bluuebunny/crossref_metadata_2025 huggingface dataset:
Microbial Adherence to Contact Lenses and Pseudomonas aeruginosa as a Model Organism for Microbial Keratitis
Authors: Campolo Allison , Pifer Reed , Shannon Paul , Crary Monica
Published: November 2022

Microbial keratitis (MK), the infection of the cornea, is a devastating disease and the fifth leading cause of blindness and visual impairment around the world. The overwhelming majority of MK cases are linked to contact lens wear combined with factors which promote infection such as corneal abrasion, an immunocompromised state, improper contact lens use, or failing to routinely disinfect lenses after wear. Contact lens-related MK involves the adherence of microorganisms to the contact lens. Therefore, this review discusses the information currently available regarding the disease pathophysiology, the common types of microorganisms causing MK, physical and organic mechanisms of adhesion, material properties which are involved in adhesion, and current antimicrobial strategies. This review also concludes that Pseudomonas aeruginosa is a model organism for the investigation of contact lens microbial adherence due to its prevalence in MK cases, its extremely robust adhesion, antimicrobial-resistant properties, and the severity of the disease it causes.
Whole Blood versus Plasma Samples—How Does the Type of Specimen Collected for Testing Affect the Monitoring of Cytomegalovirus Viremia?
Authors: Rzepka Mateusz , Depka Dagmara , Gospodarek-Komkowska Eugenia , Bogiel Tomasz
Published: November 2022

Viral infections, or their reactivations, are one of the most important groups of transplantation complications that can occur among recipients of both hematopoietic cells and solid organ transplants. They are the most commonly caused by cytomegalovirus (CMV). Currently, the use of whole blood or plasma samples is recommended for CMV viral load monitoring. The aim of the study was to assess and compare the level of CMV DNA, depending on the type of clinical material—whole blood or plasma fraction derived from the same patient. The studies were carried out on 156 whole blood samples in which the presence of CMV genetic material was confirmed and the corresponding plasma samples from the same rounds of sampling. CMV DNA was not present in 59 (37.8%) of plasma samples compared to whole blood-positive counterparts. Of the samples positive in both types of clinical specimen, 77 (79.4%) had higher viral DNA levels in the whole blood samples. There were statistically significant differences in the detected CMV DNA load in the whole blood compared to plasma fraction counterparts (p < 0.001). The detected CMV DNA value is usually higher in whole blood compared to plasma samples of the same patient. Due to the variability in CMV viral load depending on the clinical material used for a particular patient, one type of specimen should be always used consequently for CMV viremia monitoring.
Differential Impact of Specific Amino Acid Residues on the Characteristics of Avian Influenza Viruses in Mammalian Systems
Authors: Mashaal Dayly , Mahmoud Sara H. , Müller Christin , Abo Shama Noura M. , Kamer Amal Abo , Abdelaziz Ahmed A. , Ali Mohamed A. , Pleschka Stephan , Mostafa Ahmed
Published: November 2022

Avian influenza virus (AIV) H9N2 was declared to be endemic in birds of the Middle East, in particular in Egypt, with multiple cases of human infections. Despite concerns about the pandemic threat posed by H9N2 AIV, due to the fact that its receptor specificity is similar to that of human influenza viruses, its morbidity and mortality rates in humans are so far negligible. However, the acquisition of specific adaptive amino acid (aa) mutations in the viral polymerase can enhance cross-species transmission of the virus itself or of reassortants, which gained these changes. The polymerase basic protein 2 (PB2) is one of the key determinants for AIV adaptation towards mammals. Although mammalian pathogenicity-related mutations (MPMs) in PB2 genes were identified in different AIVs, the specific effect of single or multiple mutations on viral fitness has not been compared so far. Here, we studied the effect of the aa K at position 591, which was frequently reported in the PB2 of Egyptian H9N2 isolates, on the proliferation efficiency and polymerase activity of an H5N1 (clade 2.2.1.2) AIV already carrying the mammalian adaptive mutation 627K. Using reverse genetics, we generated a set of recombinant parental strains and H5N1 variants carrying the avian-like 591Q/627E or mammalian-like adaptive mutations 591K/627K (H5N1EGY, H9N2EGY, H5N1PB2-H9N2EGY, H5N1H9N2_PB2_K591Q, H5N1PB2_K627E, H5N1PB2_K627E/591K, H5N1PB2_627K/591K). Regardless of the avian-like 627E or the mammalian-adaptive 627K, both variants carrying the 591K (H5N1PB2_K627E/591K, H5N1PB2_627K/591K) and the reassortant H5N1PB2-H9N2EGY replicated to significantly higher levels in mammalian continuous MDCK and Calu-3 cell lines and primary normal human bronchial epithelial cells than the parental H5N1EGY virus (carrying solely the 627K adaptive mutation). Expectedly, the H5N1 variants carrying avian-like PB2 mutations (H5N1H9N2_PB2_K591Q, H5N1PB2_K627E) replicated to significantly lower levels than the parental H5N1EGY virus in the predefined primary and continuous mammalian cell line systems. Consistently, the activity of H5N1 subtype AIV polymerase complexes comprising PB2 segments with singular 591K or combined with 627K was significantly enhanced when compared to parental H5N1EGY and H9N2EGY. This study emphasizes the significant impact of 591K containing PB2 segments in the background of H5N1 polymerase on viral fitness in addition to the well-known MPM 627K in vitro.
Pathology of African Swine Fever in Wild Boar Carcasses Naturally Infected with German Virus Variants
Authors: Sehl-Ewert Julia , Deutschmann Paul , Breithaupt Angele , Blome Sandra
Published: November 2022

In 2020, African swine fever (ASF) was first identified in German wild boar, reaching a case number of about 4400 to date. Upon experimental infection, pathology is well documented; however, data on field infections are scarce in domestic pigs and not available from wild boar, respectively. Although the ASF viral genome is considered exceptionally stable, a total of five lineages with 10 distinct virus variants of genotype II have emerged in Eastern Germany. To investigate the pathology in naturally infected wild boar and to evaluate virus variants II, III and IV for their virulence, wild boar carcasses were obtained from three different outbreak areas. The carcasses underwent virological and pathomorphological investigation. The animals revealed characteristic ASF lesions of the highest severity accompanied by bacterial infections in several cases. In particular, wild boar infected with variant IV from Spree-Neiße (SN) district showed lower viral genome loads and total viral antigen scores, but simultaneously tended to reveal more chronic lesions. Our findings indicate a protracted course of the disease at least after infection with variant IV, but need confirmation under standardized experimental conditions. There is a strong need to monitor differences in the virulence among variants to identify potential attenuation that might complicate diagnosis. In addition, veterinarians, hunters and farmers need to be made aware of less acute courses of ASF to consider this as an important differential to chronic classical swine fever.
Association of Single-Nucleotide Polymorphisms in Interleukin Genes with Microbial Keratitis in a South Indian Population
Authors: Konda Nagaraju , Chakrabarti Subhabrata , Garg Prashant , Willcox Mark D. P.
Published: November 2022

Background: To examine the relationship between single-nucleotide polymorphisms (SNPs) in interleukin (IL) genes and keratitis and its clinical manifestations. Methods: SNPs in IL1B, IL6, CXCL8, IL10, and IL12B were analysed. Differences in frequencies of alleles, genotypes and haplotypes between cases and controls as well as associations between SNPs and clinical variables were calculated by χ2 tests with odds ratios. Results: The minor homologous genotype in IL1B rs16944 (p = 0.036; odds ratio (OR) = 2.063, 95% confidence interval (CI): 1.048–4.061) and CXCL8 rs4073 (p = 0.041; OR = 0.463, 95% CI: 0.224–0.956) and the heterologous genotypes in IL6 rs1800795 (p = 0.046; OR = 0.563, 95% CI: 0.326–0.972) and IL12B rs2569254 (p = 0.0446; OR = 0.557, 95% CI: 0.314–0.989) or rs730691 (p = 0.0051; OR = 0.451, 95% CI: 0.260–0.784) were associated with keratitis. The minor genotype of rs16944 was associated with severe infection (p = 0.046). The heterologous genotype in rs2569254 was associated with hospital admission, photophobia, and mode of contact lens wear (p ≤ 0.041). The heterologous genotype in rs730691 was associated with blurred vision, discharge, anterior chamber reaction, and mode of wear (p ≤ 0.047). Conclusions: This study demonstrates that SNPs in IL1B and CXCL8 are associated with risk of developing keratitis. The study also found relationships between SNPs and clinical measures of keratitis. The potential for ethnic differences in frequency of SNPs and their association with keratitis should be followed up using different populations.
Re-Emergence of Circulation of Seasonal Influenza during COVID-19 Pandemic in Russia and Receptor Specificity of New and Dominant Clade 3C.2a1b.2a.2 A(H3N2) Viruses in 2021–2022
Authors: Kolosova Natalia P. , Ilyicheva Tatiana N. , Unguryan Vasily V. , Danilenko Alexey V. , Svyatchenko Svetlana V. , Onhonova Galina S. , Goncharova Natalia I. , Kosenko Maksim N. , Gudymo Andrey S. , Marchenko Vasiliy Y. , Shvalov Alexander N. , Susloparov Ivan M. , Tregubchak Tatiana V. , Gavrilova Elena V. , Maksyutov Rinat A. , Ryzhikov Alexander B.
Published: November 2022

The circulation of seasonal influenza in 2020–2021 around the world was drastically reduced after the start of the COVID-19 pandemic and the implementation of mitigation strategies. The influenza virus circulation reemerged in 2021–2022 with the global spread of the new genetic clade 3C.2a1b.2a.2 of A(H3N2) viruses. The purpose of this study was to characterize influenza viruses in the 2021–2022 season in Russia and to analyze the receptor specificity properties of the 3C.2a1b.2a.2 A(H3N2) viruses. Clinical influenza samples were collected at the local Sanitary-and-Epidemiological Centers of Rospotrebnadzor. Whole genome sequencing was performed using NGS. The receptor specificity of hemagglutinin was evaluated using molecular modeling and bio-layer interferometry. Clinical samples from 854 cases of influenza A and B were studied; A(H3N2) viruses were in the majority of the samples. All genetically studied A(H3N2) viruses belonged to the new genetic clade 3C.2a1b.2a.2. Molecular modeling analysis suggested a higher affinity of hemagglutinin of 3C.2a1b.2a.2. A(H3N2) viruses to the α2,6 human receptor. In vitro analysis using a trisaccharide 6’-Sialyl-N-acetyllactosamine receptor analog did not resolve the differences in the receptor specificity of 3C.2a1b.2a.2 clade viruses from viruses belonging to the 3C.2a1b.2a.1 clade. Further investigation of the A(H3N2) viruses is required for the evaluation of their possible adaptive advantages. Constant monitoring and characterization of influenza are critical for epidemiological analysis.
Naringin’s Prooxidant Effect on Tumor Cells: Copper’s Role and Therapeutic Implications
Authors: Farhan Mohd
Published: November 2022

Plant-derived polyphenolic chemicals are important components of human nutrition and have been found to have chemotherapeutic effects against a variety of cancers. Several studies in animal models have proven polyphenols’ potential to promote apoptosis and tumor regression. However, the method by which polyphenols show their anticancer effects on malignant cells is not well understood. It is generally known that cellular copper rises within malignant cells and in the serum of cancer patients. In this communication, investigations reveal that naringin (a polyphenol found in citrus fruits) can strongly suppress cell proliferation and trigger apoptosis in various cancer cell lines in the presence of copper ions. The cuprous chelator neocuproine, which confirms copper-mediated DNA damage, prevents such cell death to a large extent. The studies further show that the cellular copper transporters CTR1 and ATP7A have a role in the survival dynamics of malignant cells after naringin exposure. The findings emphasize the crucial function of copper dynamics and mobilization in cancer cells and pave the path for a better understanding of polyphenols as nutraceutical supplements for cancer prevention and treatment.
Acute and Reproductive Toxicity Evaluation of Ormona® SI and Ormona® RC—Two New Nutraceuticals with Geranylgeraniol, Tocotrienols, Anthocyanins, and Isoflavones—In Adult Zebrafish
Authors: da Rocha Clarice Flexa , Flexa Camila de Nazaré Nunes , de Souza Gisele Custodio , Pereira Arlindo César Matias , Carvalho Helison de Oliveira , do Nascimento Aline Lopes , de Jesus Vasconcelos Natasha Juliana Perdigão , da Silva Heitor Ribeiro , Carvalho José Carlos Tavares
Published: November 2022

The zebrafish is a popular organism to test the toxicity of compounds. Here, we evaluate the acute and reproductive toxicity of Ormona SI® (OSI) and RC® (ORC), two herbal products developed for menopausal women with tocotrienols, geranylgeraniol, isoflavones, and anthocyanins. The acute toxicity was evaluated by behavioral alterations, lethality, and tissue changes (intestine, liver, kidney) after oral treatment with high product doses (500, 1000, and 2000 mg/kg). The reproductive toxicity was evaluated after 21 days of oral treatment with OSI and ORC at 200 mg/kg. Our results show that the LD50 could not be assessed due to the low mortality rate even with the highest dose; the behavioral alterations were not different from those of the group treated only with the vehicle (2% DMSO). The tissue changes were minor in OSI and more severe in ORC at the highest (2000 mg/kg) dose, while no tissue abnormality was observed at 500 mg/kg. In the reproductive assessment, continuous treatment could decrease the maturation of the reproductive cells, which also significantly decreases the egg spawning. This effect was attributed to the estrogenic activity of the isoflavones. In conclusion, the acute toxicity analysis shows that the products did not elicit lethal or sublethal effects observed in the model when used up to 500 mg/kg. Regarding the reproductive toxicity, decreased fertility was observed, which was expected due to the presence of isoflavones (phytoestrogens). Considering that the product is intended for menopausal and postmenopausal women, the presence of isoflavones is beneficial. Further studies should be performed to corroborate these results in mammals.
Integrated Chemical Characterization, Network Pharmacology and Transcriptomics to Explore the Mechanism of Sesquiterpenoids Isolated from Gynura divaricata (L.) DC. against Chronic Myelogenous Leukemia
Authors: Ye Xinyuan , Wang Long , Yang Xin , Yang Jie , Zhou Jie , Lan Cai , Kantawong Fahsai , Kumsaiyai Warunee , Wu Jianming , Zeng Jing
Published: November 2022

Chronic myelogenous leukemia (CML) is a serious threat to human health, while drugs for CML are limited. Herbal medicines with structural diversity, low toxicity and low drug resistance are always the most important source for drug discoveries. Gynura divaricata (L.) DC. is a well-known herbal medicine whose non-alkaline ingredients (GD-NAIs) were isolated. The GD-NAIs demonstrated potential anti-CML activity in our preliminary screening tests. However, the chemical components and underlying mechanism are still unknown. In this study, GD-NAIs were tentatively characterized using UHPLC-HRMS combined with molecular networking, which were composed of 75 sesquiterpenoids. Then, the anti-CML activities of GD-NAIs were evaluated and demonstrated significant suppression of proliferation and promotion of apoptosis in K562 cells. Furthermore, the mechanism of GD-NAIs against CML were elucidated using network pharmacology combined with RNA sequencing. Four sesquiterpenoids would be the main active ingredients of GD-NAIs against CML, which could regulate PD-L1 expression and the PD-1 checkpoint pathway in cancer, PI3K/AKT, JAK/STAT, TGF-β, estrogen, Notch and Wnt signaling pathways. In conclusion, our study reveals the composition of GD-NAIs, confirms its anti-CML activity and elucidates their underlying mechanism, which is a potential countermeasure for the treatment of CML.
Fasudil Ameliorates Methotrexate-Induced Hepatotoxicity by Modulation of Redox-Sensitive Signals
Authors: Aboubakr Esam M. , Ibrahim Ahmed R. N. , Ali Fares E. M. , Mourad Ahmed A. E. , Ahmad Adel M. , Hofni Amal
Published: November 2022

Methotrexate (MTX) is one of the most widely used cytotoxic chemotherapeutic agents, and it is used in the treatment of different autoimmune disorders. However, the clinical applications of MTX are limited by its hepatic toxicity. Hence, the present study was conducted to evaluate the efficacy of fasudil (Rho-Kinase inhibitor) in the amelioration of MTX hepatotoxicity and the possible underlying mechanisms. Experimentally, 32 male Sprague Dawley rats were used and divided into four groups: control, MTX (20 mg/kg, i.p., single dose), fasudil (10 mg/kg/day i.p.) for one week, and fasudil plus MTX. It was found that MTX significantly induced hepatitis and hepatocellular damage, as shown by abnormal histological findings and liver dysfunction (ALT and AST), with up-regulation of the inflammatory mediators NF-κB-p65 and IL-1β. Moreover, MTX remarkably disrupted oxidant/antioxidant status, as evidenced by malondialdehyde (MDA) up-regulation associated with the depletion of superoxide dismutase (SOD), catalase, and reduced glutathione (GSH) levels. Moreover, MTX reduced the hepatic expression of B-cell lymphoma 2 (Bcl-2). On the contrary, the i.p. administration of fasudil significantly ameliorated MTX hepatotoxicity by histopathological improvement, restoring oxidant/antioxidant balance, preventing hepatic inflammation, and improving the hepatic anti-apoptotic capability. Furthermore, fasudil hepatic concentration was determined for the first time using the validated RP-HPLC method. In conclusion, the present study revealed that fasudil has a reliable hepatoprotective effect against MTX hepatotoxicity with underlying antioxidant, anti-inflammatory, and anti-apoptotic mechanisms. It also introduced a new method for the determination of fasudil hepatic tissue concentration using the RP-HPLC technique.
Evaluation of Different Thermoanalytical Methods for the Analysis of the Stability of Naproxen-Loaded Amorphous Solid Dispersions
Authors: Szabó Edina , Haraszti Anna , Záhonyi Petra , Vadas Dániel , Csontos István , Nagy Zsombor Kristóf , Van den Mooter Guy , Marosi György
Published: November 2022

The aim of this research was to investigate three thermoanalytical techniques from the glass transition temperature (Tg) determination point of view. In addition, the examination of the correlation between the measured Tg values and the stability of the amorphous solid dispersions (ASDs) was also an important part of the work. The results showed that a similar tendency of the Tg can be observed in the case of the applied methods. However, Tg values measured by thermally stimulated depolarization currents showed higher deviation from the theoretical calculations than the values measured by modulated differential scanning calorimetry, referring better to the drug-polymer interactions. Indeed, the investigations after the stress stability tests revealed that micro-thermal analysis can indicate the most sensitive changes in the Tg values, better indicating the instability of the samples. In addition to confirming that the active pharmaceutical ingredient content is a crucial factor in the stability of ASDs containing naproxen and poly(vinylpyrrolidone-co-vinyl acetate), it is worthwhile applying orthogonal techniques to better understand the behavior of ASDs. The development of stable ASDs can be facilitated via mapping the molecular mobilities with suitable thermoanalytical methods.
Peptide-Based [68Ga]Ga Labeled PET Tracer for Tumor Imaging by Targeting Tumor-Associated Macrophages
Authors: Huang Mingxing , Wang Rang , Li Mufeng , Cai Huawei , Tian Rong
Published: November 2022

Tumor-associated macrophages (TAMs) are known to promote cancer development and metastasis. In this study, a TAMs-targeting peptide named M2pep was selected to investigate the feasibility of [68Ga]Ga-labeled M2pep as a noninvasive probe in targeted TAMs imaging. The peptide M2pep was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with 68Ga. The cellular uptake and binding assay were assessed in M2 macrophages and in the B16F10 cell line. Micro-PET imaging and a biodistribution study were performed on B16F10 tumor-bearing mice. High radiochemical purity [68Ga]Ga-DOTA-M2pep (>95%) was prepared and was stabilized in saline and bovine serum at 37 °C for 2 h. In vitro studies demonstrated high uptake of [68Ga]Ga-DOTA-M2pep in M2 macrophages, which was effectively blocked by the “cold” M2pep (free peptide). The micro-PET imaging and biodistribution study revealed that [68Ga]Ga-DOTA-M2pep reached the tumor site rapidly and showed high accumulation in the tumor at 1 h post-injection. In addition, the probe was rapidly cleared from the blood and mainly excreted via the kidneys, resulting in a high tumor/background ratio. Preclinical studies have shown that [68Ga]Ga-DOTA-M2pep specifically targets TAMs and might be a promising molecular probe for the noninvasive visualization of TAMs expression.
Dengue, West Nile, and Zika Viruses: Potential Novel Antiviral Biologics Drugs Currently at Discovery and Preclinical Development Stages
Authors: Martins Ivo C. , Ricardo Rafaela C. , Santos Nuno C.
Published: November 2022

Dengue, West Nile and Zika viruses are vector-borne flaviviruses responsible for numerous disease outbreaks in both Hemispheres. Despite relatively low mortality, infection may lead to potentially severe situations such as (depending on the virus): hypovolemic shock, encephalitis, acute flaccid paralysis, Guillain-Barré syndrome, congenital malformations (e.g., microcephaly) and, in some situations, death. Moreover, outbreaks also have major socioeconomic repercussions, especially in already vulnerable societies. Thus far, only generic symptoms relief is possible, as there are no specific treatments available yet. Dengvaxia was the world’s first dengue vaccine. However, it is not fully effective. Prophylactic approaches against West Nile and Zika viruses are even more limited. Therefore, therapeutic strategies are required and will be discussed hereafter. We will first briefly present these viruses’ epidemiology, life cycle and structure. Then, we introduce the clinical presentation, diagnosis approaches and available vaccines. Finally, we list and discuss promising compounds at discovery and preclinical development stages already deposited at the GlobalData database and divided into three main types, according to therapeutic molecule: antibody-based, peptide-based molecules and, other compounds. To conclude, we discuss and compare promising developments, useful for future therapies against these three flaviviruses of major concern to human health.
FDA-Approved Small Molecules in 2022: Clinical Uses and Their Synthesis
Authors: Benedetto Tiz Davide , Bagnoli Luana , Rosati Ornelio , Marini Francesca , Santi Claudio , Sancineto Luca
Published: November 2022

This review describes the recently FDA-approved drugs (in the year 2022). Many of these products contain active moieties that FDA had not previously approved, either as a single ingredient or as part of a combination. These products frequently provide important new therapies for patients with multiple unmet diseases. The diverse small molecules are described according to the date of approval and their syntheses is discussed. This review comprises classical chemical scaffolds together with innovative drugs such as a deuterium-containing drug.
Effectiveness of an Advanced Naloxone Training, Simulation, and Assessment of Second-Year Pharmacy Students
Authors: Courtney Jennifer , Kreys Eugene , Luu Bryan , Kreys Tiffany , Vinall Ruth , Quang Vy , Titus-Lay Erika
Published: November 2022

Background: Opioid overdoses continue to be one of the most urgent public health priorities. In 2020, reported overdose deaths in the United States reached a high of over 93,000 cases. As the COVID-19 pandemic and opioid crisis continues to be addressed, life-saving agents must be more widely accessible to those with a high overdose risk. An essential step to increasing access is to train student pharmacists to dispense naloxone. Once licensed, the number of personnel authorized to dispense naloxone can increase. Objectives: To design a training program to educate second-year pharmacy (P2) students on furnishing naloxone under a state protocol. Methods: A multi-phased curriculum-based naloxone training program was delivered to P2 students and included lecture-based education, team-based learning (TBL) applications, case-based scenarios, and summative assessments to improve student knowledge and confidence in furnishing naloxone. Students were surveyed on their knowledge and confidence with naloxone prior to training, after the in-class training and TBL applications and after three assessments. Assessments included simulated patient counseling, case-based scenarios, and proper dispensing of naloxone in a community pharmacy simulation lab. Results: A total of 185 student pharmacists completed the naloxone training program and 68 completed all three surveys. Average scores for naloxone assessments were 83% for the APPS lab patient case, 90.5% for the prescription label typed for the naloxone product, and 88.5% for patient counseling. Statistically significant increases in knowledge-based quiz-like scores (42.1% after training vs. 7.2% after assessment) and in the proportion of students affirmatively answering survey questions after training and assessment was observed. Conclusion: Multi-phase curriculum-based naloxone training program improved pharmacy student knowledge and confidence in furnishing naloxone under a state BOP protocol.
Pronounced Declines in Meperidine in the US: Is the End Imminent?
Authors: Harrison Lavinia R. , Arnet Rhudjerry E. , Ramos Anthony S. , Chinga Poul A. , Anthony Trinidy R. , Boyle John M. , McCall Kenneth L. , Nichols Stephanie D. , Piper Brian J.
Published: November 2022

Background: Once a widely used analgesic in the United States (US), meperidine offered an alternative opioid to other opioids as a pain reliever and was widely assumed to be safer with acute pancreatitis. However, within the last two decades meperidine, has gone from a frequently used drug to being used only when patients exhibit atypical reactions to opioids (e.g., morphine and hydromorphone), to being taken off the World Health Organization List of Essential Medications and receiving strong recommendations for overall avoidance. The aim of this study was to identify changes in meperidine distribution in the US, and regional disparities as reported to the Drug Enforcement Administration’s Automation of Reports and Consolidated Orders System (DEA ARCOS) and Medicaid. Methods: Data related to meperidine distribution was obtained through ARCOS (2001–2021) and Medicaid public use files (2016–2021). Heat maps were used to visualize regional disparities in distribution by state. States outside a 95% confidence interval were statistically significant. Results: Meperidine distribution between 2001 and 2021 decreased by 97.4% (R = −0.97, p < 0.0001). There was a 34-fold state-level difference in meperidine distribution between Arkansas (16.8 mg/10 persons) and Connecticut (0.5 mg/10 persons) in 2020. Meperidine distribution in 2020 was elevated in Arkansas, Mississippi, and Alabama. In 2021, meperidine distribution was highest in Arkansas (16.7 mg/10 persons) and lowest in Connecticut (0.8 mg/10 persons). Total prescriptions of meperidine as reported by Medicaid decreased by 73.8% (R = −0.67, p = 0.045) between 2016 and 2021. Conclusion: We observed a decrease in the overall distribution of meperidine in the past two decades, with a similar recent decline in prescribing it to Medicaid enrollees. The shortage of some parenteral formulations is an important contributor to these declines, however, the most likely explanation for this global decline in use is related to an increased recognition of safety concerns related to important drug interactions and a neurotoxic metabolite. This data may reflect plans to phase out the use of this opioid, especially in the many situations where safer and more preferred opioids are available.
Over-the-Counter Drug Misuse and Dependence: Public Health Ethics’ Foray into Fight against the Codeine Crisis
Authors: Ino Hiroyasu , Nakazawa Eisuke
Published: November 2022

Over-the-counter (OTC) drugs, such as codeine, are available as an OTC drug at common drugstores and major e-commerce platforms, despite their known propensity for causing psychological dependence and harm from overuse. Misuse of and dependence on over-the-counter drugs are serious public health issues. Possible measures include stricter regulation and control, as well as regulation of access to information and awareness activities, but their effectiveness is limited. Up-scheduling, in which OTC drugs are placed under prescription or full regulation, is expected to have a definite effect. However, up-scheduling poses public health ethical challenges. Up-scheduling restricts the freedom of consumers to purchase OTC drugs, and the economic right of manufacturers and sellers. Up-scheduling may also interfere with people’s right to seek self-care through the proper use of OTC drugs. Limited up-scheduling with respect to age may be an effective way to implement up-scheduling while avoiding ethical issues. However, from a public health perspective, it is necessary to improve the information infrastructure so that prescription drug information can be shared electronically, and to strengthen measures to prevent mental health problems among young people that lead to OTC drug misuse, even after up-scheduling.
Joint Pre- and Post-Equalization with Higher-Order Modulation Formats in SDM-Based Optical MIMO Systems
Authors: Singh Jasmeet , Ahrens Andreas , Lochmann Steffen
Published: November 2022

The multiple-input and multiple-output (MIMO) technology is a promising area of research to cope up with the demands of higher data rates and capacity. In the optical communication domain, the combination of space-division multiplexing (SDM) with higher-order modulation (HOM) formats over an optical MIMO system actively addresses these challenges. By allowing multi-level signaling with limited increment in the transmitter’s complexity, a jointly designed pre- and post-equalization (PPE) for an optical MIMO system with a multi-mode fiber (MMF) link is proposed. Cost-effectiveness of the system is incorporated by utilizing intensity modulation/direct detection (IM/DD) with HOM formats such as pulse-amplitude modulation (PAM) schemes. With the aid of a numerical optimization algorithm, the proposed joint-PPE filter coefficients are optimized with respect to the MMF channel and the transmit power constraint. In contrast to existing research on the single-mode fiber (SMF) based optical systems, the effectiveness of the proposed joint-PPE filter is analyzed on an MMF link, which is considerably degraded by the modal dispersion. In the analyzed experimental scenario, the proposed joint-PPE scheme confirms to be beneficial as compared to the post-equalization only (PE-only) in terms of bit-error rate (BER) performance. Furthermore, the required average received optical power to reach a BER 10−4 by the joint-PPE scheme is improved by 2 dB with comparison to the minimum mean-squared error (MMSE) PE-only.
Utilizing Dynamic Scattering for Learning Radar Cross-Section of a Flapping-Wing Aircraft
Authors: Zhou Zeyang , Huang Jun
Published: November 2022

To study the radar cross-section (RCS) of a flapping-wing aircraft, a method of flapping-wing dynamic scattering is presented. The aircraft has two rigid wings and a fuselage similar to a bird’s body, where the plane shape of the wing is U-type. The aircraft model is established and the pitching and flapping actions of the wing are simulated. The electromagnetic scattering characteristics of aircraft under two flight modes, different radar wave frequencies and observation angles are investigated. The results show that in the given gliding mode, the fuselage provides the main contribution to the lateral peak value. For the given forward azimuth range in the flapping mode, increasing the azimuth can reduce the mean and peak of the aircraft dynamic RCS curve, while increasing the elevation angle will increase the peak and mean of the aircraft dynamic RCS curve. In the flapping mode, the mean RCS of the aircraft in the lateral backward azimuth is significantly lower than that in the lateral forward azimuth. For the given tail azimuth range, the increase of azimuth will increase the mean and peak level of aircraft dynamic RCS curve. The presented method is effective to study the dynamic RCS characteristics of the flapping-wing aircraft.
Singlemode-Multimode-Singlemode Fiber-Optic Interferometer Signal Demodulation Using MUSIC Algorithm and Machine Learning
Authors: Ushakov Nikolai , Markvart Aleksandr , Liokumovich Leonid
Published: November 2022

The paper is aimed at improving the efficiency of signal processing for intermode fiber-optic interferometers. To do so, we propose to use the MUSIC algorithm. It is shown that the use of traditional methods for estimating the number of signal components leads to poor operation of the MUSIC algorithm when applied to intermode interference signals. The possibility of using machine learning to estimate the number of signal components was investigated. The advantage of the proposed signal processing for demodulating the signals of an intermode interferometer over the Fourier transform has been experimentally demonstrated on the examples of simultaneous strain and curvature measurement, as well as pulse-wave sensing. The results can be also applied for processing signals of other optical-fiber sensors and multi-component signals of a different nature, for example, optical coherence tomography and radar signals.
Light-Induced Self-Oscillations and Spoiling of the Bragg Resonance Due to Nonlinear Optical Propagation in Heliconical Cholesteric Liquid Crystals
Authors: Gevorgyan Ashot H. , Simoni Francesco
Published: November 2022

In a recent paper, we have reported the results of a study of the nonlinear light propagation of a beam traveling along the helix direction of a heliconical cholesteric liquid crystal, showing that optical reorientation leads to instabilities in the optical transmission when the light wavelength is close to the Bragg resonance. Here we report a detailed study of this phenomenon, using Ambartsumian’s layer addition modified method to take into account the continuous modification of the wave field during propagation. We show that the whole transmission spectrum is modified by increasing the light intensity and point out that self-induced oscillations take place at lower intensities on the red side edge of the Bragg resonance while stable values of transmittivity are still observed on the blue side edge. A further increase in the intensity leads to oscillations of lower amplitude on the blue side while an irregular behavior of the transmission is achieved on the red side. At higher intensities, the Bragg resonance disappears and transmission becomes unstable for any light wavelength. A simple phenomenological model is proposed to account for the onset of the oscillations and the asymmetry of the behavior at the opposite side of the Bragg resonance. We also point out that the static electric field is a driving parameter to switch from stable to oscillatory to irregular behavior in the transmittivity at a given light wavelength.
Diverse Physiological Roles of Flavonoids in Plant Environmental Stress Responses and Tolerance
Authors: Shomali Aida , Das Susmita , Arif Namira , Sarraf Mohammad , Zahra Noreen , Yadav Vaishali , Aliniaeifard Sasan , Chauhan Devendra Kumar , Hasanuzzaman Mirza
Published: November 2022

Flavonoids are characterized as the low molecular weight polyphenolic compounds universally distributed in planta. They are a chemically varied group of secondary metabolites with a broad range of biological activity. The increasing amount of evidence has demonstrated the various physiological functions of flavonoids in stress response. In this paper, we provide a brief introduction to flavonoids’ biochemistry and biosynthesis. Then, we review the recent findings on the alternation of flavonoid content under different stress conditions to come up with an overall picture of the mechanism of involvement of flavonoids in plants’ response to various abiotic stresses. The participation of flavonoids in antioxidant systems, flavonoid-mediated response to different abiotic stresses, the involvement of flavonoids in stress signaling networks, and the physiological response of plants under stress conditions are discussed in this review. Moreover, molecular and genetic approaches to tailoring flavonoid biosynthesis and regulation under abiotic stress are addressed in this review.
The Cultural and Commercial Value of Tulsi (Ocimum tenuiflorum L.): Multidisciplinary Approaches Focusing on Species Authentication
Authors: Bhamra Sukvinder Kaur , Heinrich Michael , Johnson Mark R. D. , Howard Caroline , Slater Adrian
Published: November 2022

Tulsi (Holy basil, Ocimum tenuiflorum L., Lamiaceae), native to Asia, has become globalised as the cultural, cosmetic, and medicinal uses of the herb have been popularised. DNA barcoding, a molecular technique used to identify species based on short regions of DNA, can discriminate between different species and identify contaminants and adulterants. This study aimed to explore the values associated with Tulsi in the United Kingdom (UK) and authenticate samples using DNA barcoding. A mixed methods approach was used, incorporating social research (i.e., structured interviews) and DNA barcoding of Ocimum samples using the ITS and trnH-psbA barcode regions. Interviews revealed the cultural significance of Tulsi: including origins, knowledge exchange, religious connotations, and medicinal uses. With migration, sharing of plants and seeds has been seen as Tulsi plants are widely grown in South Asian (SA) households across the UK. Vouchered Ocimum specimens (n = 33) were obtained to create reference DNA barcodes which were not available in databases. A potential species substitution of O. gratissimum instead of O. tenuiflorum amongst SA participants was uncovered. Commercial samples (n = 47) were difficult to authenticate, potentially due to DNA degradation during manufacturing processes. This study highlights the cultural significance of Tulsi, despite a potential species substitution, the plant holds a prestigious place amongst SA families in the UK. DNA barcoding was a reliable way to authenticate Ocimum species.
Combined Approach of GWAS and Phylogenetic Analyses to Identify New Candidate Genes That Participate in Arabidopsis thaliana Primary Root Development Using Cellular Measurements and Primary Root Length
Authors: López-Ruiz Brenda Anabel , Quezada-Rodríguez Elsa H. , Piñeyro-Nelson Alma , Tovar Hugo , García-Ponce Berenice , Sánchez María de la Paz , Álvarez-Buylla Elena R. , Garay-Arroyo Adriana
Published: November 2022

Genome-wide association studies (GWAS) have allowed the identification of different loci associated with primary root (PR) growth, and Arabidopsis is an excellent model for these studies. The PR length is controlled by cell proliferation, elongation, and differentiation; however, the specific contribution of proliferation and differentiation in the control of PR growth is still poorly studied. To this end, we analyzed 124 accessions and used a GWAS approach to identify potential causal genomic regions related to four traits: PR length, growth rate, cell proliferation and cell differentiation. Twenty-three genes and five statistically significant SNPs were identified. The SNP with the highest score mapped to the fifth exon of NAC048 and this change makes a missense variant in only 33.3% of the accessions with a large PR, compared with the accessions with a short PR length. Moreover, we detected five more SNPs in this gene and in NAC3 that allow us to discover closely related accessions according to the phylogenetic tree analysis. We also found that the association between genetic variants among the 18 genes with the highest scores in our GWAS and the phenotypic classes into which we divided our accessions are not straightforward and likely follow historical patterns.
Taxonomy Complexity of Some Tyrrhenian Endemic Limonium Species Belonging to L. multiforme Group (Plumbaginaceae): New Insights from Molecular and Morphometric Analyses
Authors: Iamonico Duilio , De Castro Olga , Di Iorio Emanuela , Nicolella Gianluca , Iberite Mauro
Published: November 2022

The delimitation of Limonium taxa is highly complicated due to hybridization, polyploidy, and apomixis. Many “microspecies” were described and aggregated into groups, most of which are still poorly known from both molecular and morphological points of view. The aim of this study is to investigate four endemic species from the Tyrrhenian coast of central Italy and the Ponziane Archipelago belonging to the L. multiforme group (L. amynclaeum, L. circaei, L. pandatariae, and L. pontium) by means of molecular and morphometric analyses. Molecular data by sequencing ITS and three plastid markers and morphometric data highlight new information about the taxonomy of these taxa so as to reduce them into a single specific entity. In fact, the better taxonomic choice is to consider the populations studied as part of a single species, i.e., Limonium pontium. Three subspecies are recognized, i.e., subsp. pontium [= L. circaei = L. amynclaeum; from Circeo to Gianola localities (excluding Terracina) and from islands Ponza, Palmarola, Zannone, and Santo Stefano], subsp. pandatariae comb. et stat. nov. (from island of Ventotene), and subsp. terracinense subsp. nov. (from Terracina).
Varietal Resistance and Chemical Ecology of the Rice Stink Bug, Oebalus pugnax, on Rice, Oryza sativa
Authors: Bhavanam Santhi , Stout Michael J.
Published: November 2022

The rice stink bug, Oebalus pugnax F. (Hemiptera: Pentatomidae), is a key pest of heading rice in the southern United States. Chemical insecticide application is currently the primary method of control of O. pugnax, warranting an improved management program for this species. The potential other management tactics for O. pugnax include eco-friendly measures such as host-plant resistance, silicon application, and the use of semiochemicals. In this study, the feeding preference and performance of O. puganx on cultivated and non-cultivated rice varieties were examined. Choice tests showed that the rice varieties Cheniere and Kaybonnet were most and least preferred by O. pugnax for feeding, respectively. The results of a no-choice experiment showed that the number of nymphs surviving to the adult stage did not differ among rice varieties, although the percent survival was low on the varieties Kaybonnet and Jazzman. Here, we also showed for the first time that silicon application had a significant negative impact on O. pugnax performance, increasing the nymph development time and reducing survival by almost 40% relative to the control. Based on these results, it could be suggested that silicon amendment is a promising management strategy for this pest. Further research is needed to examine whether silicon application also reduces the feeding damage caused by O. puganx. In addition, the chemical compositions of the metathoracic gland and dorsal abdominal gland extracts were also characterized for the first time in this study, and their biological roles and potential use in pest management are discussed.
Monographic Quality Parameters and Genotoxicity Assessment of Asphodelus bento-rainhae and Asphodelus macrocarpus Root Tubers as Herbal Medicines
Authors: Malmir Maryam , Serrano Rita , Lima Katelene , Duarte Maria Paula , Moreira da Silva Isabel , Silva Lima Beatriz , Caniça Manuela , Silva Olga
Published: November 2022

Root tubers of Asphodelus bento-rainhae subsp. bento-rainhae (AbR), an endemic species with relevant interest due to conservation concerns, and Asphodelus macrocarpus subsp. macrocarpus (AmR) have been traditionally used for culinary and medicinal purposes, mainly associated with skin infection and inflammation. The present study aims to establish the quality control criteria for the proper characterization of dried root tubers of both species as herbal substances, together with their preclinical safety assessments. Botanical identification using macroscopic and microscopic techniques and phytochemical evaluation/quantification of the main classes of marker secondary metabolites, including phenolic compounds (flavonoid, anthraquinone, condensed and hydrolysable tannin) and terpenoids were performed. Additionally, in vitro genotoxicity/mutagenicity was evaluated by Ames test. Evident morphological differences in the development of tubercles (3.5 × 1 cm in AbR and 8.7 × 1.4 cm in AmR) and microscopicly in the arrangements and characteristics of the vascular cylinder (metaxylem and protoxylems) were found. Anatomical similarities such as multiple-layered epidermis (velamen) and the cortex area with thin-walled idioblasts (134 ± 2.9 µm and 150 ± 27.6 µm) containing raphide crystals (37.2 ± 14.2 µm and 87.7 ± 15.3 µm) were observed between AbR and AmR, respectively. Terpenoids (173.88 ± 29.82 and 180.55 ± 10.57 mg OAE/g dried weight) and condensed tannins (128.64 ± 14.05 and 108.35 ± 20.37 mg CAE/g dried weight) were found to be the main class of marker secondary metabolites of AbR and AmR extracts, respectively. No genotoxicity (up to 5 mg/plate, without metabolic activation) was detected in these medicinal plants’ tested extracts. The obtained results will contribute to the knowledge of the value of the Portuguese flora and their future commercial cultivation utilization as raw materials for industrial and pharmaceutical use.
Environmental Signals Act as a Driving Force for Metabolic and Defense Responses in the Antarctic Plant Colobanthus quitensis
Authors: Bertini Laura , Proietti Silvia , Fongaro Benedetta , Holfeld Aleš , Picotti Paola , Falconieri Gaia Salvatore , Bizzarri Elisabetta , Capaldi Gloria , Polverino de Laureto Patrizia , Caruso Carla
Published: November 2022

During evolution, plants have faced countless stresses of both biotic and abiotic nature developing very effective mechanisms able to perceive and counteract adverse signals. The biggest challenge is the ability to fine-tune the trade-off between plant growth and stress resistance. The Antarctic plant Colobanthus quitensis has managed to survive the adverse environmental conditions of the white continent and can be considered a wonderful example of adaptation to prohibitive conditions for millions of other plant species. Due to the progressive environmental change that the Antarctic Peninsula has undergone over time, a more comprehensive overview of the metabolic features of C. quitensis becomes particularly interesting to assess its ability to respond to environmental stresses. To this end, a differential proteomic approach was used to study the response of C. quitensis to different environmental cues. Many differentially expressed proteins were identified highlighting the rewiring of metabolic pathways as well as defense responses. Finally, a different modulation of oxidative stress response between different environmental sites was observed. The data collected in this paper add knowledge on the impact of environmental stimuli on plant metabolism and stress response by providing useful information on the trade-off between plant growth and defense mechanisms.