bluuebunny/crossref_metadata_2025 huggingface dataset:
Dermatological Manifestations in COVID-19: A Case Study of SARS-CoV-2 Infection in a Genetic Thrombophilic Patient with Mthfr Mutation
Authors: Celestino Gabriela Gomes , Amarante Marla Karine , Vespero Eliana Carolina , Tavares Eliandro Reis , Yamauchi Lucy Megumi , Candido Érika Donizetti , de Oliveira Danielle Bruna Leal , Durigon Edison Luiz , Yamada-Ogatta Sueli Fumie , Faccin-Galhardi Ligia Carla
Published: March 2023

The present case study describes the dermatological manifestations of COVID-19 in a patient with genetic thrombophilia (MTHFR–C677T mutation) and the identification of a SARS-CoV-2 variant of interest (VOI). A female patient, 47 years old, unvaccinated, with thrombophilia, was diagnosed with COVID-19. She presented with urticarial and maculopapular eruptions from the seventh day of symptoms, which progressed to multiple lesions with dark centers (D-dimer value > 1450 ng/mL). The dermatological manifestations disappeared after 30 days, corroborating the reduction in D-dimer levels. Viral genome sequencing revealed infection by the VOI Zeta (P.2). Antibody testing, performed 30 days after the onset of symptoms, detected only IgG. The virus neutralization test showed the highest neutralizing titer for a P.2 strain, validating the genotypic identification. Lesions were suggested to be due to infection in skin cells causing a direct cytopathic effect or release of pro-inflammatory cytokines triggering erythematous and urticarial eruptions. In addition, vascular complications are also proposed to be due to the MTHFR mutation and increased D-dimer values. This case report is an alert about COVID-19 in patients with pre-existing vascular diseases, especially in unvaccinated patients, by VOI.
Field Resistance to Rose Rosette Disease as Determined by Multi-Year Evaluations in Tennessee and Delaware
Authors: Windham Mark T. , Evans Thomas , Collins Sara , Lake Juniper A. , Lau Jeekin , Riera-Lizarazu Oscar , Byrne David H.
Published: March 2023

Rose rosette disease (RRD) caused by the rose rosette emaravirus (RRV) and transmitted by the eriophyid mite Phyllocoptes fructiphilus (Pf), both native to North America, has caused significant damage to roses over the last several decades. As cultural and chemical control of this disease is difficult and expensive, a field trial was established to systematically screen rose germplasm for potential sources of resistance. One hundred and eight rose accessions representing the diversity of rose germplasm were planted in Tennessee and Delaware, managed to encourage disease development, and evaluated for symptom development and viral presence for three years. All major commercial rose cultivars were susceptible to this viral disease to varying levels. The rose accessions with no or few symptoms were species accessions from the sections Cinnamomeae, Carolinae, Bracteatae, and Systylae or hybrids with these. Among these, some were asymptomatic; they displayed no symptoms but were infected by the virus. Their potential depends on their ability to serve as a source of viruses. The next step is to understand the mechanism of resistance and genetic control of the various sources of resistance identified.
‘Candidatus Rickettsia andeanae’ and Probable Exclusion of Rickettsia parkeri in Ticks from Dogs in a Natural Area of the Pampa Biome in Brazil
Authors: Krawczak Felipe S. , Binder Lina C. , Gregori Fábio , Martins Thiago F. , Pádua Gracielle T. , Sponchiado Jonas , Melo Geruza L. , Polo Gina , Labruna Marcelo B.
Published: March 2023

Spotted fever illness caused by the tick-borne pathogen Rickettsia parkeri has emerged in the Pampa biome in southern Brazil, where the tick Amblyomma tigrinum is implicated as the main vector. Because domestic dogs are commonly parasitized by A. tigrinum, this canid is also a suitable sentinel for R. parkeri-associated spotted fever. Herein, we investigate rickettsial infection in ticks, domestic dogs and small mammals in a natural reserve of the Pampa biome in southern Brazil. The ticks A. tigrinum, Amblyomma aureolatum and Rhipicephalus sanguineus were collected from dogs. Molecular analyses of ticks did not detect R. parkeri; however, at least 34% (21/61) of the A. tigrinum ticks were infected by the non-pathogenic agent ‘Candidatus Rickettsia andeanae’. Serological analyses revealed that only 14% and 3% of 36 dogs and 34 small mammals, respectively, were exposed to rickettsial antigens. These results indicate that the study area is not endemic for R. parkeri rickettsiosis. We tabulated 10 studies that reported rickettsial infection in A. tigrinum populations from South America. There was a strong negative correlation between the infection rates by R. parkeri and ‘Candidatus R. andeanae’ in A. tigrinum populations. We propose that high infection rates by ‘Candidatus R. andeanae’ might promote the exclusion of R. parkeri from A. tigrinum populations. The mechanisms for such exclusion are yet to be elucidated.
Endogenous Lipid Carriers—Bench-to-Bedside Roadblocks in Production and Drug Loading of Exosomes
Authors: Richards Terjahna , Patel Himaxi , Patel Ketan , Schanne Frank
Published: March 2023

Exosomes are cell-derived, nano-sized extracellular vesicles comprising a lipid bilayer membrane that encapsulates several biological components, such as nucleic acids, lipids, and proteins. The role of exosomes in cell–cell communication and cargo transport has made them promising candidates in drug delivery for an array of diseases. Despite several research and review papers describing the salient features of exosomes as nanocarriers for drug delivery, there are no FDA-approved commercial therapeutics based on exosomes. Several fundamental challenges, such as the large-scale production and reproducibility of batches, have hindered the bench-to-bedside translation of exosomes. In fact, compatibility and poor drug loading sabotage the possibility of delivering several drug molecules. This review provides an overview of the challenges and summarizes the potential solutions/approaches to facilitate the clinical development of exosomal nanocarriers.
SPECT Imaging with Tc-99m-Labeled HYNIC-FAPI-04 to Extend the Differential Time Window in Evaluating Tumor Fibrosis
Authors: Luo Xiu , Zhang Zhe , Cheng Chao , Wang Tao , Fang Danzhou , Zuo Changjing , Yuan Gengbiao , Li Rou , Li Xiao
Published: March 2023

The so-far used Ga-68- or F-18-labelled tracers are of a relative short time window in differentiating tumor fibrosis. SPECT applicable imaging probe, 99mTc-HYNIC-FAPI-04, was synthesized and evaluated in tumor cells and animal models of FAP-positive glioma and FAP-negative hepatoma, and then compared with 18F-FDG or 68Ga-FAPI-04 PET/CT. The radio-labeling rate of 99mTc-HYNIC-FAPI-04 was greater than 90%, and the radiochemical purity was >99% after purification with sep-pak C18 column. In vitro cell uptake experiments of 99mTc-HYNIC-FAPI-04 showed good FAP binding specificity, and the cellular uptake significantly decreased when blocked by DOTA-FAPI-04, reflecting the similar targeting mechanism of HYNIC-FAPI-04 and DOTA-FAPI-04. SPECT/CT imaging showed that U87MG tumor was distinguishable and of a high uptake of 99mTc-HYNIC-FAPI-04 (2.67 ± 0.35 %ID/mL at 1.5 h post injection (h P.I.), while tumor signal of FAP-negative HUH-7 was as low as 0.34 ± 0.06 %ID/mL. At 5 h P.I., U87MG tumor was still distinguishable (1.81 ± 0.20 %ID/mL). In comparison, although U87MG tumor was of obvious 68Ga-FAPI-04 uptake and clearly visible at 1 h P.I., the tumorous radioactive signals were fuzzy at 1.5 h P.I. 99mTc-HYNIC-FAPI-04 specifically bound to FAP-positive tumors and qualified with the ability of evaluating tumor fibrosis over longer time windows.
Exploring Probenecid Derived 1,3,4-Oxadiazole-Phthalimide Hybrid as α-Amylase Inhibitor: Synthesis, Structural Investigation, and Molecular Modeling
Authors: Khan Bilal Ahmad , Hamdani Syeda Shamila , Khalid Muhammad , Ashfaq Muhammad , Munawar Khurram Shahzad , Tahir Muhammad Nawaz , Braga Ataualpa A. C. , Shawky Ahmed M. , Alqahtani Alaa M. , Abourehab Mohammed A. S. , Gabr Gamal A. , Ibrahim Mahmoud A. A. , Sidhom Peter A.
Published: March 2023

1,3,4-Oxadiazole moiety is a crucial pharmacophore in many biologically active compounds. In a typical synthesis, probenecid was subjected to a sequence of reactions to obtain a 1,3,4-oxadiazole–phthalimide hybrid (PESMP) in high yields. The NMR (1H and 13C) spectroscopic analysis initially confirmed the structure of PESMP. Further spectral aspects were validated based on a single-crystal XRD analysis. Experimental findings were confirmed afterwards by executing a Hirshfeld surface (HS) analysis and quantum mechanical computations. The HS analysis showed the role of the π⋯π stacking interactions in PESMP. PESMP was found to have a high stability and lower reactivity in terms of global reactivity parameters. α-Amylase inhibition studies revealed that the PESMP was a good inhibitor of α-amylase with an s value of 10.60 ± 0.16 μg/mL compared with that of standard acarbose (IC50 = 8.80 ± 0.21 μg/mL). Molecular docking was also utilized to reveal the binding pose and features of PESMP against the α-amylase enzyme. Via docking computations, the high potency of PESMP and acarbose towards the α-amylase enzyme was unveiled and confirmed by docking scores of −7.4 and −9.4 kcal/mol, respectively. These findings shine a new light on the potential of PESMP compounds as α-amylase inhibitors.
Add-On Treatment with Passiflora incarnata L., herba, during Benzodiazepine Tapering in Patients with Depression and Anxiety: A Real-World Study
Authors: Zanardi Raffaella , Carminati Matteo , Fazio Valentina , Maccario Melania , Verri Greta , Colombo Cristina
Published: March 2023

Chronic and inappropriate benzodiazepine intake represents an important health and social concern worldwide. The aim of our study was to investigate the effectiveness of P. incarnata L., herba, in reducing benzodiazepine misuse in a real-world population of depressed and anxious patients in a long-term treatment with benzodiazepines. We conducted a retrospective naturalistic study on 186 patients undergoing benzodiazepine downtitration, 93 with the addition of a dry extract of P. incarnata L., herba (Group A), and 93 without any add-on treatment (Group B). Regarding the benzodiazepine dosage variation in the two groups, a repeated measure ANOVA showed a significant effect of time (p < 0.001), group (p = 0.018), and time x group interaction (p = 0.011). We found a significantly higher rate, i.e., of 50%, reduction in Group A vs. Group B at 1 month (p < 0.001) and at 3 months (p < 0.001) and complete benzodiazepine discontinuation at 1 month (p = 0.002) and at 3 months (p = 0.016). Our findings suggest the role of P. incarnata as an effective add-on treatment during benzodiazepine tapering. These findings highlight the need for further studies to better investigate the promising properties of P. incarnata in the management of such a relevant clinical and social issue.
Design, Synthesis, and Antiviral Activities of New Benzotriazole-Based Derivatives
Authors: Ibba Roberta , Corona Paola , Nonne Francesca , Caria Paola , Serreli Gabriele , Palmas Vanessa , Riu Federico , Sestito Simona , Nieddu Maria , Loddo Roberta , Sanna Giuseppina , Piras Sandra , Carta Antonio
Published: March 2023

Several human diseases are caused by enteroviruses and are currently clinically untreatable, pushing the research to identify new antivirals. A notable number of benzo[d][1,2,3]triazol-1(2)-yl derivatives were designed, synthesized, and in vitro evaluated for cytotoxicity and antiviral activity against a wide spectrum of RNA positive- and negative-sense viruses. Five of them (11b, 18e, 41a, 43a, 99b) emerged for their selective antiviral activity against Coxsackievirus B5, a human enteroviruses member among the Picornaviridae family. The EC50 values ranged between 6 and 18.5 μM. Among all derivatives, compounds 18e and 43a were interestingly active against CVB5 and were selected to better define the safety profile on cell monolayers by transepithelial resistance test (TEER). Results indicated compound 18e as the hit compound to investigate the potential mechanism of action by apoptosis assay, virucidal activity test, and the time of addition assay. CVB5 is known to be cytotoxic by inducing apoptosis in infected cells; in this study, compound 18e was proved to protect cells from viral infection. Notably, cells were mostly protected when pre-treated with derivative 18e, which had, however, no virucidal activity. From the performed biological assays, compound 18e turned out to be non-cytotoxic as well as cell protective against CVB5 infection, with a mechanism of action ascribable to an interaction on the early phase of infection, by hijacking the viral attachment process.
The Ethanolic Extract of Piper glabratum Kunth Is Teratogenic and Interferes with the Ossification Process of Swiss Mice Fetuses
Authors: Nunes Rogério Carlos Sanfelice , Neves Silvia Cordeiro das , Salustriano Fabricia Rodrigues , Vilela Marcelo Luiz Brandão , Nascimento Valter Aragão do , Arunachalam Karuppusamy , Gomes Roberto da Silva , Kassuya Candida Aparecida Leite , Mota Jonas da Silva , Oliveira Rodrigo Juliano
Published: March 2023

Piper glabratum Kunth is a plant traditionally used to treat pain and inflammation in the Mato Grosso do Sul, Brazil. Even pregnant women consume this plant. Toxicology studies of the ethanolic extract from the leaves of P. glabratum (EEPg) could establish the safety of popular use of P. glabratrum. Thus, the effects of the ethanolic extract of leaves of P. glabratum (EEPg) on the reproductive performance and embryofetal development of Swiss mice were evaluated. Pregnant female mice were treated with 100, 1000 and 2000 mg/kg throughout the gestational period by gavage (p.o). The control group received the EEPg vehicle (Tween 80–1%) in the proportion of 0.1 mL/10 g (p.o.). The results demonstrated that EEPg has low maternal toxic potential and does not alter the reproductive performance of females. However, it altered embryofetal development and caused fetal weight reduction (increasing the frequency of small-for-gestational-age fetuses) at the two highest doses. In addition, it interfered with placental weight, placental index and placental efficiency. The frequency of visceral malformations increased by 2.8 times for the lowest dose of EEPg, and skeletal malformations increased by 2.48, 1.89 and 2.11 times for doses of 100, 1000 and 2000 mg/kg of EEPg, respectively. It is noteworthy that 100% of the offspring treated with EEPg showed changes in the ossification process. Thus, it is considered that the EEPg has low maternal toxic potential; it does not alter the reproductive performance of females. However, it is teratogenic and interferes, mainly, in the ossification process, and therefore its use is contraindicated in the gestational period.
Quatsomes Loaded with Squaraine Dye as an Effective Photosensitizer for Photodynamic Therapy
Authors: Bordignon Nicolò , Köber Mariana , Chinigò Giorgia , Pontremoli Carlotta , Sansone Ettore , Vargas-Nadal Guillem , Moran Plata Maria Jesus , Fiorio Pla Alessandra , Barbero Nadia , Morla-Folch Judit , Ventosa Nora
Published: March 2023

Photodynamic therapy is a non-invasive therapeutic strategy that combines external light with a photosensitizer (PS) to destroy abnormal cells. Despite the great progress in the development of new photosensitizers with improved efficacy, the PS’s photosensitivity, high hydrophobicity, and tumor target avidity still represent the main challenges. Herein, newly synthesized brominated squaraine, exhibiting intense absorption in the red/near-infrared region, has been successfully incorporated into Quatsome (QS) nanovesicles at different loadings. The formulations under study have been characterized and interrogated in vitro for cytotoxicity, cellular uptake, and PDT efficiency in a breast cancer cell line. The nanoencapsulation of brominated squaraine into QS overcomes the non-water solubility limitation of the brominated squaraine without compromising its ability to generate ROS rapidly. In addition, PDT effectiveness is maximized due to the highly localized PS loadings in the QS. This strategy allows using a therapeutic squaraine concentration that is 100 times lower than the concentration of free squaraine usually employed in PDT. Taken together, our results reveal the benefits of the incorporation of brominated squaraine into QS to optimize their photoactive properties and support their applicability as photosensitizer agents for PDT.
A Novel Trans-Tracheostomal Retrograde Inhalation Technique Increases Subglottic Drug Deposition Compared to Traditional Trans-Oral Inhalation
Authors: Allon Raviv , Bhardwaj Saurabh , Sznitman Josué , Shoffel-Havakuk Hagit , Pinhas Sapir , Zloczower Elchanan , Shapira-Galitz Yael , Lahav Yonatan
Published: March 2023

Subglottic stenosis represents a challenging clinical condition in otolaryngology. Although patients often experience improvement following endoscopic surgery, recurrence rates remain high. Pursuing measures to maintain surgical results and prevent recurrence is thus necessary. Steroids therapy is considered effective in preventing restenosis. Currently, however, the ability of trans-oral steroid inhalation to reach and affect the stenotic subglottic area in a tracheotomized patient is largely negligible. In the present study, we describe a novel trans-tracheostomal retrograde inhalation technique to increase corticosteroid deposition in the subglottic area. We detail our preliminary clinical outcomes in four patients treated with trans-tracheostomal corticosteroid inhalation via a metered dose inhaler (MDI) following surgery. Concurrently, we leverage computational fluid-particle dynamics (CFPD) simulations in an extra-thoracic 3D airway model to gain insight on possible advantages of such a technique over traditional trans-oral inhalation in augmenting aerosol deposition in the stenotic subglottic region. Our numerical simulations show that for an arbitrary inhaled dose (aerosols spanning 1–12 µm), the deposition (mass) fraction in the subglottis is over 30 times higher in the retrograde trans-tracheostomal technique compared to the trans-oral inhalation technique (3.63% vs. 0.11%). Importantly, while a major portion of inhaled aerosols (66.43%) in the trans-oral inhalation maneuver are transported distally past the trachea, the vast majority of aerosols (85.10%) exit through the mouth during trans-tracheostomal inhalation, thereby avoiding undesired deposition in the broader lungs. Overall, the proposed trans-tracheostomal retrograde inhalation technique increases aerosol deposition rates in the subglottis with minor lower-airway deposition compared to the trans-oral inhalation technique. This novel technique could play an important role in preventing restenosis of the subglottis.
Preparation of Apixaban Solid Dispersion for the Enhancement of Apixaban Solubility and Permeability
Authors: Lee Juseung , Lee Jong-Ju , Lee Seungyeol , Dinh Linh , Oh Hangyu , Abuzar Sharif Md , Ahn Jun-Hyun , Hwang Sung-Joo
Published: March 2023

(1) Background: Solid dispersion (SD) can help increase the bioavailability of poorly water-soluble drugs. Meanwhile, apixaban (APX)—a new anticoagulation drug—has low water solubility (0.028 mg/mL) and low intestinal permeability (0.9 × 10−6 cm/s across Caco-2 colonic cells), thus resulting in a low oral bioavailability of <50%; (2) Methods: To solve the drawbacks of conventional APX products, a novel SD of APX in Soluplus® was prepared, characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared (FTIR) spectroscopy techniques and evaluated for its solubility, intestinal permeability and pharmacokinetic performance. (3) Results: The crystallinity of the prepared APX SD was confirmed. The saturation solubility and apparent permeability coefficient increased 5.9 and 2.54 times compared to that of raw APX, respectively. After oral administration to the rats, the bioavailability of APX SD was improved by 2.31-fold compared to that of APX suspension (4) Conclusions: The present study introduced a new APX SD that potentially exhibits better solubility and permeability, thus increasing APX’s bioavailability.
Current Evidence on Bisphenol A Exposure and the Molecular Mechanism Involved in Related Pathological Conditions
Authors: Della Rocca Ylenia , Traini Enrico Matteo , Diomede Francesca , Fonticoli Luigia , Trubiani Oriana , Paganelli Alessia , Pizzicannella Jacopo , Marconi Guya Diletta
Published: March 2023

Bisphenol A (BPA) is one of the so-called endocrine disrupting chemicals (EDCs) and is thought to be involved in the pathogenesis of different morbid conditions: immune-mediated disorders, type-2 diabetes mellitus, cardiovascular diseases, and cancer. The purpose of this review is to analyze the mechanism of action of bisphenol A, with a special focus on mesenchymal stromal/stem cells (MSCs) and adipogenesis. Its uses will be assessed in various fields: dental, orthopedic, and industrial. The different pathological or physiological conditions altered by BPA and the related molecular pathways will be taken into consideration.
Protective Efficacy of a Mucosal Influenza Vaccine Formulation Based on the Recombinant Nucleoprotein Co-Administered with a TLR2/6 Agonist BPPcysMPEG
Authors: Sanchez Maria Victoria , Ebensen Thomas , Schulze Kai , Cargnelutti Diego Esteban , Scodeller Eduardo A. , Guzmán Carlos A.
Published: March 2023

Current influenza vaccines target highly variable surface glycoproteins; thus, mismatches between vaccine strains and circulating strains often diminish vaccine protection. For this reason, there is still a critical need to develop effective influenza vaccines able to protect also against the drift and shift of different variants of influenza viruses. It has been demonstrated that influenza nucleoprotein (NP) is a strong candidate for a universal vaccine, which contributes to providing cross-protection in animal models. In this study, we developed an adjuvanted mucosal vaccine using the recombinant NP (rNP) and the TLR2/6 agonist S-[2,3-bispalmitoyiloxy-(2R)-propyl]-R-cysteinyl-amido-monomethoxyl-poly-ethylene-glycol (BPPcysMPEG). The vaccine efficacy was compared with that observed following parenteral vaccination of mice with the same formulation. Mice vaccinated with 2 doses of rNP alone or co-administered with BPPcysMPEG by the intranasal (i.n.) route showed enhanced antigen-specific humoral and cellular responses. Moreover, NP-specific humoral immune responses, characterized by significant NP-specific IgG and IgG subclass titers in sera and NP-specific IgA titers in mucosal territories, were remarkably increased in mice vaccinated with the adjuvanted formulation as compared with those of the non-adjuvanted vaccination group. The addition of BPPcysMPEG also improved NP-specific cellular responses in vaccinated mice, characterized by robust lymphoproliferation and mixed Th1/Th2/Th17 immune profiles. Finally, it is notable that the immune responses elicited by the novel formulation administered by the i.n. route were able to confer protection against the influenza H1N1 A/Puerto Rico/8/1934 virus.
Thymus vulgaris Essential Oil in Beta-Cyclodextrin for Solid-State Pharmaceutical Applications
Authors: Arrais Aldo , Bona Elisa , Todeschini Valeria , Caramaschi Alice , Massa Nadia , Roncoli Maddalena , Minervi Alessia , Perin Elena , Gianotti Valentina
Published: March 2023

Antimicrobial resistance related to the misuse of antibiotics is a well-known current topic. Their excessive use in several fields has led to enormous selective pressure on pathogenic and commensal bacteria, driving the evolution of antimicrobial resistance genes with severe impacts on human health. Among all the possible strategies, a viable one could be the development of medical features that employ essential oils (EOs), complex natural mixtures extracted from different plant organs, rich in organic compounds showing, among others, antiseptic properties. In this work, green extracted essential oil of Thymus vulgaris was included in cyclic oligosaccharides cyclodextrins (CD) and prepared in the form of tablets. This essential oil has been shown to have a strong transversal efficacy both as an antifungal and as an antibacterial agent. Its inclusion allows its effective use because an extension of the exposure time to the active compounds is obtained and, therefore, a more marked efficacy, especially against biofilm-producing microorganisms such as P. aeruginosa and S. aureus, was registered. The efficacy of the tablet against candidiasis opens their possible use as a chewable tablet against oral candidiasis and as a vaginal tablet against vaginal candidiasis. Moreover, the registered wide efficacy is even more positive since the proposed approach can be defined as effective, safe, and green. In fact, the natural mixture of the essential oil is produced by the steam current method; therefore, the manufacturer employs substances that are not harmful, with very low production and management costs.
A Review of Quantitative Systems Pharmacology Models of the Coagulation Cascade: Opportunities for Improved Usability
Authors: Chung Douglas , Bakshi Suruchi , van der Graaf Piet H.
Published: March 2023

Despite the numerous therapeutic options to treat bleeding or thrombosis, a comprehensive quantitative mechanistic understanding of the effects of these and potential novel therapies is lacking. Recently, the quality of quantitative systems pharmacology (QSP) models of the coagulation cascade has improved, simulating the interactions between proteases, cofactors, regulators, fibrin, and therapeutic responses under different clinical scenarios. We aim to review the literature on QSP models to assess the unique capabilities and reusability of these models. We systematically searched the literature and BioModels database reviewing systems biology (SB) and QSP models. The purpose and scope of most of these models are redundant with only two SB models serving as the basis for QSP models. Primarily three QSP models have a comprehensive scope and are systematically linked between SB and more recent QSP models. The biological scope of recent QSP models has expanded to enable simulations of previously unexplainable clotting events and the drug effects for treating bleeding or thrombosis. Overall, the field of coagulation appears to suffer from unclear connections between models and irreproducible code as previously reported. The reusability of future QSP models can improve by adopting model equations from validated QSP models, clearly documenting the purpose and modifications, and sharing reproducible code. The capabilities of future QSP models can improve from more rigorous validation by capturing a broader range of responses to therapies from individual patient measurements and integrating blood flow and platelet dynamics to closely represent in vivo bleeding or thrombosis risk.
Electrically Triggered Quercetin Release from Polycaprolactone/Bismuth Ferrite Microfibrous Scaffold for Skeletal Muscle Tissue
Authors: Ayran Musa , Karabulut Hatice , Deniz Kudret , Akcanli Gamze , Ulag Songul , Croitoru Alexa-Maria , Tihăuan Bianca-Maria , Sahin Ali , Ficai Denisa , Gunduz Oguzhan , Ficai Anton
Published: March 2023

Skeletal muscle tissue engineering presents a promising avenue to address the limitations pertaining to the regenerative potential of stem cells in case of injury or damage. The objective of this research was to evaluate the effects of utilizing novel microfibrous scaffolds, containing the compound quercetin (Q), on skeletal muscle regeneration. Morphological test results showed us that the combination of bismuth ferrite (BFO), polycaprolactone (PCL), and Q were bonded and well-ordered with each other, and a uniform microfibrous structure was obtained. Antimicrobial susceptibility testing of PCL/BFO/Q was conducted, and microbial reduction was found to be over 90% in the highest concentration of Q-loaded microfibrous scaffolds with the most inhibitory effect on S. aureus strains. Further, biocompatibility was investigated by performing MTT testing, fluorescence testing, and SEM imaging on mesenchymal stem cells (MSCs) to determine whether they could act as suitable microfibrous scaffolds for skeletal muscle tissue engineering. Incremental changes in the concentration of Q led to increased strength and strain, allowing muscles to withstand stretching during the healing process. In addition, electrically conductive microfibrous scaffolds enhanced the drug release capability by revealing that Q can be released significantly more quickly by applying the appropriate electric field, compared with conventional drug-release techniques. These findings suggest a possible use for PCL/BFO/Q microfibrous scaffolds in skeletal muscle regeneration by demonstrating that the combined action of both guidance biomaterials was more successful than Q itself acting alone.
Sustainable Nanomaterials for Biomedical Applications
Authors: Zhang Yuhang , Poon Kingsley , Masonsong Gweneth Sofia P. , Ramaswamy Yogambha , Singh Gurvinder
Published: March 2023

Significant progress in nanotechnology has enormously contributed to the design and development of innovative products that have transformed societal challenges related to energy, information technology, the environment, and health. A large portion of the nanomaterials developed for such applications is currently highly dependent on energy-intensive manufacturing processes and non-renewable resources. In addition, there is a considerable lag between the rapid growth in the innovation/discovery of such unsustainable nanomaterials and their effects on the environment, human health, and climate in the long term. Therefore, there is an urgent need to design nanomaterials sustainably using renewable and natural resources with minimal impact on society. Integrating sustainability with nanotechnology can support the manufacturing of sustainable nanomaterials with optimized performance. This short review discusses challenges and a framework for designing high-performance sustainable nanomaterials. We briefly summarize the recent advances in producing sustainable nanomaterials from sustainable and natural resources and their use for various biomedical applications such as biosensing, bioimaging, drug delivery, and tissue engineering. Additionally, we provide future perspectives into the design guidelines for fabricating high-performance sustainable nanomaterials for medical applications.
Development and Optimization of Sildenafil Orodispersible Mini-Tablets (ODMTs) for Treatment of Pediatric Pulmonary Hypertension Using Response Surface Methodology
Authors: Alalaiwe Ahmed , Alsenaidy Mohammad A. , Almalki Ziyad S. , Fayed Mohamed H.
Published: March 2023

The availability of age-appropriate oral dosage forms for pediatric patients has remained a challenge. Orodispersible mini-tablets (ODMTs) are a promising delivery system for pediatric patients. The purpose of this work was the development and optimization of sildenafil ODMTs as a new dosage form for the treatment of pulmonary hypertension in children using a design-of-experiment (DoE) approach. A two-factor, three levels (32) full-factorial design was employed to obtain the optimized formulation. The levels of microcrystalline cellulose (MCC; 10–40% w/w) and partially pre-gelatinized starch (PPGS; 2–10% w/w) were set as independent formulation variables. In addition, mechanical strength, disintegration time (DT), and percent drug release were set as critical quality attributes (CQAs) of sildenafil ODMTs. Further, formulation variables were optimized using the desirability function. ANOVA analysis proved that MCC and PPGS had a significant (p < 0.05) impact on CQAs of sildenafil ODMTs with a pronounced influence of PPGS. The optimized formulation was achieved at low (10% w/w) and high (10% w/w) levels of MCC and PPGS, respectively. The optimized sildenafil ODMTs showed crushing strength of 4.72 ± 0.34 KP, friability of 0.71 ± 0.04%, DT of 39.11 ± 1.03 s, and sildenafil release of 86.21 ± 2.41% after 30 min that achieves the USP acceptance criteria for ODMTs. Validation experiments have shown that the acceptable prediction error (<5%) indicated the robustness of the generated design. In conclusion, sildenafil ODMTs have been developed as a suitable oral formulation for the treatment of pediatric pulmonary hypertension using the fluid bed granulation process and the DoE approach.
Angiotensin II Receptor Blockers Reduce Tau/Aß42 Ratio: A Cerebrospinal Fluid Biomarkers’ Case-Control Study
Authors: García-Lluch Gemma , Peña-Bautista Carmen , Royo Lucrecia Moreno , Baquero Miguel , Cañada-Martínez Antonio José , Cháfer-Pericás Consuelo
Published: March 2023

(1) Background: The role of antihypertensives in Alzheimer’s Disease (AD) prevention is controversial. This case-control study aims to assess whether antihypertensive medication has a protective role by studying its association with amyloid and tau abnormal levels. Furthermore, it suggests a holistic view of the involved pathways between renin-angiotensin drugs and the tau/amyloidß42 ratio (tau/Aß42 ratio); (2) Methods: The medical records of the participant patients were reviewed, with a focus on prescribed antihypertensive drugs and clinical variables, such as arterial blood pressure. The Anatomical Therapeutic Chemical classification was used to classify each drug. The patients were divided into two groups: patients with AD diagnosis (cases) and cognitively healthy patients (control); (3) Results: Age and high systolic blood pressure are associated with a higher risk of developing AD. In addition, combinations of angiotensin II receptor blockers are associated with a 30% lower t-tau/Aß42 ratio than plain angiotensin-converting enzyme inhibitor consumption; (4) Conclusions: Angiotensin II receptor blockers may play a potential role in neuroprotection and AD prevention. Likewise, several mechanisms, such as the PI3K/Akt/GSK3ß or the ACE1/AngII/AT1R axis, may link cardiovascular pathologies and AD presence, making its modulation a pivotal point in AD prevention. The present work highlights the central pathways in which antihypertensives may affect the presence of pathological amyloid and tau hyperphosphorylation.
Evaluation of In Vitro and In Vivo Antiviral Activities of Vitamin D for SARS-CoV-2 and Variants
Authors: Mok Chee-Keng , Ng Yan Ling , Ahidjo Bintou Ahmadou , Aw Zhen Qin , Chen Huixin , Wong Yi Hao , Lee Regina Ching Hua , Loe Marcus Wing Choy , Liu Jing , Tan Kai Sen , Kaur Parveen , Wang De Yun , Hao Erwei , Hou Xiaotao , Tan Yong Wah , Deng Jiagang , Chu Justin Jang Hann
Published: March 2023

The COVID-19 pandemic has brought about unprecedented medical and healthcare challenges worldwide. With the continual emergence and spread of new COVID-19 variants, four drug compound libraries were interrogated for their antiviral activities against SARS-CoV-2. Here, we show that the drug screen has resulted in 121 promising anti-SARS-CoV-2 compounds, of which seven were further shortlisted for hit validation: citicoline, pravastatin sodium, tenofovir alafenamide, imatinib mesylate, calcitriol, dexlansoprazole, and prochlorperazine dimaleate. In particular, the active form of vitamin D, calcitriol, exhibits strong potency against SARS-CoV-2 on cell-based assays and is shown to work by modulating the vitamin D receptor pathway to increase antimicrobial peptide cathelicidin expression. However, the weight, survival rate, physiological conditions, histological scoring, and virus titre between SARS-CoV-2 infected K18-hACE2 mice pre-treated or post-treated with calcitriol were negligible, indicating that the differential effects of calcitriol may be due to differences in vitamin D metabolism in mice and warrants future investigation using other animal models.
‘Prioritized Distribution of Equal Shares’—An Ethical and Practicable Allocation Framework for COVID-19 Vaccines
Authors: Heuberger Lina Corinna , Forster Sophia , Frewer Andreas
Published: March 2023

In the context of the global COVID-19 pandemic, the fast and equitable distribution of effective vaccines worldwide is one of the challenges faced by international institutions in charge, as global equity in vaccine supply has not yet been achieved. Our paper explains the current state of ethical research on equity in global COVID-19 vaccine allocation, focusing on the COVAX Facility established by the WHO, acting as the global vaccine distributor. The article presents a detailed analysis of the first year of COVAX allocation in 2021 identifying problematic aspects of its allocation framework regarding the implementation of COVAX’s fundamental allocation principles. We argue that the COVAX Facility has developed a proper concept to deal with global vaccine allocation—but to address uncovered defaults, we introduce the ‘Prioritized Distribution of Equal Shares’ model—a both ethical and practically feasible alternative allocation framework to protect the value of human lives in both high- and low-income countries through fair and fast global vaccine distribution in health emergencies. Nonetheless, we argue that the COVAX Facility remains the main organization to provide equitable access to vaccines. Yet, the global community has to consider further aspects such as patent protection, vaccine production and the lack of power of global structures to address the inequities that have arisen. Since new wars and further crises have arisen, a shift in public global attention endangers the processing of COVID-19-related issues. That is why now more than ever extensive efforts to achieve vaccine equity are needed.
Is Casual Sex Good for You? Casualness, Seriousness and Wellbeing in Intimate Relationships
Authors: Ben-Ze'ev Aaron
Published: March 2023

Enduring romantic love is highly significant for our wellbeing, and there is much scientific evidence for its value. There is also evidence that marital sex is important for the flourishing of wellbeing for both partners. Casual sexual relationships and experiences (CSREs) are often characterized in a non-normative way, as sexual behavior occurring outside a committed romantic relationship. However, the prevailing normative description is negative, perceived as superficial behavior that harms our wellbeing. Although sexual activities are linked to many psychological and physical health benefits, these are rarely attributed to casual sex. Instead, scholars and laymen have warned against the negative consequences of non-committed sex, particularly for women. Yet, positive reactions to casual sex, such as satisfaction, confidence, self-knowledge and social engagement, are stronger and more common than negative reactions. Accordingly, the two major aims of this article are to understand the complexity of CSREs better, and to substantiate the claim that in various circumstances, CSREs contribute to our wellbeing.
Half-Ring Microlasers Based on InGaAs Quantum Well-Dots with High Material Gain
Authors: Zubov Fedor , Moiseev Eduard , Maximov Mikhail , Vorobyev Alexander , Mozharov Alexey , Shernyakov Yuri , Kalyuzhnyy Nikolay , Mintairov Sergey , Kulagina Marina , Dubrovskii Vladimir , Kryzhanovskaya Natalia , Zhukov Alexey
Published: March 2023

We report on half-ring lasers that are 100–200 µm in diameter and are fabricated by cleaving the initial full rings into halves. Characteristics of the half-ring and half-disk lasers fabricated from the same wafer are compared. The active area of the microlasers is based on the quantum heterostructures of mixed (0D/2D) dimensionality, referred to as quantum well-dots with very high material gain. Half-ring lasers show directional light emission and single-mode lasing near the threshold. A maximal continuous-wave output power of 76 mW is achieved for a half-ring that is 200 µm in diameter. Half-rings demonstrate better wall-plug efficiency as compared to half-disks. Lasing in pulse mode is observed up to 140 °C, the characteristic temperature is 100–125 K, depending on the half-ring size. P-side down bonding onto Si-board significantly improves power and temperature characteristics. In CW mode, lasing is maintained up to 97 °C, limited by active-area overheating.
Generation of a Fundamental/Doubled Frequency Phase-Coded Microwave Signal Based on Polarization Multiplexed Technology
Authors: Yin Jing , Zhao Yan , Yang Feng , Yang Dengcai , Wang Yunxin
Published: March 2023

Microwave photonic phase-shifting technology can be used to generate high-frequency, broadband, and tunable phase-coded microwave signals, which are helpful in solving the contradiction between the detection range and the range resolution in radar systems. A method for generating a reconfigurable carrier phase-coded signal of a fundamental or doubled carrier frequency, based on polarization multiplexed technology, is proposed and verified by the experiments in this paper. A dual-parallel dual-polarization Mach–Zehnder modulator (DP-DPMZM) and a polarization-dependent phase modulator (PD-PM) were used to load the carrier and the phase-shifting signal, respectively. By reasonably configuring the state of the RF switch and the bias voltages of the sub-DPMZM, the fundamental or doubled carrier frequency can be obtained through photoelectric conversion. The reconfigurable carrier frequency gives the system a wider work bandwidth range and can effectively reduce the frequency requirement for local oscillator (LO) signals. By adjusting the driving voltage, the broadband microwave signal can be phase-shifted within the range of 360°, and when the phase-shifted control signal is a multilevel amplitude signal, it can generate binary, quaternary, or other high-order phase-coded signals, which have high reconfigurable performance and potential application value in multifunctional radar systems. In addition, the scheme has wideband tunability, since no optical filter is involved. The proposed scheme was theoretically analyzed and experimentally verified. Binary, quaternary, and octal phase-coded signals, with fundamental and doubled frequencies centered at 8 GHz and 16 GHz, were successfully generated.
Experimental Study on Measuring Petzval Image Plane of Streak Tube with Single Image
Authors: Cai Houzhi , Wang Yong , Zong Fangke , Niu Lihong , Yang Qinlao , Zhang Jingjin
Published: March 2023

In the process of image reconstruction of compressed sensing algorithms, building a measurement matrix related to the parameters of the imaging system is necessary to improve its imaging quality. Additionally, building a compressed ultrafast imaging system based on a streak camera, which includes aberrations in the imaging system, is necessary. However, the aberration coefficient of the streak tube can be obtained only by numerical calculation based on the known internal structure of the streak tube, and it does not apply to a tube with an unknown structure. Based on the Lagrange–Helmholtz relation, which is widely established in electronic optical imaging systems, this study proposes a method to obtain the Petzval image plane of a streak tube by measuring only a single image without considering the internal structure of the streak tube. This method provides a reference for the construction of the measurement matrix in the application of the compressed sensing algorithm; additionally, it provides a test scheme for the performance index of the streak tube after assembly in commercial production to further optimize the assembly process and improve the yield of production.
Modeling and Analysis of Device Orientation, Analog and Digital Performance of Electrode Design for High Speed Electro-Optic Modulator
Authors: Gaur Tushar , Mishra Pragya , Hegde Gopalkrishna , Srinivas Talabattula
Published: March 2023

Electro-optic modulators (EOMs) are crucial devices for modern communication enabling high bandwidth optical communication links. Traveling wave electrodes are used to obtain high-speed modulation in these EOMs. We present the electrode design and analysis along with the study of effects of changing orientation on device performance for a thin-film lithium niobate tunable Mach–Zehnder interferometer (MZI) that offers sub-THz bandwidth operations. High velocity and impedance matching with low RF attenuation, high third-order SFDR (∼121 dB/Hz2/3) and a low half-wave voltage length product (1.74 V.cm) have been achieved for a bandwidth of 136 GHz. High-speed digital modulation using multi-level signal formats (PAM-2, QAM-4 and QAM-16) with low BER for 400 Gbps data has been demonstrated to assess the digital performance of the device.
Multi-User Visible Light Communication and Positioning System Based on Dual-Domain Multiplexing Scheme
Authors: Liu Zhongxu , Yu Changyuan
Published: March 2023

Visible light communication and positioning (VLCP) is a promising candidate for constructing a multi-functional wireless network with large-scale connectivity and centimeter-level positioning. However, there is still a lack of effective methods to offer simultaneous visible light communication (VLC) and visible light positioning (VLP) functions for multiple users. Thus, we propose a multi-user VLCP system based on a dual-domain multiplexing (DDM) scheme, where both the time and code resources are multiplexed to transmit VLCP signals for multiple users simultaneously. In the proposed system, the data of different users are distinguished by using code division multiplexing technology, while the VLCP signals transmitted from different LEDs are separated by adopting time division multiplexing technology. The performances, including bit-error rate and positioning error, are evaluated through both simulation and experimentation to verify the feasibility of the proposed multi-user VLCP system. In the experiment, a VLCP system with four LED transmitters was able to simultaneously support low-speed VLC with free error and accurate VLP with a 2 cm precision for eight users. This offers an effective solution to support a large number of users with simultaneous VLC and VLP functions in the future multi-functional wireless network.
Chemical Constituents from Leaves of Baccharis sphenophylla (Asteraceae) and Their Antioxidant Effects
Authors: Retamozo Marcela H. , Silva Christian C. , Tamayose Cinthia I. , Carvalho Juliana C. S. , Romoff Paulete , Fávero Oriana A. , Ferreira Marcelo J. P.
Published: March 2023

Baccharis is one of the largest genera of Asteraceae and its species are used in folk medicine for several medicinal purposes due to the presence of bioactive compounds. We investigated the phytochemical composition of polar extracts of B. sphenophylla. Using chromatographic procedures, diterpenoids (ent-kaurenoic acid), flavonoids (hispidulin, eupafolin, isoquercitrin, quercitrin, biorobin, rutin, and vicenin-2), caffeic acid, and chlorogenic acid derivatives (5-O-caffeoylquinic acid and its methyl ester, 3,4-di-O-caffeoylquinic acid, 4,5-di-O-caffeoylquinic acid, and 3,5-di-O-caffeoylquinic acid and its methyl ester) were isolated from polar fractions and are described. The extract, polar fractions, and fifteen isolated compounds were evaluated in relation to radical scavenging activity using two assays. Chlorogenic acid derivatives and flavonols exhibited higher antioxidant effects, confirming that B. sphenophylla is an important source of phenolic compounds with antiradical properties.