bluuebunny/crossref_metadata_2025 huggingface dataset:
The Long-Term Tectonism of the Longshou Shan in the Southwest Alxa Block—Constrained by (U-Th)/He Thermochronometric Data
Authors: Feng Changhuan , Zheng Wenjun , Jia Jiabao , Wei Shiqi , Wang Weitao
Published: January 2024

The Longshou Shan, located in western China, plays a crucial role in connecting the Tarim Continent with the North China Craton. It provides valuable insights into the Cenozoic intracontinental deformation, the complex dynamics of Eurasian tectonics, and the relationship between the pre-Cenozoic Tethys and Central Asian orogenic systems. Consequently, comprehending the evolution of the Phanerozoic era in this region holds immense significance. Zircon (U-Th)/He (ZHe) dating was conducted on three granite samples (n = 18) collected from the Longshou Shan. The ZHe dates of these granite rocks range from 7.2 to 517.7 Ma, showing a negative correlation with eU values. Furthermore, a limestone sample from the Longshou Shan yielded ZHe (n = 4) ages of 172.0–277.1 Ma and AHe (n = 4) ages of 17–111.9 Ma. The area has undergone complex tectonic processes involving multiple phases of uplift and burial. Using both forward and inverse modeling methods, we aim to establish plausible thermal histories. Our models reveal: (1) Late Paleozoic unroofing; (2) Early Mesozoic cooling and Late Mesozoic regional stabilization; and (3) Cenozoic reheating and subsequent cooling. By investigating the intricate thermal history of the Longshou Shan through multi-method modeling, we compare different approaches and assess the capabilities of single ZHe dating for understanding a thermal history. This research contributes to unraveling the region’s geological complexities and aids in evaluating various modeling methods.
Characterization of Historic Lime Mortars from the Arch of San Martin to Identify the Construction Phases of the City Wall of Burgos (Spain)
Authors: Ponce-Antón Graciela , Zuluaga Maria Cruz , Ortega Luis Ángel , Jiménez Echevarría Javier , Alonso Fernández Carmen
Published: January 2024

Historical lime mortars provide valuable information on the construction phases of buildings and allow reconstruction of the chronology of the historical structures. The City Wall of Burgos and the Mudejar Arch of San Martin were declared an Asset of Cultural Interest and have been protected since 1949. Several restorations at the end of the 20th century altered the original appearance of the wall and the current gate, making it difficult to establish stratigraphic relationships between the two structures. Given the scarcity of information on the construction phases of the wall and the uncertainty of the historical dates, a mineralogical and chemical characterization of the mortars was carried out, and the suitability of the binder for radiocarbon dating was assessed. The petrographic, mineralogical and chemical analyses of the lime mortars from the Arc of San Matin show distinctive characteristics, suggesting different construction periods and production processes, where the selection of raw materials and production methods was conducted according to the construction requirements. Moreover, the presence of contaminant phases and microparticles of charcoal in the binder fraction led to discard all the samples for mortar radiocarbon dating.
Dentine Remineralisation Induced by “Bioactive” Materials through Mineral Deposition: An In Vitro Study
Authors: Kunert Marta , Piwonski Ireneusz , Hardan Louis , Bourgi Rim , Sauro Salvatore , Inchingolo Francesco , Lukomska-Szymanska Monika
Published: January 2024

This study aimed to assess the ability of modern resin-based “bioactive” materials (RBMs) to induce dentine remineralisation via mineral deposition and compare the results to those obtained with calcium silicate cements (CSMs). The following materials were employed for restoration of dentine cavities: CSMs: ProRoot MTA (Dentsply Sirona), MTA Angelus (Angelus), Biodentine (Septodont), and TheraCal LC (Bisco); RBMs: ACTIVA BioACTIVE Base/Liner (Pulpdent), ACTIVA Presto (Pulpdent), and Predicta Bioactive Bulk (Parkell). The evaluation of the mineral deposition was performed through scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX) on the material and dentine surfaces, as well as at the dentine–material interface after immersion in simulated body fluid. Additionally, the Ca/P ratios were also calculated in all the tested groups. The specimens were analysed after setting (baseline) and at 24 h, 7, 14, and 28 days. ProRoot MTA, MTA Angelus, Biodentine, and TheraCal LC showed significant surface precipitation, which filled the gap between the material and the dentine. Conversely, the three RBMs showed only a slight ability to induce mineral precipitation, although none of them was able to remineralise the dentine–material interface. In conclusion, in terms of mineral precipitation, modern “bioactive” RBMs are not as effective as CSMs in inducing dentine remineralisation; these latter represent the only option to induce a possible reparative process at the dentin–material interface.
Differences in Consumption Behaviour of Dietary Supplements in Competitive Athletes Depends on Sports Discipline
Authors: Isenmann Eduard , Tolle Pia , Geisler Stephan , Flenker Ulrich , Diel Patrick
Published: January 2024

Background: The consumption of dietary supplements (DS) is widespread among the general population and competitive athletes. However, only a few competitive athletes seek information from experts about the effects and use of DS. Furthermore, it is currently unknown whether certain sports have a higher affinity for DS than others. Methods: This study aimed to identify differences between different sports categories and subgroups that may have a very high affinity for DS. For this purpose, competitive athletes were surveyed. The survey included the type of sport, the training frequency, the number of competitions, the consumption behaviour of five DS categories (general health, regeneration promotion, performance enhancement, booster, and weight loss) as well as personal data such as biological sex and age. Subsequently, correlations, configural frequencies (CFA), and multiple correspondence analyses (MCA) were used to identify subgroups with a high affinity of consumption behaviour. Results: A total of 409 questionnaires could be evaluated. It was found that all DS categories except weight loss were related. In addition, it was observed that in sports from the power category and from the endurance category, there was even higher consumption behaviour than in other sports categories. Male power athletes in particular have a higher affinity for consuming DS than other subgroups. Conclusions: This study shows that there is a clear different consumption behaviour depending on the type of sport. Male power athletes in particular are the subgroup with the greatest consumption behaviour and therefore require special education on the effects and use of DS. This subgroup in particular should receive increased attention in counselling on DS to minimise the possible risks of DS use.
Kinetics of Cellular Cobalamin Uptake and Conversion: Comparison of Aquo/Hydroxocobalamin to Cyanocobalamin
Authors: Fedosov Sergey N. , Nexo Ebba , Heegaard Christian W.
Published: January 2024

Cyanocobalamin (CNCbl) and aquo/hydroxocobalamin (HOCbl) are the forms of vitamin B12 that are most commonly used for supplementation. They are both converted to methylcobalamin (MeCbl) and 5′-deoxyadenosylcobalamin (AdoCbl), which metabolize homocysteine and methylmalonic acid, respectively. Here, we compare the kinetics of uptake and the intracellular transformations of radiolabeled CNCbl vs. HOCbl in HeLa cells. More HOCbl was accumulated over 4–48 h, but further extrapolation indicated similar uptake (>90%) for both vitamin forms. The initially synthesized coenzyme was MeCbl, which noticeably exceeded AdoCbl during 48 h. Yet, the synthesis of AdoCbl accelerated, and the predicted final levels of Cbls were MeCbl ≈ AdoCbl ≈ 40% and HOCbl ≈ 20%. The designed kinetic model revealed the same patterns of the uptake and turnover for CNCbl and HOCbl, apart from two steps. First, the “activating” intracellular processing of the internalized HOCbl was six-fold faster. Second, the detachment rates from the cell surface (when the “excessive” Cbl-molecules were refluxed into the external medium) related as 4:1 for CNCbl vs. HOCbl. This gave a two-fold faster cellular accumulation and processing of HOCbl vs. CNCbl. In medical terms, our data suggest (i) an earlier response to the treatment of Cbl-deficiency with HOCbl, and (ii) the manifestation of a successful treatment initially as a decrease in homocysteine.
Seasonal Variations in 25-Hydroxyvitamin D Levels among Pediatric Patients Attending the Healthcare Centre
Authors: Benameur Tarek
Published: January 2024

Vitamin D plays an essential role in maintaining bone density, building the immune system, and regulating cell growth alongside other key biological functions. Limited data are available about the seasonal variation in vitamin D levels in the pediatric population in Saudi Arabia. This study aimed to investigate the seasonal influence on the pediatric circulating levels of 25(OH)D. A total of 1790 pediatric outpatients who visited the University healthcare centre were included in this study. Overall, there was a noticeably high prevalence (69%) of both combined 25(OH)D deficiency and insufficiency. The highest mean serum concentration of 25(OH)D was recorded in summer (29 ng/mL) and autumn (27 ng/mL). The deficient and insufficient categories were predominant, accounting for 33% and 36%, respectively. Comparable patterns were recorded during autumn, winter, and spring. Interestingly, the 25(OH)D level was significantly associated with the four seasons (p = 0.001), with females having a higher prevalence of 25(OH)D deficiency in the spring and summer than males. Furthermore, only in autumn and winter, we found a significant association between gender and 25(OH)D status (p < 0.001 for both). Another association between nationality and the circulating levels 25(OH)D was found during autumn and winter (p < 0.001 and p = 0.01), respectively. In all seasons, age had a negative impact on serum (OH)D levels. However, this relationship was statistically significant (p < 0.05) only in summer, autumn, and winter. Gender was a significant predictor, with 25(OH)D levels in autumn and winter and an odds ratio of 1.67 in autumn and 2 in winter, indicating that being men had a positive influence on circulating 25(OH)D levels. There were highly significant differences in 25(OH)D concentrations among different age categories. The Saudi population experiences low levels of vitamin D, particularly in autumn and winter periods. This study showed that seasonality, age category, nationality, and gender influence vitamin D status, suggesting the need for tailored intervention and monitoring of 25(OH)D status to reach adequate levels of vitamin D. Healthcare practitioners and policymakers may consider the interplay between age, nationality, gender, and seasonal variations when addressing vitamin D status and a targeted supplementation approach for high-risk groups that may develop health issues.
Micronutrient Status of Critically Ill Patients with COVID-19 Pneumonia
Authors: Rozemeijer Sander , Hamer Henrike M. , Heijboer Annemieke C. , de Jonge Robert , Jimenez Connie R. , Juffermans Nicole P. , Dujardin Romein W. G. , Girbes Armand R. J. , de Man Angélique M. E.
Published: January 2024

Micronutrient deficiencies can develop in critically ill patients, arising from factors such as decreased intake, increased losses, drug interactions, and hypermetabolism. These deficiencies may compromise important immune functions, with potential implications for patient outcomes. Alternatively, micronutrient blood levels may become low due to inflammation-driven redistribution rather than consumption. This explorative pilot study investigates blood micronutrient concentrations during the first three weeks of ICU stay in critically ill COVID-19 patients and evaluates the impact of additional micronutrient administration. Moreover, associations between inflammation, disease severity, and micronutrient status were explored. We measured weekly concentrations of vitamins A, B6, D, and E; iron; zinc; copper; selenium; and CRP as a marker of inflammation state and the SOFA score indicating disease severity in 20 critically ill COVID-19 patients during three weeks of ICU stay. Half of the patients received additional (intravenous) micronutrient administration. Data were analyzed with linear mixed models and Pearson’s correlation coefficient. High deficiency rates of vitamins A, B6, and D; zinc; and selenium (50–100%) were found at ICU admission, along with low iron status. After three weeks, vitamins B6 and D deficiencies persisted, and iron status remained low. Plasma levels of vitamins A and E, zinc, and selenium improved. No significant differences in micronutrient levels were found between patient groups. Negative correlations were identified between the CRP level and levels of vitamins A and E, iron, transferrin, zinc, and selenium. SOFA scores negatively correlated with vitamin D and selenium levels. Our findings reveal high micronutrient deficiency rates at ICU admission. Additional micronutrient administration did not enhance levels or expedite their increase. Spontaneous increases in vitamins A and E, zinc, and selenium levels were associated with inflammation resolution, suggesting that observed low levels may be attributed, at least in part, to redistribution rather than true deficiencies.
Exploring the Link between Lifestyle, Inflammation, and Insulin Resistance through an Improved Healthy Living Index
Authors: Bruckner Franz , Gruber Judith R. , Ruf Alea , Edwin Thanarajah Sharmili , Reif Andreas , Matura Silke
Published: January 2024

Lifestyle factors—such as diet, physical activity (PA), smoking, and alcohol consumption—have a significant impact on mortality as well as healthcare costs. Moreover, they play a crucial role in the development of type 2 diabetes mellitus (DM2). There also seems to be a link between lifestyle behaviours and insulin resistance, which is often a precursor of DM2. This study uses an enhanced Healthy Living Index (HLI) integrating accelerometric data and an Ecological Momentary Assessment (EMA) to explore differences in lifestyle between insulin-sensitive (IS) and insulin-resistant (IR) individuals. Moreover, it explores the association between lifestyle behaviours and inflammation. Analysing data from 99 participants of the mPRIME study (57 women and 42 men; mean age 49.8 years), we calculated HLI scores—ranging from 0 to 4— based on adherence to specific low-risk lifestyle behaviours, including non-smoking, adhering to a healthy diet, maximally moderate alcohol consumption, and meeting World Health Organization (WHO) PA guidelines. Insulin sensitivity was assessed using a Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and C-reactive protein (CRP) levels were used as a proxy for inflammation. Lifestyle behaviours, represented by HLI scores, were significantly different between IS and IR individuals (U = 1529.0; p = 0.023). The difference in the HLI score between IR and IS individuals was mainly driven by lower adherence to PA recommendations in the IR group. Moreover, reduced PA was linked to increased CRP levels in the IR group (r = −0.368, p = 0.014). Our findings suggest that enhancing PA, especially among individuals with impaired insulin resistance, holds significant promise as a preventive strategy.
The Microbiota–Gut–Brain Axis in Metabolic Syndrome and Sleep Disorders: A Systematic Review
Authors: dos Santos Adriano , Galiè Serena
Published: January 2024

Background: Over recent decades, a growing body of evidence has emerged linking the composition of the gut microbiota to sleep regulation. Interestingly, the prevalence of sleep disorders is commonly related to cardiometabolic comorbidities such as diabetes, impaired lipid metabolism, and metabolic syndrome (MetS). In this complex scenario, the role of the gut–brain axis as the main communicating pathway between gut microbiota and sleep regulation pathways in the brain reveals some common host–microbial biomarkers in both sleep disturbances and MetS. As the biological mechanisms behind this complex interacting network of neuroendocrine, immune, and metabolic pathways are not fully understood yet, the present systematic review aims to describe common microbial features between these two unrelated chronic conditions. Results: This systematic review highlights a total of 36 articles associating the gut microbial signature with MetS or sleep disorders. Specific emphasis is given to studies evaluating the effect of dietary patterns, dietary supplementation, and probiotics on MetS or sleep disturbances. Conclusions: Dietary choices promote microbial composition and metabolites, causing both the amelioration and impairment of MetS and sleep homeostasis.
Vitamin D Supplementation: A Review of the Evidence Arguing for a Daily Dose of 2000 International Units (50 µg) of Vitamin D for Adults in the General Population
Authors: Pludowski Pawel , Grant William B. , Karras Spyridon N. , Zittermann Armin , Pilz Stefan
Published: January 2024

Vitamin D deficiency is considered a public health problem due to its worldwide high prevalence and adverse clinical consequences regarding musculoskeletal health. In addition, vitamin D may also be crucial for the prevention of certain extraskeletal diseases. Despite decades of intensive scientific research, several knowledge gaps remain regarding the precise definition of vitamin D deficiency and sufficiency, the health benefits of improving vitamin D status, and the required vitamin D intakes. Consequently, various societies and expert groups have released heterogeneous recommendations on the dosages for vitamin D supplementation. In this brief narrative review, we outline and discuss recent advances regarding the scientific evidence arguing for a daily vitamin D supplementation with 2000 international units (IU) (50 µg) of vitamin D3 to prevent and treat vitamin D deficiency. According to data from randomized controlled trials (RCTs), such a dose may improve some health outcomes and is sufficient to raise and maintain serum 25(OH)D concentrations above 50 nmol/L (20 ng/mL) and above 75 nmol/L (30 ng/mL) in >99% and >90% of the general adult population, respectively. According to large vitamin D RCTs, there are no significant safety concerns in supplementing such a dose for several years, even in individuals with an already sufficient vitamin D status at baseline. A daily vitamin D supplementation with 2000 IU (50 µg) may be considered a simple, effective, and safe dosage to prevent and treat vitamin D deficiency in the adult general population.
Experiences of Vegans with General Practitioners in the Austrian Health Care System: A Qualitative Study
Authors: Jirovsky-Platter Elena , Wakolbinger Maria , Kühn Tilman , Hoffmann Kathryn , Rieder Anita , Haider Sandra
Published: January 2024

This article explores the factors influencing the choice of general practitioners (GPs) and their role in the health care of vegans in Austria. The number of people identifying as vegan is on the rise, and GPs are increasingly confronted with vegan patients. A qualitative method was chosen for this study, and 14 semi-structured interviews with vegans were conducted between April 2022 and July 2022. Participants were recruited primarily through vegan social media groups. In their experiences with health care, vegans felt treated unequally or sometimes incorrectly. The experiences described highlight that participants felt that most GPs were biased against their veganism. Information exchange among vegans primarily takes place online and through publications of vegan associations, while GPs play a minor role in information provision. As the number of vegans grows, an appreciative way of communicating between GPs and vegan patients ought to be promoted. Voluntary interdisciplinary nutritional training, collaboration of the medical field with support organizations, provision of evidence-based information, and collaboration with dietitians and nutritionists could enrich the care of patients with a vegan diet.
Antifungal Resistance in Cryptococcal Infections
Authors: Melhem Marcia S. C. , Leite Júnior Diniz Pereira , Takahashi Juliana P. F. , Macioni Milena Bronze , Oliveira Lidiane de , de Araújo Lisandra Siufi , Fava Wellington S. , Bonfietti Lucas X. , Paniago Anamaria M. M. , Venturini James , Espinel-Ingroff Ana
Published: January 2024

Antifungal therapy, especially with the azoles, could promote the incidence of less susceptible isolates of Cryptococcus neoformans and C. gattii species complexes (SC), mostly in developing countries. Given that these species affect mostly the immunocompromised host, the infections are severe and difficult to treat. This review encompasses the following topics: 1. infecting species and their virulence, 2. treatment, 3. antifungal susceptibility methods and available categorical endpoints, 4. genetic mechanisms of resistance, 5. clinical resistance, 6. fluconazole minimal inhibitory concentrations (MICs), clinical outcome, 7. environmental influences, and 8. the relevance of host factors, including pharmacokinetic/pharmacodynamic (PK/PD) parameters, in predicting the clinical outcome to therapy. As of now, epidemiologic cutoff endpoints (ECVs/ECOFFs) are the most reliable antifungal resistance detectors for these species, as only one clinical breakpoint (amphotericin B and C. neoformans VNI) is available.
Risperidone Decreases Expression of Serotonin Receptor-2A (5-HT2A) and Serotonin Transporter (SERT) but Not Dopamine Receptors and Dopamine Transporter (DAT) in PBMCs from Patients with Schizophrenia
Authors: Alvarez-Herrera Samantha , Rosel Vales Mauricio , Pérez-Sánchez Gilberto , Becerril-Villanueva Enrique , Flores-Medina Yvonne , Maldonado-García José Luis , Saracco-Alvarez Ricardo , Escamilla Raúl , Pavón Lenin
Published: January 2024

Dopamine and serotonin receptors and transporters play an essential role in the pathophysiology of schizophrenia; changes in their expression have been reported in neurons and leukocytes. Each antipsychotic induces a unique pattern in leukocyte function and phenotype. However, the use of polytherapy to treat schizophrenia makes it challenging to determine the specific effects of risperidone on peripheral blood mononuclear cells (PBMCs). The aim of this study was to evaluate the changes in the expression of D3, D5, DAT, 5-HT2A, and SERT in PBMCs from healthy volunteers (HV), drug-naive patients with schizophrenia (PWS), drug-free PWS, and PWS treated with risperidone for up to 40 weeks using quantitative PCR. Our study revealed elevated mRNA levels of D3, DAT, 5-HT2A, and SERT in unmedicated PWS. Treatment with risperidone led to a reduction only in the expression of 5-HT2A and SERT. Furthermore, we observed a moderate correlation between 5-HT2A expression and the positive and negative syndrome scale (PANSS), as well as SERT expression and PANSS scale. We also found a moderate correlation between 5-HT2A and SERT expression and the positive subscale. The duration of risperidone consumption had a significant negative correlation with the expression of 5-HT2A and SERT. Our study introduces the measurement of 5-HT2A and SERT expression in PBMCs as a useful parameter for assessing the response to risperidone in PWS.
Chitosan-Based Polymeric Nanoparticles as an Efficient Gene Delivery System to Cross Blood Brain Barrier: In Vitro and In Vivo Evaluations
Authors: Khan Ishaq N. , Navaid Shiza , Waqar Walifa , Hussein Deema , Ullah Najeeb , Khan Muhammad Umar Aslam , Hussain Zakir , Javed Aneela
Published: January 2024

Significant progress has been made in the field of gene therapy, but effective treatments for brain tumors remain challenging due to their complex nature. Current treatment options have limitations, especially due to their inability to cross the blood-brain barrier (BBB) and precisely target cancer cells. Therefore options that are safer, more effective, and capable of specifically targeting cancer cells are urgently required as alternatives. This current study aimed to develop highly biocompatible natural biopolymeric chitosan nanoparticles (CNPs) as potential gene delivery vehicles that can cross the BBB and serve as gene or drug delivery vehicles for brain disease therapeutics. The efficiency of the CNPs was evaluated via in vitro transfection of Green Fluorescent Protein (GFP)-tagged plasmid in HEK293-293 and brain cancer MG-U87 cell lines, as well as within in vivo mouse models. The CNPs were prepared via a complex coacervation method, resulting in nanoparticles of approximately 260 nm in size. In vitro cytotoxicity analysis revealed that the CNPs had better cell viability (85%) in U87 cells compared to the chemical transfection reagent (CTR) (72%). Moreover, the transfection efficiency of the CNPs was also higher, as indicated by fluorescent emission microscopy (20.56% vs. 17.79%) and fluorescent-activated cell sorting (53% vs. 27%). In vivo assays using Balb/c mice revealed that the CNPs could efficiently cross the BBB, suggesting their potential as efficient gene delivery vehicles for targeted therapies against brain cancers as well as other brain diseases for which the efficient targeting of a therapeutic load to the brain cells has proven to be a real challenge.
Recent Advances in Nanotechnology-Based Strategies for Bone Tuberculosis Management
Authors: Luo Yuanrui , Chen Hongwei , Chen Hua , Xiu Peng , Zeng Jiancheng , Song Yueming , Li Tao
Published: January 2024

Bone tuberculosis, an extrapulmonary manifestation of tuberculosis, presents unique treatment challenges, including its insidious onset and complex pathology. While advancements in anti-tubercular therapy have been made, the efficacy is often limited by difficulties in achieving targeted drug concentrations and avoiding systemic toxicity. The intricate bone structure and presence of granulomas further impede effective drug delivery. Nano-drug delivery systems have emerged as a promising alternative, offering the enhanced targeting of anti-tubercular drugs. These systems, characterized by their minute size and adaptable surface properties, can be tailored to improve drug solubility, stability, and bioavailability, while also responding to specific stimuli within the bone TB microenvironment for controlled drug release. Nano-drug delivery systems can encapsulate drugs for precise delivery to the infection site. A significant innovation is their integration with prosthetics or biomaterials, which aids in both drug delivery and bone reconstruction, addressing the infection and its osteological consequences. This review provides a comprehensive overview of the pathophysiology of bone tuberculosis and its current treatments, emphasizing their limitations. It then delves into the advancements in nano-drug delivery systems, discussing their design, functionality, and role in bone TB therapy. The review assesses their potential in preclinical research, particularly in targeted drug delivery, treatment efficacy, and a reduction of side effects. Finally, it highlights the transformative promise of nanotechnology in bone TB treatments and suggests future research directions in this evolving field.
Controlling the Quality of Nanodrugs According to Their New Property—Radiothermal Emission
Authors: Petrov Gleb V. , Galkina Daria A. , Koldina Alena M. , Grebennikova Tatiana V. , Eliseeva Olesya V. , Chernoryzh Yana Yu. , Lebedeva Varvara V. , Syroeshkin Anton V.
Published: January 2024

Previous studies have shown that complexly shaped nanoparticles (NPs) have their intrinsic radiothermal emission in the millimeter range. This article presents a method for controlling the quality of nanodrugs—immunobiological preparations (IBPs)—based on the detection of their intrinsic radiothermal emissions. The emissivity of interferon (IFN) medicals, determined without opening the primary package, is as follows (µW/m2): IFN-α2b—80 ± 9 (105 IU per package), IFN-β1a—40 ± 5 (24 × 106 IU per package), IFN-γ—30 ± 4 (105 IU per package). The emissivity of virus-like particles (VLP), determined using vaccines Gam-VLP-multivac (120 μg) in an injection bottle (crimp cap vials), was as follows: 12 ± 1 µW/m2, Gam-VLP—rota vaccines—9 ± 1 µW/m2. This study shows the reproducibility of emissivity over the course of a year, subject to the storage conditions of the immunobiological products. It has been shown that accelerated aging and a longer shelf life are accompanied by the coagulation of active NPs, and lead to a manyfold drop in emissivity. The dependence of radiothermal emission on temperature has a complex, non-monotonic nature. The emission intensity depends on the form of dosage, but remains within the order of magnitude for IFN-α2b for intranasal aqueous solution, ointments, and suppositories. The possibility of the remote quantitative control of the first phases of the immune response (increased synthesis of IFNs) to the intranasal administration of VLP vaccines has been demonstrated in experimental animals.
The Effect of Cholesterol Content on the Adjuvant Activity of Nucleic-Acid-Free Lipid Nanoparticles
Authors: Anindita Jessica , Tanaka Hiroki , Yamakawa Takuma , Sato Yuka , Matsumoto Chika , Ishizaki Kota , Oyama Taiji , Suzuki Satoko , Ueda Keisuke , Higashi Kenjirou , Moribe Kunikazu , Sasaki Kasumi , Ogura Yumika , Yonemochi Etsuo , Sakurai Yu , Hatakeyama Hiroto , Akita Hidetaka
Published: January 2024

RNA vaccines are applicable to the treatment of various infectious diseases via the inducement of robust immune responses against target antigens by expressing antigen proteins in the human body. The delivery of messenger RNA by lipid nanoparticles (LNPs) has become a versatile drug delivery system used in the administration of RNA vaccines. LNPs are widely considered to possess adjuvant activity that induces a strong immune response. However, the properties of LNPs that contribute to their adjuvant activity continue to require clarification. To characterize the relationships between the lipid composition, particle morphology, and adjuvant activity of LNPs, the nanostructures of LNPs and their antibody production were evaluated. To simply compare the adjuvant activity of LNPs, empty LNPs were subcutaneously injected with recombinant proteins. Consistent with previous research, the presence of ionizable lipids was one of the determinant factors. Adjuvant activity was induced when a tiny cholesterol assembly (cholesterol-induced phase, ChiP) was formed according to the amount of cholesterol present. Moreover, adjuvant activity was diminished when the content of cholesterol was excessive. Thus, it is plausible that an intermediate structure of cholesterol (not in a crystalline-like state) in an intra-particle space could be closely related to the immunogenicity of LNPs.
Polymer Delivery Systems for Long-Acting Antiretroviral Drugs
Authors: Nayan Mohammad Ullah , Panja Sudipta , Sultana Ashrafi , Zaman Lubaba A. , Vora Lalitkumar K. , Sillman Brady , Gendelman Howard E. , Edagwa Benson
Published: January 2024

The success of long-acting (LA) drug delivery systems (DDSs) is linked to their biocompatible polymers. These are used for extended therapeutic release. For treatment or prevention of human immune deficiency virus type one (HIV-1) infection, LA DDSs hold promise for improved regimen adherence and reduced toxicities. Current examples include Cabenuva, Apretude, and Sunlenca. Each is safe and effective. Alternative promising DDSs include implants, prodrugs, vaginal rings, and microarray patches. Each can further meet patients’ needs. We posit that the physicochemical properties of the formulation chemical design can optimize drug release profiles. We posit that the strategic design of LA DDS polymers will further improve controlled drug release to simplify dosing schedules and improve regimen adherence.
Potentiation of Antibiotic Activity of Aztreonam against Metallo-β-Lactamase-Producing Multidrug-Resistant Pseudomonas aeruginosa by 3-O-Substituted Difluoroquercetin Derivatives
Authors: Lee Seongyeon , Lee Taegum , Kim Mi Kyoung , Ahn Joong Hoon , Jeong Seri , Park Ki-Ho , Chong Youhoon
Published: January 2024

The combination of aztreonam (ATM) and ceftazidime–avibactam (CAZ-AVI; CZA) has shown therapeutic potential against serine-β-lactamase (SBL)- and metallo-β-lactamase (MBL)-producing Enterobacterales. However, the ability of CZA to restore the antibiotic activity of ATM is severely limited in MBL-producing multidrug-resistant (MDR) Pseudomonas aeruginosa strains because of the myriad of intrinsic and acquired resistance mechanisms associated with this pathogen. We reasoned that the simultaneous inhibition of multiple targets associated with multidrug resistance mechanisms may potentiate the antibiotic activity of ATM against MBL-producing P. aeruginosa. During a search for the multitarget inhibitors through a molecular docking study, we discovered that di-F-Q, the previously reported efflux pump inhibitor of MDR P. aeruginosa, binds to the active sites of the efflux pump (MexB), as well as various β-lactamases, and these sites are open to the 3-O-position of di-F-Q. The 3-O-substituted di-F-Q derivatives were thus synthesized and showed hereto unknown multitarget MDR inhibitory activity against various ATM-hydrolyzing β-lactamases (AmpC, KPC, and New Delhi metallo-β-lactamase (NDM)) and the efflux pump of P. aeruginosa, presumably by forming additional hydrophobic contacts with the targets. The multitarget MDR inhibitor 27 effectively potentiated the antimicrobial activity of ATM and reduced the MIC of ATM more than four-fold in 19 out of 21 MBL-producing P. aeruginosa clinical strains, including the NDM-producing strains which were highly resistant to various combinations of ATM with β-lactamase inhibitors and/or efflux pump inhibitors. Our findings suggest that the simultaneous inhibition of multiple MDR targets might provide new avenues for the discovery of safe and efficient MDR reversal agents which can be used in combination with ATM against MBL-producing MDR P. aeruginosa.
Nanocarrier Design for Dual-Targeted Therapy of In-Stent Restenosis
Authors: Alferiev Ivan S. , Zhang Kehan , Folchman-Wagner Zoë , Adamo Richard F. , Guerrero David T. , Fishbein Ilia , Soberman Danielle , Levy Robert J. , Chorny Michael
Published: January 2024

The injury-triggered reocclusion (restenosis) of arteries treated with angioplasty to relieve atherosclerotic obstruction remains a challenge due to limitations of existing therapies. A combination of magnetic guidance and affinity-mediated arterial binding can pave the way to a new approach for treating restenosis by enabling efficient site-specific localization of therapeutic agents formulated in magnetizable nanoparticles (MNPs) and by maintaining their presence at the site of arterial injury throughout the vulnerability period of the disease. In these studies, we investigated a dual-targeted antirestenotic strategy using drug-loaded biodegradable MNPs, surface-modified with a fibrin-avid peptide to provide affinity for the injured arterial wall. The MNPs were characterized with regard to their magnetic properties, efficiency of surface functionalization, disassembly kinetics, and interaction with fibrin-coated substrates. The antiproliferative effects of MNPs formulated with paclitaxel were studied in vitro using a fetal cell line (A10) exhibiting the defining characteristics of neointimal smooth muscle cells. Animal studies examined the efficiency of combined (physical/affinity) MNP targeting to stented arteries in Sprague Dawley rats using fluorimetric analysis and fluorescent in vivo imaging. The antirestenotic effect of the dual-targeted therapy was determined in a rat model of in-stent restenosis 28 days post-treatment. The results showed that MNPs can be efficiently functionalized to exhibit a strong binding affinity using a simple two-step chemical process, without adversely affecting their size distribution, magnetic properties, or antiproliferative potency. Dual-targeted delivery strongly enhanced the localization and retention of MNPs in stented carotid arteries up to 7 days post-treatment, while minimizing redistribution of the carrier particles to peripheral tissues. Of the two targeting elements, the effect of magnetic guidance was shown to dominate arterial localization (p = 0.004 vs. 0.084 for magnetic targeting and peptide modification, respectively), consistent with the magnetically driven MNP accumulation step defining the extent of the ultimate affinity-mediated arterial binding and subsequent retention of the carrier particles. The enhanced arterial uptake and sustained presence of paclitaxel-loaded MNPs at the site of stent deployment were associated with a strong inhibition of restenosis in the rat carotid stenting model, with both the neointima-to-media ratio (N/M) and % stenosis markedly reduced in the dual-targeted treatment group (1.62 ± 0.2 and 21 ± 3 vs. 2.17 ± 0.40 and 29 ± 6 in the control animals; p < 0.05). We conclude that the dual-targeted delivery of antirestenotic agents formulated in fibrin-avid MNPs can provide a new platform for the safe and effective treatment of in-stent restenosis.
Antiviral Action against SARS-CoV-2 of a Synthetic Peptide Based on a Novel Defensin Present in the Transcriptome of the Fire Salamander (Salamandra salamandra)
Authors: Barros Ana Luisa A. N. , Silva Vladimir C. , Ribeiro-Junior Atvaldo F. , Cardoso Miguel G. , Costa Samuel R. , Moraes Carolina B. , Barbosa Cecília G. , Coleone Alex P. , Simões Rafael P. , Cabral Wanessa F. , Falcão Raul M. , Vasconcelos Andreanne G. , Rocha Jefferson A. , Arcanjo Daniel D. R. , Batagin-Neto Augusto , Borges Tatiana Karla S. , Gonçalves João , Brand Guilherme D. , Freitas-Junior Lucio H. G. , Eaton Peter , Marani Mariela , Kato Massuo J. , Plácido Alexandra , Leite José Roberto S. A.
Published: January 2024

The potential emergence of zoonotic diseases has raised significant concerns, particularly in light of the recent pandemic, emphasizing the urgent need for scientific preparedness. The bioprospection and characterization of new molecules are strategically relevant to the research and development of innovative drugs for viral and bacterial treatment and disease management. Amphibian species possess a diverse array of compounds, including antimicrobial peptides. This study identified the first bioactive peptide from Salamandra salamandra in a transcriptome analysis. The synthetic peptide sequence, which belongs to the defensin family, was characterized through MALDI TOF/TOF mass spectrometry. Molecular docking assays hypothesized the interaction between the identified peptide and the active binding site of the spike WT RBD/hACE2 complex. Although additional studies are required, the preliminary evaluation of the antiviral potential of synthetic SS-I was conducted through an in vitro cell-based SARS-CoV-2 infection assay. Additionally, the cytotoxic and hemolytic effects of the synthesized peptide were assessed. These preliminary findings highlighted the potential of SS-I as a chemical scaffold for drug development against COVID-19, hindering viral infection. The peptide demonstrated hemolytic activity while not exhibiting cytotoxicity at the antiviral concentration.
Design of High-Q-Gradient Dielectric Nanoparticle Chain Surface Plasmonic Cavities
Authors: Liu Jing , Peng Xuanran , Kang Yaru , Mao Xu , Yan Wei , Zhao Yongmei , Liu Kong , Yang Fuhua , Li Zhaofeng
Published: January 2024

Surface plasmonic cavities consisting of dielectric nanoparticle chains directly placed on a metal substrate are designed and studied, including a periodic nanoparticle chain (PNC) cavity and several different surface plasmon trap (SPT) cavities. The SPT cavities are designed by adjusting the nanoparticle sizes and the spacing between nanoparticles. Among them, the nanoparticle sizes range from 10 nm to 140 nm, and the spacings between the nanoparticles range from 200 nm to 280 nm. Compared to the PNC cavity, the SPT cavities support a single mode operation with higher Q factors within a relatively wide bandwidth. In particular, when the particle size and the spacing between the particles of the chain are set to vary in a parabolic gradient profile, the Q factor of the SPT cavity can be improved up to 85% compared to the PNC cavity. Our designs can be applied in the development of high-Q-factor plasmonic nanolasers.
One-Step Non-Contact Additive LIFT Printing of Silver Interconnectors for Flexible Printed Circuits
Authors: Nastulyavichus Alena , Kudryashov Sergey , Shelygina Svetlana , Smirnov Nikita , Pakholchuk Petr , Saraeva Irina , Zayarny Dmitry , Ulturgasheva Evgenia , Khmelenin Dmitry , Emelyanova Olga , Pryakhina Victoria , Pokryshkin Nikolay , Kuzmin Evgeny , Gorevoy Alexey , Minh Pham Hong , Van Duong Pham
Published: January 2024

The single-pass one-step method for printing conductive silver tracks on a glass surface, using the laser-induced forward transfer (LIFT) technique, was proposed, providing a unique opportunity for high-throughput printing of surface micro- and nanostructures with high electrical conductivity and positioning accuracy. This method was developed via our multi-parametric research, resulting in the selection of the optimal material, laser irradiation, and transfer conditions. Optical, scanning and transmission electron, and atomic force microscopy methods, as well as X-ray diffraction, were used to characterize the surface structure and phase state of the printed structures, while energy-dispersive X-ray and X-ray photoelectron microscopy were employed for their chemical microanalysis. Depending on the laser irradiation parameters, the specific electrical conductivity of the printed tracks varied from 0.18 to 83 kS/cm, approaching that of donor magnetron-sputtered films. This single-pass one-step method significantly facilitates fast, large-scale, on-demand local laser printing of metallic (sub)microcomponents of microelectronic devices.
Fully Phase-Locked Fiber Dual Comb Enables Accurate Frequency and Phase Detection in Multidimensional Coherent Spectroscopy
Authors: Xiong Shiping , Deng Zejiang , Zuo Zhong , Pan Jiayi , Zhao Zilin , Xie Gehui , Li Wenxue
Published: January 2024

High-resolution optical multidimensional coherent spectroscopy (MDCS) requires frequency-stable laser sources and high-resolution heterodyne spectra. Fully phase-locked dual-comb spectroscopy (DCS) enables the achievement of high resolution, high accuracy, broad bandwidth, and a rapid multi-heterodyne spectrum, which results in the DCS’s potential to replace the spectrometer and phase detection system in MDCS. We verified the phase measurement capability of the MDCS system based on fully phase-locked fiber DCS by studying phase-sensitive photon echoes and double-quantum processes. The accurate phase and frequency of linear and nonlinear signals were obtained simultaneously using a single detector without subsequent frequency drift correction. Subsequently, the acquisition of longtime quantum beat signals demonstrates the high phase coherence between excitation pulses. Additionally, the two-dimensional coherent spectrum (2DCS) with high signal-to-noise-ratio and 100 MHz resolution was obtained via the MDCS system based on fully phase-locked fiber DCS. These results exhibit that fully phase-locked fiber DCS is an effective method for high-resolution 2DCS measurement, which facilitates further research on cold atoms, higher-order nonlinear spectra, and molecular fingerprint vibrational spectroscopy.
A Promising Route to Compact and Economic Sub-15 fs, PW-Level Ti:Sapphire Lasers
Authors: Wu Fenxiang , Hu Jiabing , Zhang Zongxin , Zhao Yang , Bai Peile , Chen Haidong , Chen Xun , Xu Yi , Leng Yuxin , Li Ruxin
Published: January 2024

In quest of achieving compact and economic PW-level Ti:Sapphire (Ti:sa) lasers with a sub-15 fs pulse duration, a modified hybrid amplification scheme, which combines the optical parametric chirped pulse amplifier (OPCPA) and the chirped pulse amplifier (CPA), is presented and numerically investigated in this paper. The key characteristic of this scheme is that the conventional Ti:sa regenerative amplifier and preamplifier are replaced by a dual-crystal OPCPA front-end, which is spectrally matched with the upstream seed source and the downstream Ti:sa amplifiers and, therefore, can realize a broader spectrum. Moreover, some useful laser techniques are also applied to suppress the spectral gain narrowing and redshift in the Ti:sa CPA chain and to control the residual dispersion in the laser system. This way, fewer amplification stages and pump lasers are required to reach PW-level peak power compared with traditional all-CPA Ti:sa lasers. Numerical results indicate that pulse energy and spectral bandwidth can reach up to ∼22 J and ∼125 nm at full width at half maximum (FWHM), respectively, only by employing three-stage amplifiers. After compression, PW-level lasers with a ∼13.3 fs pulse duration are expected. This work can offer a promising route for the development of compact and economic PW-level Ti:sa lasers.
Statistical Properties of a Twisted Gaussian Schell-Model Beam Carrying the Cross Phase in a Turbulent Atmosphere
Authors: Hou Wenshuo , Liu Leixin , Liu Xianlong , Cai Yangjian , Peng Xiaofeng
Published: January 2024

In this letter, we conducted a detailed investigation of the statistical properties, such as spectral density, spectral degree of coherence (SDOC), orbital angular momentum (OAM) flux density, and propagation factor M2, of a twisted Gaussian Schell-model (TGSM) beam carrying the cross phase in a turbulent atmosphere. Our findings revealed that atmospheric turbulence induces degeneration of the intensity distribution and spectral degree of coherence of a Gaussian Schell-model beam with the cross phase during propagation, while the twist phase acts as an antidote to degradation. Furthermore, we observed that the z-component of the time-averaged angular momentum flux is determined by the twist phase, whereas the cross phase influences the distribution of the OAM flux density in the beam. Additionally, we explored the variations in the propagation factor M2 of a TGSM beam with the cross phase in a turbulent atmosphere. Notably, we discovered that the deleterious effects of the atmospheric conditions can be mitigated by modulating both the twist and the cross phases. This work contributes valuable insights for information transfer and optical manipulations.
Enhanced bi-LSTM for Modeling Nonlinear Amplification Dynamics of Ultra-Short Optical Pulses
Authors: Saraeva Karina , Bednyakova Anastasia
Published: January 2024

Fiber amplifiers are essential devices for optical communication and laser physics, yet the intricate nonlinear dynamics they exhibit pose significant challenges for numerical modeling. In this study, we propose using a bi-LSTM neural network to predict the evolution of optical pulses along a fiber amplifier, accounting for the dynamically changing gain profile and the Raman scattering. The neural network can learn information from both past and future data, adhering to the fundamental principles of physics governing pulse evolution over time. We conducted experiments with a diverse range of initial pulse parameters, covering the variation in the ratio between dispersion and nonlinear length, ranging from 0.25 to 250. This deliberate choice has resulted in a wide variety of propagation regimes, ranging from smooth attractor-like to noise-like behaviors. Through a comprehensive evaluation of the neural network performance, we demonstrated its ability to generalize across the various propagation regimes. Notably, our results showcase a relative speedup of 2000 times for evaluating the intensity evolution map using our proposed neural network compared to the NLSE numerical solution employing the split-step Fourier method.