomous systems, a critical gap emerges: although there is much work on governance and attribution of accountability, there is a significant lack of methods for the operationalisation of accountability within the socio-technical layer of autonomous systems. In the case of autonomous unmanned aerial vehicles or drones—the critical question of how to maintain accountability as they undertake fully autonomous flights becomes increasingly important as their uses multiply in both the commercial and military fields. In this paper, we aim to fill the operationalisation gap by proposing a socio-technical framework to guarantee human oversight and accountability in drone deployments, showing its enforceability in the real case of military surveillance drones. By keeping a focus on accountability and human oversight as values, we align with the emphasis placed on human responsibility, while requiring a concretisation of what these principles mean for each specific application, connecting them with concrete socio-technical requirements. In addition, by constraining the framework to observable elements of pre- and post-deployment, we do not rely on assumptions made on the internal workings of the drone nor the technical fluency of the operator.
Analysis of Insect Pests in an 18th-Century Historical Pharmacy: A Case Study in Ferrara
Authors: Palazzo Loren Anna , Vicentini Chiara Beatrice , Marchetti Maria Gabriella , Leis Marilena , Chicca Milvia , Scapoli Chiara , Bonacci Teresa , Pezzi Marco
Published: September 2021

Historical pharmacies are valuable artistic, cultural, and scientific assets. In Italy, 482 historical pharmacies have been catalogued thus far, among which is the Navarra-Bragliani Pharmacy in Ferrara, whose wood furniture dates back to the 18th century. A study on insects causing biodeterioration was carried out for the first time on this valuable asset in order to monitor and preserve it. Insect samples were collected during surveys and examined by stereomicroscopy and scanning electron microscopy, using taxonomical keys for identification. The results revealed the presence of three species of Coleoptera—the first one specialised to attack wood materials, the second one polyphagous, and the third one feeding on materials of animal origin. The data obtained in this investigation may be useful for the preservation of the precious furnishing of the historical Navarra-Bragliani Pharmacy for performing similar studies on other ancient pharmacies aimed to protect these valuable cultural and scientific assets.
Resistance Affects the Field Performance of Insecticides Used for Control of Choristoneura rosaceana in Michigan Apples and Cherries
Authors: Hafez Abdulwahab M. , Mota-Sanchez David , Vandervoort Christine , Wise John C.
Published: September 2021

Field-based residual bioassays and residue analysis were conducted to assess the field performance and toxicity longevity of different insecticides that had previously been associated with resistance of Choristoneura rosaceana populations collected from apple and cherry orchards. In this study, 12–24 h-old larvae of apple and cherry populations were exposed to apple and cherry leaf samples, respectively, at post-application intervals and a susceptible population served as a reference of each. In the apple and cherry trials, the order of residual longevity of insecticides that effectively controlled the tested populations was as follows: bifenthrin and spinetoram (apple: 14, cherry 21-day post-application), phosmet (apple: 7, cherry 14-day post-application), chlorantraniliprole (apple: 7-day post-application), and indoxacarb and emamectin benzoate (apple: 1, cherry 7-day post-application). Compared to the susceptible population, the resistant populations resulted in a measurable loss of field performance, or “practical resistance”, for the insecticides emamectin benzoate (at 7-day post-application), chlorantraniliprole (at 21-day post-application), and indoxacarb (at all post-application intervals) in the apple trials, while in cherry trial just indoxacarb at 7-day post-application showed a reduced efficacy. In terms of long-lasting residues, only chlorantraniliprole and indoxacarb maintained measurable leaf residues over all post-application intervals while the leaf residues of the other compounds had largely degraded within the first 7 days. These findings can help fruit growers make adjustments to their spray/re-application intervals and optimally utilize important chemical tools in their integrated pest management programs.
“Lessons Learned” Preventing Recurrent Ischemic Strokes through Secondary Prevention Programs: A Systematic Review
Authors: Lambert Clare , Olulana Oluwaseyi , Bailey-Davis Lisa , Abedi Vida , Zand Ramin
Published: September 2021

Recurrent ischemic strokes are a cause of significant healthcare burdens globally. Patients with uncontrolled vascular risk factors are more likely to develop recurrent ischemic strokes. This study aims to compile information gained from current secondary prevention programs. A pre-defined literature search strategy was applied to PubMed, SCOPUS, CINAHL, and Google Scholar databases, and studies from 1997 to 2020 were evaluated for quality, study aims, and outcomes. The search produced 1175 articles (1092 after duplicates were removed) and titles were screened; 55 titles were retained for the full-text analysis. Of the remaining studies, 31 were retained for assessment, five demonstrated long-term effectiveness, eight demonstrated short-term effectiveness, and 18 demonstrated no effectiveness. The successful studies utilized a variety of different techniques in the categories of physical fitness, education, and adherence to care plans to reduce the risk of recurrent strokes. The lessons we learned from the current prevention programs included (1) offer tailored care for underserved groups, (2) control blood pressure, (3) provide opportunities for medication dosage titration, (4) establish the care plan prior to discharge, (5) invest in supervised exercise programs, (6) remove barriers to accessing care in low resource settings, and (7) improve the transition of care.
Inflammatory Bowel Disease and Sarcopenia: Its Mechanism and Clinical Importance
Authors: Nishikawa Hiroki , Nakamura Shiro , Miyazaki Takako , Kakimoto Kazuki , Fukunishi Shinya , Asai Akira , Nishiguchi Shuhei , Higuchi Kazuhide
Published: September 2021

Malnutrition is a major contributor to muscle loss and muscle dysfunction, known as sarcopenia. Malnutrition is common in patients with inflammatory bowel disease (IBD). IBD includes ulcerative colitis (UC) and Crohn’s disease (CD). The number of patients with IBD has recently been increasing. More severe malnutrition is often seen in CD compared to UC, probably due to CD affecting the main site of nutrient absorption, extensive mucosal lesions, fistulas, short bowel syndrome after resection, or obstruction of the gastrointestinal tract. A recent meta-analysis showed the high prevalence of sarcopenia in patients with IBD, and thus sarcopenia is a very important problem for IBD. Although IBD is more common in younger patients, sarcopenia can develop through a variety of mechanisms, including malnutrition, chronic inflammation, increased inflammatory status in adipose tissue, vitamin deficiency, and imbalance of the muscle–gut axis. In addition, sarcopenia has a negative impact on postoperative complications and hospital stay in patients with IBD. Appropriate intervention for sarcopenia may be important, in addition to clinical remission and endoscopic mucosal healing in patients with IBD. Much more attention will thus be paid to sarcopenia in patients with IBD. In this review, we outline IBD and sarcopenia, based on the current evidence.
High-Sensitivity Cardiac Troponin T in Patients with Severe Chronic Kidney Disease and Suspected Acute Coronary Syndrome
Authors: Alushi Brunilda , Jost-Brinkmann Fabian , Kastrati Adnan , Cassese Salvatore , Fusaro Massimiliano , Stangl Karl , Landmesser Ulf , Thiele Holger , Lauten Alexander
Published: September 2021

(1) Background: Patients with severe chronic kidney disease (CKD G4–G5) often have chronically elevated high-sensitivity cardiac troponin T (hs-cTnT) values above the 99th percentile of the upper reference limit. In these patients, optimal cutoff levels for diagnosing non-ST-elevation acute coronary syndrome (NSTE-ACS) requiring revascularization remain undefined. (2) Methods: Of 11,912 patients undergoing coronary angiography from 2012 to 2017 for suspected NSTE-ACS, 325 (3%) had severe CKD. Of these, 290 with available serial hs-cTnT measurements were included, and 300 matched patients with normal renal function were selected as a control cohort. (3) Results: In the CKD cohort, 222 patients (76%) had NSTE-ACS with indication for coronary revascularization. Diagnostic performance was high at presentation and similar to that of the control population (AUC, 95% CI: 0.81, 0.75–0.87 versus 0.85, 0.80–0.89, p = 0.68), and the ROC-derived cutoff value was 4 times higher compared to the conventional 99th percentile. Combining the ROC-derived cutoff levels for hs-cTnT at presentation and absolute 3 h changes, sensitivity increased to 98%, and PPV and NPV improved up to 93% and 86%, respectively. (4) Conclusions: In patients with severe CKD and suspected ACS, the diagnostic accuracy of hs-cTnT for the diagnosis of NSTE-ACS requiring revascularization is improved by using higher assay-specific cutoff levels combined with early absolute changes.
Sleeve Gastrectomy and Roux-En-Y Gastric Bypass. Two Sculptors of the Pancreatic Islet
Authors: Pérez-Arana Gonzalo-Martín , Fernández-Vivero José , Camacho-Ramírez Alonso , Díaz Gómez Alfredo , Bancalero de los Reyes José , Ribelles-García Antonio , Almorza-Gomar David , Carrasco-Molinillo Carmen , Prada-Oliveira José-Arturo
Published: September 2021

Several surgical procedures are performed for the treatment of obesity. A main outcome of these procedures is the improvement of type 2 diabetes mellitus. Trying to explain this, gastrointestinal hormone levels and their effect on organs involved in carbohydrate metabolism, such as liver, gut, muscle or fat, have been studied intensively after bariatric surgery. These effects on endocrine-cell populations in the pancreas have been less well studied. We gathered the existing data on these pancreatic-cell populations after the two most common types of bariatric surgery, the sleeve gastrectomy (SG) and the roux-en-Y gastric bypass (RYGB), with the aim to explain the pathophysiological mechanisms underlying these surgeries and to improve their outcome.
Real-World Incidence of Febrile Neutropenia among Patients Treated with Single-Agent Amrubicin: Necessity of the Primary Prophylactic Administration of Granulocyte Colony-Stimulating Factor
Authors: Dotsu Yosuke , Yamaguchi Hiroyuki , Fukuda Minoru , Suyama Takayuki , Honda Noritaka , Umeyama Yasuhiro , Taniguchi Hirokazu , Gyotoku Hiroshi , Takemoto Shinnosuke , Tagawa Ryuta , Ogata Ryosuke , Tomono Hiromi , Shimada Midori , Senju Hiroaki , Nakatomi Katsumi , Nagashima Seiji , Soda Hiroshi , Ikeda Hiroaki , Ashizawa Kazuto , Mukae Hiroshi
Published: September 2021

Background: Single-agent amrubicin chemotherapy is a key regimen, especially for small cell lung cancer (SCLC); however, it can cause severe myelosuppression. Purpose: The purpose of this study was to determine the real-world incidence of febrile neutropenia (FN) among patients treated with single-agent amrubicin chemotherapy for thoracic malignancies. Patients and methods: The medical records of consecutive patients with thoracic malignancies, including SCLC and non-small cell lung cancer (NSCLC), who were treated with single-agent amrubicin chemotherapy in cycle 1 between January 2010 and March 2020, were retrospectively analyzed. Results: One hundred and fifty-six patients from four institutions were enrolled. Their characteristics were as follows: median age (range): 68 (32–86); male/female: 126/30; performance status (0/1/2): 9/108/39; SCLC/NSCLC/others: 111/30/15; and prior treatment (0/1/2/3-): 1/96/31/28. One hundred and thirty-four (86%) and 97 (62%) patients experienced grade 3/4 and grade 4 neutropenia, respectively. One hundred and twelve patients (72%) required therapeutic G-CSF treatment, and 47 (30%) developed FN. Prophylactic PEG-G-CSF was not used in cycle 1 in any case. The median overall survival of the patients with FN was significantly shorter than that of the patients without FN (7.2 vs. 10.0 months, p = 0.025). Conclusions: The real-world incidence rate of FN among patients with thoracic malignancies that were treated with single-agent amrubicin chemotherapy was 30%. It is suggested that prophylactic G-CSF should be administered during the practical use of single-agent amrubicin chemotherapy for patients who have already received chemotherapy.
An Integrated Account of Expert Perspectives on Functioning in Schizophrenia
Authors: Nuño Laura , Guilera Georgina , Rojo Emilio , Gómez-Benito Juana , Barrios Maite
Published: September 2021

An integrated and interdisciplinary care system for individuals with schizophrenia is essential, which implies the need for a tool that assesses the difficulties and contextual factors of relevance to their functioning, and facilitates coordinated working across the different professions involved in their care. The International Classification of Functioning, Disability and Health Core Sets (ICF-CS) cover these requirements. This study aimed to evaluate the content validity of the ICF-CSs for schizophrenia from the perspective of experts. Six three-round Delphi studies were conducted with expert panels from different professional backgrounds which have played a significant role in the treatment of individuals with schizophrenia (psychiatry, psychology, nursing, occupational therapy, social work and physiotherapy). In total, 790 experts from 85 different countries participated in the first round. In total, 90 ICF categories and 28 Personal factors reached expert consensus (reached consensus from four or more professional perspectives). All the categories in the brief version of the ICF-CS for schizophrenia reached consensus from all the professional perspectives considered. As for the comprehensive version, 89.7% of its categories reached expert consensus. The results support the worldwide content validity of the ICF-CSs for schizophrenia from an expert perspective and underline the importance of assessing functioning by considering all the components implied.
Structure–Function Relationship and Vision-Related Quality of Life in Glaucoma Secondary to Anterior Uveitis: Comparison with Open Angle Glaucoma
Authors: Lee Ji-Young , Kim Jin-Ho , La Tae-Yoon , Choi Jin-A
Published: September 2021

Purpose: The aim of this study is to investigate the structure–function characteristics and vision-related quality of life (VR-QoL) in uveitic glaucoma (UG) compared with open-angle glaucoma (OAG). Method: The study included 69 patients with UG and 138 patients with primary open angle glaucoma, normal-tension glaucoma. A 25-item National Eye Institute Visual Function Questionnaire (VFQ-25) was used to evaluate the patients’ VR-QoL. The retinal nerve fiber layer thickness (RNFLT) was measured using optical coherence tomography, and the integrated visual field (IVF) was determined using the best location method. Results: There were no significant differences in the binocular IVF and mean deviation (MD) of the affected eye between the OAG and UG group, whereas the average RNFLT was significant thinner in the OAG group (p = 0.008). The patients with UG showed a significantly lower composite score and five subscales of the VFQ-25, compared with those with OAG (p < 0.05, for all, general linear model). Multivariate linear regression analyses showed that the composite score showed the strongest associations with the whole IVF (β = 1.240, p < 0.001) in the OAG group, whereas in the UG group, a significant association was seen only with the inferior VF of the affected eye (β = 0.596, p = 0.038). Conclusions: The eyes with UG exhibited distinctive structure–function characteristics and worse VR-QoL that differentiated them from OAG eyes.
Aortic Valve Stenosis and Cardiac Amyloidosis: A Misleading Association
Authors: Bonelli Andrea , Paris Sara , Nardi Matilde , Henein Michael Y. , Agricola Eustachio , Troise Giovanni , Faggiano Pompilio
Published: September 2021

The association between aortic stenosis (AS) and cardiac amyloidosis (CA) is more frequent than expected. Albeit rare, CA, particularly the transthyretin (ATTR) form, is commonly found in elderly people. ATTR-CA is also the most prevalent form in patients with AS. These conditions share pathophysiological, clinical and imaging findings, making the diagnostic process very challenging. To date, a multiparametric evaluation is suggested in order to detect patients with both AS and CA and choose the best therapeutic option. Given the accuracy of modern non-invasive techniques (i.e., bone scintigraphy), early diagnosis of CA is possible. Flow-charts with the main CA findings which may help clinicians in the diagnostic process have been proposed. The prognostic impact of the combination of AS and CA is not fully known; however, new available specific treatments of ATTR-CA have changed the natural history of the disease and have some impact on the decision-making process for the management of AS. Hence the relevance of detecting these two conditions when simultaneously present. The specific features helping the detection of AS-CA association are discussed in this review, focusing on the shared pathophysiological characteristics and the common clinical and imaging hallmarks.
Fertility-Sparing Surgery for Ovarian Cancer
Authors: Canlorbe Geoffroy , Chabbert-Buffet Nathalie , Uzan Catherine
Published: September 2021

(1) Background: although most patients with epithelial ovarian cancer (EOC) undergo radical surgery, patients with early-stage disease, borderline ovarian tumor (BOT) or a non-epithelial tumor could be offered fertility-sparing surgery (FSS) depending on histologic subtypes and prognostic factors. (2) Methods: we conducted a systematic review to assess the safety and fertility outcomes of FSS in the treatment of ovarian cancer. We queried the MEDLINE, PubMed, Cochrane Library, and Cochrane (“Cochrane Reviews”) databases for articles published in English or French between 1985 and 15 January 2021. (3) Results: for patients with BOT, FSS should be offered to young women with a desire to conceive, even if peritoneal implants are discovered at the time of initial surgery. Women with mucinous BOT should undergo initial unilateral salpingo-oophorectomy, whereas cystectomy is an acceptable option for women with serous BOT. Assisted reproductive technology (ART) can be initiated in patients with stage I BOT if infertility persists after surgery. For patients with EOC, FSS should only be considered after staging for women with stage IA grade 1 (and probably 2, or low-grade in the current classification) serous, mucinous or endometrioid tumors. FSS could also be offered to patients with stage IC grade 1 (or low-grade) disease. For women with serous, mucinous or endometrioid high-grade stage IA or low-grade stage IC1 or IC2 EOC, bilateral salpingo-oophorectomy and uterine conservation could be offered to allow pregnancy by egg donation. Finally, FSS has a large role to play in patients with non- epithelial ovarian cancer, and particularly women with malignant ovarian germ cell tumors.