bluuebunny/crossref_metadata_2025 huggingface dataset:
Micro RNA in Semen/Urine from Non-Obstructive Azoospermia Patients as Biomarkers to Predict the Presence of Testicular Spermatozoa and Spermatogonia
Authors: Willems Margo , Devriendt Céline , Olsen Catharina , Caljon Ben , Janssen Toon , Gies Inge , Vloeberghs Veerle , Tournaye Herman , Van Saen Dorien , Goossens Ellen
Published: February 2023

About half of testicular sperm extraction (TESE) procedures in men with non-obstructive azoospermia (NOA), including men with Klinefelter syndrome (KS), are unsuccessful. To avoid unnecessary invasive surgery, biomarkers for spermatozoa were studied. In addition, markers for spermatogonia in testis tissue were explored. This study aimed to find biomarkers in the semen and/or urine of NOA patients to predict the presence of spermatogonia in the testis. Differentially expressed miRNAs were identified (1) between samples from patients with and without a positive TESE procedure as well as (2) between TESE-negative patients with and without spermatogonia. A total of thirteen upregulated miRNAs (ten in seminal plasma and three in urine) were found in the TESE-negative/spermatogonia-positive group compared to the TESE-negative/spermatogonia-negative group. These miRNAs could be potential biomarkers for spermatogonia; however, more research is necessary to validate their predictive power.
Plants as Biofactories for Therapeutic Proteins and Antiviral Compounds to Combat COVID-19
Authors: England Corbin , TrejoMartinez Jonathan , PerezSanchez Paula , Karki Uddhab , Xu Jianfeng
Published: February 2023

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had a profound impact on the world’s health and economy. Although the end of the pandemic may come in 2023, it is generally believed that the virus will not be completely eradicated. Most likely, the disease will become an endemicity. The rapid development of vaccines of different types (mRNA, subunit protein, inactivated virus, etc.) and some other antiviral drugs (Remdesivir, Olumiant, Paxlovid, etc.) has provided effectiveness in reducing COVID-19’s impact worldwide. However, the circulating SARS-CoV-2 virus has been constantly mutating with the emergence of multiple variants, which makes control of COVID-19 difficult. There is still a pressing need for developing more effective antiviral drugs to fight against the disease. Plants have provided a promising production platform for both bioactive chemical compounds (small molecules) and recombinant therapeutics (big molecules). Plants naturally produce a diverse range of bioactive compounds as secondary metabolites, such as alkaloids, terpenoids/terpenes and polyphenols, which are a rich source of countless antiviral compounds. Plants can also be genetically engineered to produce valuable recombinant therapeutics. This molecular farming in plants has an unprecedented opportunity for developing vaccines, antibodies, and other biologics for pandemic diseases because of its potential advantages, such as low cost, safety, and high production volume. This review summarizes the latest advancements in plant-derived drugs used to combat COVID-19 and discusses the prospects and challenges of the plant-based production platform for antiviral agents.
Assessment of Exercise Capacity in Post-COVID-19 Patients: How Is the Appropriate Test Chosen?
Authors: Torres-Castro Rodrigo , Núñez-Cortés Rodrigo , Larrateguy Santiago , Alsina-Restoy Xavier , Barberà Joan Albert , Gimeno-Santos Elena , García Agustin Roberto , Sibila Oriol , Blanco Isabel
Published: February 2023

There is a wide range of sequelae affecting COVID-19 survivors, including impaired physical capacity. These sequelae can affect the quality of life and return to work of the active population. Therefore, one of the pillars of following-up is the evaluation of physical capacity, which can be assessed with field tests (such as the six-minute walk test, the one-minute standing test, the Chester step test, and the shuttle walking test) or laboratory tests (such as the cardiopulmonary exercise test). These tests can be performed in different contexts and have amply demonstrated their usefulness in the assessment of physical capacity both in post-COVID-19 patients and in other chronic respiratory, metabolic, cardiologic, or neurologic diseases. However, when traditional tests cannot be performed, physical function can be a good substitute, especially for assessing the effects of an intervention. For example, the Short Physical Performance Battery assessment and the Timed Up and Go assessment are widely accepted in older adults. Thus, the test should be chosen according to the characteristics of each subject.
Clustering of Activity-Related Behaviors in Relation to Self-Reported Causes of Stress among Pre-Adolescents: Results from a National Epidemiological Study
Authors: Kosti Rena I. , Tsiampalis Thomas , Kouvari Matina , Gketsios Ioannis , Kanellopoulou Aikaterini , Notara Venetia , Antonogeorgos George , Rojas-Gil Andrea Paola , Kornilaki Ekaterina N. , Lagiou Areti , Panagiotakos Demosthenes B.
Published: February 2023

An epidemiological study was conducted among 1728 10–12-year-old students (55.1% girls) and their parents during 2014–2016 in Greece. This study aimed to identify the dominant clusters of physical activity/sedentariness among preadolescents and investigate their association with self-reported sources of stress. Children’s physical activity levels and sources of stress were evaluated using validated questionnaires that assessed daily hours of activities, both on weekdays and on weekends, including physical activity, screen-based sedentary time, and non-screen-based sedentary time. The k-means algorithm of cluster analysis was applied. Three clusters of children’s physical activity/sedentariness were revealed. Cluster 1 was characterized as “Inactive-Non sedentary”, cluster 2 as “Active –Non-screen sedentary”, and cluster 3 as “Inactive-Sedentary”. Parental needs/expectations were associated with physical activity patterns (p = 0.009), i.e., children assigned to the third and second clusters had 36% and 51% lower odds to be stressed due to parental requirements [(OR for cluster 3 = 0.64, 95% CI = 0.41–0.99), (OR for cluster 2 = 0.49, 95% CI = 0.32–0.76)], compared with their first-cluster counterparts. Considering the need to promote physical activity in early life stages, the identification of these complex activity-related patterns along with their significant interaction with parental expectations as a cause of stress could enhance the effectiveness of targeted behavior change interventions among those parent–child dyads most in need.
Dry Friction Performances of MoNx Coatings Deposited by High–Power Pulsed Magnetron Sputtering
Authors: Li Fuqiang , Dai Wei , Wang Qimin , Li Haiqing , Wu Zhengtao
Published: February 2023

A MoNx coating serves as an effective wear protection layer and is crucial for the investigation of its tribological characteristics at various temperatures. This study examined the tribological characteristics of MoNx coatings that were deposited through high-power pulsed magnetron sputtering (HiPIMS) in an Ar/N2 environment with varying N2 partial pressures. The microstructures and mechanical properties of the coatings were elucidated using scanning electron microscopy, grazing-incidence-angle X-ray diffraction, energy-dispersive spectroscopy, and nanoindentation. The dry friction performances of the coatings at different heating temperatures were studied using a ball-on-disk tribometer. The MoNx coating produced by HiPIMS was composed primarily of fcc−Mo2N and featured a fine, dense column crystal with a maximum hardness of 28.8 GPa. The MoNx coatings exhibited excellent lubrication and wear reduction properties at room temperature (RT). The dry friction performances of the MoNx coatings at elevated temperatures were expected to depend on the growth of the MoO3 tribolayer. At relatively low temperatures (300 °C and 400 °C), the MoO3 tribolayer grew slowly and was not enough to provide good lubrication, causing increases in the dry friction of the coatings. However, the δ−MoN phase formed in the MoNx coating deposited at a high N2 partial pressure could facilitate the formation of MoO3 and thus decreased the friction coefficient at 400 °C. At the relatively high heating temperature of 500 °C, however, the MoO3 tribolayer grew so rapidly that the oxide layer became thick, resulting in an increase in the wear rate. It is believed that tuning the growth rate of MoO3 via optimizing the composition and structure of the MoNx coatings might be a useful way to improve the dry friction at various elevated temperatures.
Possible Mechanisms of Stiffness Changes Induced by Stiffeners and Softeners in Catch Connective Tissue of Echinoderms
Authors: Tamori Masaki , Yamada Akira
Published: February 2023

The catch connective, or mutable collagenous, tissue of echinoderms changes its mechanical properties in response to stimulation. The body wall dermis of sea cucumbers is a typical catch connective tissue. The dermis assumes three mechanical states: soft, standard, and stiff. Proteins that change the mechanical properties have been purified from the dermis. Tensilin and the novel stiffening factor are involved in the soft to standard and standard to stiff transitions, respectively. Softenin softens the dermis in the standard state. Tensilin and softenin work directly on the extracellular matrix (ECM). This review summarizes the current knowledge regarding such stiffeners and softeners. Attention is also given to the genes of tensilin and its related proteins in echinoderms. In addition, we provide information on the morphological changes of the ECM associated with the stiffness change of the dermis. Ultrastructural study suggests that tensilin induces an increase in the cohesive forces with the lateral fusion of collagen subfibrils in the soft to standard transition, that crossbridge formation between fibrils occurs in both the soft to standard and standard to stiff transitions, and that the bond which accompanies water exudation produces the stiff dermis from the standard state.
Establishing a Multidisciplinary Team-Based Pleural Service in the Era of Financial Austerity: The Role of the Thoracic Surgeon
Authors: Kapetanakis Emmanouil I. , Sidiropoulou Tatiana , Tomos Ioannis P. , Kampolis Christos F. , Raptakis Thomas , Tomos Periklis I.
Published: February 2023

Medical thoracoscopy/pleuroscopy has become, after bronchoscopy, the second most commonly utilized endoscopic procedure in interventional pulmonology. Due to their common origin, medical thoracoscopy/pleuroscopy and video-assisted thoracic surgery (VATS) are quite similar procedures technically. In contrast to the prevailing attitude that it should predominantly be performed by interventional pulmonologists, we believe that, like all hybrid-in-nature techniques, it should be implemented as part of a combined specialist care service/team. Herewith, we describe our attempt to establish a multidisciplinary pleural disease program during a difficult economic period for our country, comprising thoracic surgeons, pulmonologists and anesthesiologists, all of whom brought in their experience, expertise and resources to establish and develop the service resulting in a hybridization of the technique, with, as reported, quite favorable results.
Social Insurance Physician Burnout—Stress Factors and Coping Strategies
Authors: Oancea Corina , Cernamoriti Anicuta , Gherman Despina Mihaela , Popescu Florina Georgeta
Published: February 2023

Background and Objective Burnout syndrome is well-documented and highly prevalent among healthcare professionals. The literature search found studies mainly aimed at front-line medical specialties, cardiologists, or physicians working in intensive care units. Workload and work conditions favor the occurrence of burnout syndrome among social insurance physicians, with many consequences on health status and a decrease in the quality of their work. We aimed to assess the degree of vulnerability to developing burnout syndrome, factors associated with stress, and coping strategies at social insurance physicians. Materials and Methods: Social insurance physicians working in territorial services for medical assessment of work capacity from Romania participated in the study. An observational study was performed to describe the extent of the exhaustion syndrome among social insurance physicians (SIPhs). Three questionnaires were filled out by the participants: a short version of MBI-HSS to analyze the degree of burnout, an interview with specific questions for the source of stress and Brief-COPE for stress control. Brief demographic data were also collected. Data were statistically analyzed with appropriate tests using PSPP software. Results: Seventy-four physicians were included in the study. Fifty-six were females (75.7%) and twenty-eight (38%) had moderate or high burnout and cognitive distortions with depression resulting as a major side-effect (p < 0.001). Professional factors, mainly deadline pressure (p < 0.001) and high workload (p = 0.012), have emerged as contributing factors to burnout syndrome. Mental disengagement (p = 0.001), active coping (p = 0.006), and acceptance (p = 0.014) would improve stress control. Conclusion: More than two-thirds of social insurance physicians had moderate and high burnout syndrome. The development of strategies to standardize workload was identified as an important action area, along with the long-term preservation of health status and professional performance.
Development of Novel Microwell-Based Spectrofluorimetry and High-Performance Liquid Chromatography with Fluorescence Detection Methods and High Throughput for Quantitation of Alectinib in Bulk Powder and Urine Samples
Authors: Almutairi Halah , Alanazi Mohammed , Darwish Ibrahim , Bakheit Ahmed , Alshehri Mona , Darwish Hany
Published: February 2023

Background and Objectives: This study presents the development and validation of the 96-microwell-based spectrofluorimetric (MW-SFL) and high performance liquid chromatography (HPLC) with fluorescence detection (HPLC-FD) methods for the quantitation of alectinib (ALC) in its bulk powder form and in urine samples. Materials and Methods: The MW-SFL was based on the enhancement of the native fluorescence of ALC by the formation of micelles with the surfactant cremophor RH 40 (Cr RH 40) in aqueous media. The MW-SFL was executed in a 96-microwell plate and the relative fluorescence intensity (RFI) was recorded by utilizing a fluorescence plate reader at 450 nm after excitation at 280 nm. The HPLC-FD involved the chromatographic separation of ALC and ponatinib (PTB), as an internal standard (IS), on a C18 column and a mobile phase composed of methanol:potassium dihydrogen phosphate pH 7 (80:20, v/v) at a flow rate of 2 mL min–1. The eluted ALC and PTB were detected by utilizing a fluorescence detector set at 365 nm for excitation and 450 nm for emission. Results: Validation of the MW-SFL and HPLC-FD analytical methods was carried out in accordance with the recommendations issued by the International Council for Harmonization (ICH) for the process of validating analytical procedures. Both methods were efficaciously applied for ALC quantitation in its bulk form as well as in spiked urine; the mean recovery values were ≥86.90 and 95.45% for the MW-SFL and HPLC-FD methods, respectively. Conclusions: Both methodologies are valuable for routine use in quality control (QC) laboratories for determination of ALC in pure powder form and in human urine samples.
The Role of Inverted Papilloma Surgical Removal for Sleep Apnea Treatment Success—A Case Report
Authors: Vlad Ana Maria , Stefanescu Cristian Dragos , Voiosu Catalina , Hainarosie Razvan
Published: February 2023

In recent years, increased attention has been directed to sleep apnea syndrome due to its high prevalence and preventable severe health consequences. Besides enhancing the risk of cardiovascular, cerebrovascular, and metabolic disorders, it determines increased daytime somnolence, cognitive impairment, and delayed reaction time. These symptoms, determined by sleep fragmentation and chronic hypoxemia, can result in a decrease in professional performance and, moreover, could have tragic implications, especially in patients with high-risk professions. We present the case of a 58-year-old male-truck driver, known to suffer from uncontrolled OSA and chronic obstructive pulmonary disease, who presented to our ENT department for incapacitating daytime somnolence and severe nasal obstruction. These symptoms were caused by a voluminous sinonasal inverted papilloma, occupying the entire left cavity with extension in the nasopharynx. Following nose permeabilization, the patients’ APAP compliance grew substantially, with a dramatic decrease in daytime sleepiness and improvement in polysomnographic parameters. Due to the overlap syndrome of OSA and COPD, an oxygen supplementation was added to PAP therapy by a pulmonologist, improving pulse-oximetry parameters and resulting in the best outcome for the patient. Through this case report, we aim to emphasize the importance of multimodal, personalized treatment of sleep apnea with a focus on nasal surgical permeabilization. At the same time, we sustain a multidisciplinary approach, especially in patients with sleep apnea and associated pathologies, to obtain therapeutic success. We propose increased attention to the early recognition and proper treatment of sleep apnea in patients with high-risk professions as it prevents catastrophes.
Mesoscale Simulation Based on the Dynamic Mean-Field Density Functional Method on Block-Copolymeric Ionomers for Polymer Electrolyte Membranes
Authors: Kang Hoseong , Cheon Muyeong , Lee Chang Hyun , Kim Tae-Ho , Hong Young Taik , Nam Sang Yong , Park Chi Hoon
Published: February 2023

Block copolymers generally have peculiar morphological characteristics, such as strong phase separation. They have been actively applied to polymer electrolyte membranes for proton exchange membrane fuel cells (PEMFCs) to obtain well-defined hydrophilic regions and water channels as a proton pathway. Although molecular simulation tools are advantageous to investigate the mechanism of water channel formation based on the chemical structure and property relationships, classical molecular dynamics simulation has limitations regarding the model size and time scale, and these issues need to be addressed. In this study, we investigated the morphology of sulfonated block copolymers synthesized for PEM applications using a mesoscale simulation based on the dynamic mean-field density functional method, widely applied to investigate macroscopic systems such as polymer blends, micelles, and multi-block/grafting copolymers. Despite the similar solubility parameters of the monomers in our block-copolymer models, very different morphologies in our 3D mesoscale models were obtained. The model with sulfonated monomers, in which the number of sulfonic acid groups is twice that of the other model, showed better phase separation and water channel formation, despite the short length of its hydrophilic block. In conclusion, this unexpected behavior indicates that the role of water molecules is important in making PEM mesoscale models well-equilibrated in the mesoscale simulation, which results in the strong phase separation between hydrophilic and hydrophobic regions and the ensuing well-defined water channel. PEM synthesis supports the conclusion that using the sulfonated monomers with a high sulfonation degree (32.5 mS/cm) will be more effective than using the long hydrophilic block with a low sulfonation degree (25.2 mS/cm).
Linear Thermal Expansion and Specific Heat Capacity of Cu-Fe System Laser-Deposited Materials
Authors: Makarenko Konstantin I. , Dubinin Oleg N. , Shishkovsky Igor V.
Published: February 2023

The coefficient of linear thermal expansion and the specific heat capacity of laser-deposited Cu-Fe alloys fabricated from tin, aluminum, chromium bronze (89–99 wt.% Cu), and SS 316L were studied. The investigated alloys had a 1:1 and a 3:1 bronze–steel ratio. The Al–bronze-based alloy showed the lowest value of linear thermal expansion coefficient: (1.212 ± 0.095)∙10−5 K−1. Contrarily, this value was the highest {[(1.878–1.959) ± 0.095]∙10−5 K−1} in the case of functionally graded parts created from alternating layers of bronze and steel. Differential scanning calorimetry provided experimental results about the specific heat capacity of the materials. In the case of Al–bronze-based specimens, it demonstrated a decrease in the specific heat capacity until ~260 °C and its further increase during a heating cycle. Exothermic peaks related to polymorphic transformations were observed in the Al–bronze-based specimens. Cooling cycles showed monotonous behavior for specific heat capacities. It had exothermic peaks in the case of Cr–bronze-based alloys. A Lennard-Jones potential equation was used for testing the relation between heat capacity and thermal expansion. A three-way interaction regression model validated the results and provided the relative thermal expansion of commercially pure DED-fabricated SS 316L. Its specific heat capacity was also studied experimentally and was 15–20% higher in comparison to the traditional method of production.
The Effect of Black-Dot Defects on FeCrAl Radiation Hardening
Authors: Sun Jian , Yu Miaosen , Wei Zhixian , Dai Hui , Ma Wenxue , Dong Yibin , Liu Yong , Gao Ning , Wang Xuelin
Published: February 2023

FeCrAl is regarded as one of the most promising cladding materials for accident-tolerant fuel at nuclear fission reactors due to its comprehensive properties of inherent corrosion resistance, excellent irradiation resistance, high-temperature oxidation resistance, and stress corrosion cracking resistance. In this work, the irradiation response of FeCrAl irradiated by 2.4 MeV He2+ ions with a fluence of 1.1 × 1016 cm−2 at room temperature was studied using X-ray diffraction, transmission electron microscopy, and nanoindentation. The characterization results of structural and mechanical properties showed that only black-dot defects exist in irradiated FeCrAl samples, and that the hardness of the irradiated samples was 11.5% higher than that of the unirradiated samples. Similar to other types of radiation defects, black-dot defects acted as fixed defect obstacles and hindered the movement of slip dislocations moving under the applied load, resulting in a significant increase in the hardness of FeCrAl. Importantly, this work points out that irradiation-induced black-dot defects can significantly affect the mechanical properties of materials, and that their contribution to radiation hardening cannot be ignored.
Application of Metabolomics in Obesity-Related Childhood Asthma Subtyping: A Narrative Scoping Review
Authors: Makrinioti Heidi , Zhu Zhaozhong , Camargo Carlos A. , Fainardi Valentina , Hasegawa Kohei , Bush Andrew , Saglani Sejal
Published: February 2023

Obesity-related asthma is a heterogeneous childhood asthma phenotype with rising prevalence. Observational studies identify early-life obesity or weight gain as risk factors for childhood asthma development. The reverse association is also described, children with asthma have a higher risk of being obese. Obese children with asthma have poor symptom control and an increased number of asthma attacks compared to non-obese children with asthma. Clinical trials have also identified that a proportion of obese children with asthma do not respond as well to usual treatment (e.g., inhaled corticosteroids). The heterogeneity of obesity-related asthma phenotypes may be attributable to different underlying pathogenetic mechanisms. Although few childhood obesity-related asthma endotypes have been described, our knowledge in this field is incomplete. An evolving analytical profiling technique, metabolomics, has the potential to link individuals’ genetic backgrounds and environmental exposures (e.g., diet) to disease endotypes. This will ultimately help define clinically relevant obesity-related childhood asthma subtypes that respond better to targeted treatment. However, there are challenges related to this approach. The current narrative scoping review summarizes the evidence for metabolomics contributing to asthma subtyping in obese children, highlights the challenges associated with the implementation of this approach, and identifies gaps in research.
A Flexible Miniature Antenna for Body-Worn Devices: Design and Transmission Performance
Authors: Al-Sehemi Abdullah , Al-Ghamdi Ahmed , Dishovsky Nikolay , Atanasov Nikolay , Atanasova Gabriela
Published: February 2023

The last few years have seen a rapid increase in body-worn devices because these devices cover a broad spectrum of potential uses. Moreover, body-worn devices still require improvements in their flexibility, size, and weight that necessitate the development of flexible and miniature antennas. In this paper, we present a new flexible miniature antenna for body-worn devices. To ensure flexibility and comfort when the antenna is in contact with the human body, a substrate from natural rubber filled with TiO2 is developed. The miniaturization is achieved using the quadratic Koch curve. The antenna design, optimization, and characterization are performed on a human body model. The performance of the antenna is analyzed in two scenarios: (1) in- to on-body, and (2) on- to off-body wireless communications. The results show that the antenna realized the maximum telemetry range of more than 80 mm for in-body communications and more than 2 m for off-body communications. Moreover, the highest 10 g specific absorption rate value was 0.62 W/kg. These results, in addition to the antenna’s compact dimensions (12 mm × 26 mm × 2.5 mm) and the low manufacturing price, make the proposed antenna an ideal candidate for health telemetry applications.
Thermal Analysis of Flip-Chip Bonding Designs for GaN Power HEMTs with an On-Chip Heat-Spreading Layer
Authors: Hong Kuo-Bin , Peng Chun-Yen , Lin Wei-Cheng , Chen Kuan-Lun , Chen Shih-Chen , Kuo Hao-Chung , Chang Edward Yi , Lin Chun-Hsiung
Published: February 2023

In this work, we demonstrated the thermal analysis of different flip-chip bonding designs for high power GaN HEMT developed for power electronics applications, such as power converters or photonic driver applications, with large gate periphery and chip size, as well as an Au metal heat-spreading layer deposited on top of a planarized dielectric/passivation layer above the active region. The Au bump patterns can be designed with high flexibility to provide more efficient heat dissipation from the large GaN HEMT chips to an AlN package substrate heat sink with no constraint in the alignment between the HEMT cells and the thermal conduction bumps. Steady-state thermal simulations were conducted to study the channel temperatures of GaN HEMTs with various Au bump patterns at different levels of current and voltage loadings, and the results were compared with the conventional face-up GaN die bonding on an AlN package substrate. The simulations were started from a single finger isolated HEMT cell and then extended to multiple fingers HEMT cells (total gate width > 40 mm) to investigate the “thermal cross-talk” effect from neighboring devices. Thermal analysis of the GaN HEMT under pulse operation was also performed to better reflect the actual conditions in power conversion or pulsed laser driver applications. Our analysis provides a combinational assessment of power GaN HEMT dies under a working condition (e.g., 1MHz, 25% duty cycle) with different flip chip packaging schemes. The analysis indicated that the channel temperature rise (∆T) of a HEMT cell in operation can be reduced by 44~46% by changing from face-up die bonding to a flip-chip bonding scheme with an optimized bump pattern design.
Emerging Immunotherapeutic and Diagnostic Modalities in Carcinoid Tumors
Authors: Vellani Shahnaz D. , Nigro Anthony , Varatharajan Shangari , Dworkin Lance D. , Creeden Justin Fortune
Published: February 2023

Evasion of innate immunity represents a frequently employed method by which tumor cells survive and thrive. Previously, the development of immunotherapeutic agents capable of overcoming this evasion has realized pronounced clinical utility across a variety of cancer types. More recently, immunological strategies have been investigated as potentially viable therapeutic and diagnostic modalities in the management of carcinoid tumors. Classic treatment options for carcinoid tumors rely upon surgical resection or non-immune pharmacology. Though surgical intervention can be curative, tumor characteristics, such as size, location, and spread, heavily limit success. Non-immune pharmacologic treatments can be similarly limited, and many demonstrate problematic side effects. Immunotherapy may be able to overcome these limitations and further improve clinical outcomes. Similarly, emerging immunologic carcinoid biomarkers may improve diagnostic capabilities. Recent developments in immunotherapeutic and diagnostic modalities of carcinoid management are summarized here.
Novel Arylsulfonylhydrazones as Breast Anticancer Agents Discovered by Quantitative Structure-Activity Relationships
Authors: Angelova Violina T. , Tatarova Teodora , Mihaylova Rositsa , Vassilev Nikolay , Petrov Boris , Zhivkova Zvetanka , Doytchinova Irini
Published: February 2023

Breast cancer (BC) is the second leading cause of cancer death in women, with more than 600,000 deaths annually. Despite the progress that has been made in early diagnosis and treatment of this disease, there is still a significant need for more effective drugs with fewer side effects. In the present study, we derive QSAR models with good predictive ability based on data from the literature and reveal the relationships between the chemical structures of a set of arylsulfonylhydrazones and their anticancer activity on human ER+ breast adenocarcinoma and triple-negative breast (TNBC) adenocarcinoma. Applying the derived knowledge, we design nine novel arylsulfonylhydrazones and screen them in silico for drug likeness. All nine molecules show suitable drug and lead properties. They are synthesized and tested in vitro for anticancer activity on MCF-7 and MDA-MB-231 cell lines. Most of the compounds are more active than predicted and show stronger activity on MCF-7 than on MDA-MB-231. Four of the compounds (1a, 1b, 1c, and 1e) show IC50 values below 1 μM on MCF-7 and one (1e) on MDA-MB-231. The presence of an indole ring bearing 5-Cl, 5-OCH3, or 1-COCH3 has the most pronounced positive effect on the cytotoxic activity of the arylsulfonylhydrazones designed in the present study.
Full-Chain FeCl3 Catalyzation Is Sufficient to Boost Cellulase Secretion and Cellulosic Ethanol along with Valorized Supercapacitor and Biosorbent Using Desirable Corn Stalk
Authors: Liu Jingyuan , Zhang Xin , Peng Hao , Li Tianqi , Liu Peng , Gao Hairong , Wang Yanting , Tang Jingfeng , Li Qiang , Qi Zhi , Peng Liangcai , Xia Tao
Published: February 2023

Cellulosic ethanol is regarded as a perfect additive for petrol fuels for global carbon neutralization. As bioethanol conversion requires strong biomass pretreatment and overpriced enzymatic hydrolysis, it is increasingly considered in the exploration of biomass processes with fewer chemicals for cost-effective biofuels and value-added bioproducts. In this study, we performed optimal liquid-hot-water pretreatment (190 °C for 10 min) co-supplied with 4% FeCl3 to achieve the near-complete biomass enzymatic saccharification of desirable corn stalk for high bioethanol production, and all the enzyme-undigestible lignocellulose residues were then examined as active biosorbents for high Cd adsorption. Furthermore, by incubating Trichoderma reesei with the desired corn stalk co-supplied with 0.05% FeCl3 for the secretion of lignocellulose-degradation enzymes in vivo, we examined five secreted enzyme activities elevated by 1.3–3.0-fold in vitro, compared to the control without FeCl3 supplementation. After further supplying 1:2 (w/w) FeCl3 into the T. reesei-undigested lignocellulose residue for the thermal-carbonization process, we generated highly porous carbon with specific electroconductivity raised by 3–12-fold for the supercapacitor. Therefore, this work demonstrates that FeCl3 can act as a universal catalyst for the full-chain enhancement of biological, biochemical, and chemical conversions of lignocellulose substrates, providing a green-like strategy for low-cost biofuels and high-value bioproducts.
Antimicrobial Activity of the Secondary Metabolites Isolated from a South African Red Seaweed, Laurencia corymbosa
Authors: Fakee Jameel , Bolton John J. , Le Roes-Hill Marilize , Durrell Kim A. , Antunes Edith , Beukes Denzil R.
Published: February 2023

South Africa’s highly diverse marine biota includes several endemic marine red algae of the Laurencia genus. Cryptic species and morphological variability make the taxonomy of Laurencia plant challenging, and a record of the secondary metabolites isolated from South African Laurencia spp. can be used to assess their chemotaxonomic significance. In addition, the rapid development of resistance against antibiotics, coupled with the inherent ability of seaweeds to resist pathogenic infection, supported this first phycochemical investigation of Laurencia corymbosa J. Agardh. A new tricyclic keto-cuparane (7) and two new cuparanes (4, 5) were obtained alongside known acetogenins, halo-chamigranes, and additional cuparanes. These compounds were screened against Acinetobacter baumannii, Enterococcus faecalis, Escherichia coli, Staphylococcus aureus, and Candida albicans, with 4 exhibiting excellent activity against the Gram-negative A. baumanii (minimum inhibitory concentration (MIC) 1 μg/mL) strain.
Amino Acid Substitutions at P1 Position Change the Inhibitory Activity and Specificity of Protease Inhibitors BmSPI38 and BmSPI39 from Bombyx mori
Authors: Li Youshan , Wei Meng , Zhang Jie , Zhu Rui , Wang Yuan , Zhang Zhaofeng , Chen Changqing , Zhao Ping
Published: February 2023

It was found that silkworm serine protease inhibitors BmSPI38 and BmSPI39 were very different from typical TIL-type protease inhibitors in sequence, structure, and activity. BmSPI38 and BmSPI39 with unique structure and activity may be good models for studying the relationship between the structure and function of small-molecule TIL-type protease inhibitors. In this study, site-directed saturation mutagenesis at the P1 position was conducted to investigate the effect of P1 sites on the inhibitory activity and specificity of BmSPI38 and BmSPI39. In-gel activity staining and protease inhibition experiments confirmed that BmSPI38 and BmSPI39 could strongly inhibit elastase activity. Almost all mutant proteins of BmSPI38 and BmSPI39 retained the inhibitory activities against subtilisin and elastase, but the replacement of P1 residues greatly affected their intrinsic inhibitory activities. Overall, the substitution of Gly54 in BmSPI38 and Ala56 in BmSPI39 with Gln, Ser, or Thr was able to significantly enhance their inhibitory activities against subtilisin and elastase. However, replacing P1 residues in BmSPI38 and BmSPI39 with Ile, Trp, Pro, or Val could seriously weaken their inhibitory activity against subtilisin and elastase. The replacement of P1 residues with Arg or Lys not only reduced the intrinsic activities of BmSPI38 and BmSPI39, but also resulted in the acquisition of stronger trypsin inhibitory activities and weaker chymotrypsin inhibitory activities. The activity staining results showed that BmSPI38(G54K), BmSPI39(A56R), and BmSPI39(A56K) had extremely high acid–base and thermal stability. In conclusion, this study not only confirmed that BmSPI38 and BmSPI39 had strong elastase inhibitory activity, but also confirmed that P1 residue replacement could change their activity and inhibitory specificity. This not only provides a new perspective and idea for the exploitation and utilization of BmSPI38 and BmSPI39 in biomedicine and pest control, but also provides a basis or reference for the activity and specificity modification of TIL-type protease inhibitors.
Acenocoumarol Exerts Anti-Inflammatory Activity via the Suppression of NF-κB and MAPK Pathways in RAW 264.7 Cells
Authors: Han Hyun-Ju , Hyun Chang-Gu
Published: February 2023

The repurposing of already-approved drugs has emerged as an alternative strategy to rapidly identify effective, safe, and conveniently available new therapeutic indications against human diseases. The current study aimed to assess the repurposing of the anticoagulant drug acenocoumarol for the treatment of chronic inflammatory diseases (e.g., atopic dermatitis and psoriasis) and investigate the potential underlying mechanisms. For this purpose, we used murine macrophage RAW 264.7 as a model in experiments aimed at investigating the anti-inflammatory effects of acenocoumarol in inhibiting the production of pro-inflammatory mediators and cytokines. We demonstrate that acenocoumarol significantly decreases nitric oxide (NO), prostaglandin (PG)E2, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β levels in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Acenocoumarol also inhibits the expression of NO synthase (iNOS) and cyclooxygenase (COX)-2, potentially explaining the acenocoumarol-induced decrease in NO and PGE2 production. In addition, acenocoumarol inhibits the phosphorylation of mitogen-activated protein kinases (MAPKs), c-Jun N terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (ERK), in addition to decreasing the subsequent nuclear translocation of nuclear factor κB (NF-κB). This indicates that acenocoumarol attenuates the macrophage secretion of TNF-α, IL-6, IL-1β, and NO, inducing iNOS and COX-2 expression via the inhibition of the NF-κB and MAPK signaling pathways. In conclusion, our results demonstrate that acenocoumarol can effectively attenuate the activation of macrophages, suggesting that acenocoumarol is a potential candidate for drug repurposing as an anti-inflammatory agent.
The (Poly)phenolic Profile of Separate Winery By-Products Reveals Potential Antioxidant Synergies
Authors: Costa-Pérez Antonio , Medina Sonia , Sánchez-Bravo Paola , Domínguez-Perles Raúl , García-Viguera Cristina
Published: February 2023

The by-products of grapes (Vitis vinifera L.) in the winemaking process present a diverse phytochemical profile of (poly)phenols, essentially represented by phenolic acids, flavonoids, and stilbenes, which have health benefits. In winemaking, solid (grape stems and pomace) and semisolid (wine lees) by-products are generated, negatively impacting the sustainability of the agro-food activity and the local environment. Although information on the phytochemical profile of grape stems and pomace has been reported, especially information concerning (poly)phenols, research on wine lees is necessary to take advantage of the compositional traits of this residue. So, in the present work, an updated, in-depth comparison of the (poly)phenolic profiles of these three resulting matrices in the agro-food industry has been carried out to provide new knowledge and interesting data on the action of yeast and lactic acid bacteria (LAB) metabolism in the diversification of phenolic composition; additionally, we extract complementarities for the possible joint application of the three residues. The phytochemical analysis of the extracts was carried out using HPLC-PDA-ESI-MSn. The (poly)phenolic profiles of the residues showed significant discrepancies. The results obtained showed that the greatest diversity of (poly)phenols was found in the stems of the grapes, followed closely by the lees. Through technological insights, it has been suggested that yeasts and LAB, responsible for the fermentation of must, might play a key role in the transformation of phenolic compounds. This would provide new molecules with specific bioavailability and bioactivity features, which might interact with different molecular targets and, consequently, improve the biological potential of these underexploited residues.
Identification and Characterization of a Novel Cathelicidin from Hydrophis cyanocinctus with Antimicrobial and Anti-Inflammatory Activity
Authors: Wang Shuocun , Fan Liming , Pan Hanyu , Li Yingying , Zhao Xin , Qiu Yan , Lu Yiming
Published: February 2023

The abuse of antibiotics and lack of new antibacterial drugs has led to the emergence of superbugs that raise fears of untreatable infections. The Cathelicidin family of antimicrobial peptide (AMP) with varying antibacterial activities and safety is considered to be a promising alternative to conventional antibiotics. In this study, we investigated a novel Cathelicidin peptide named Hydrostatin-AMP2 from the sea snake Hydrophis cyanocinctus. The peptide was identified based on gene functional annotation of the H. cyanocinctus genome and bioinformatic prediction. Hydrostatin-AMP2 showed excellent antimicrobial activity against both Gram-positive and Gram-negative bacteria, including standard and clinical Ampicillin-resistant strains. The results of the bacterial killing kinetic assay demonstrated that Hydrostatin-AMP2 had faster antimicrobial action than Ampicillin. Meanwhile, Hydrostatin-AMP2 exhibited significant anti-biofilm activity including inhibition and eradication. It also showed a low propensity to induce resistance as well as low cytotoxicity and hemolytic activity. Notably, Hydrostatin-AMP2 apparently decreased the production of pro-inflammatory cytokines in the LPS-induced RAW264.7 cell model. To sum up, these findings indicate that Hydrostatin-AMP2 is a potential peptide candidate for the development of new-generation antimicrobial drugs fighting against antibiotic-resistant bacterial infections.
Microbial Hyaluronic Acid Production: A Review
Authors: Serra Mónica , Casas Ana , Toubarro Duarte , Barros Ana Novo , Teixeira José António
Published: February 2023

Microbial production of hyaluronic acid (HA) is an area of research that has been gaining attention in recent years due to the increasing demand for this biopolymer for several industrial applications. Hyaluronic acid is a linear, non-sulfated glycosaminoglycan that is widely distributed in nature and is mainly composed of repeating units of N-acetylglucosamine and glucuronic acid. It has a wide and unique range of properties such as viscoelasticity, lubrication, and hydration, which makes it an attractive material for several industrial applications such as cosmetics, pharmaceuticals, and medical devices. This review presents and discusses the available fermentation strategies to produce hyaluronic acid.
Development of a New Route for the Immobilization of Unmodified Single-Stranded DNA on Chitosan Beads and Detection of Released Guanine after Hydrolysis
Authors: Chahri Ikram , Karrat Abdelhafid , Mohammadi Hasna , Amine Aziz
Published: February 2023

In this work, chitosan beads were used as a cost-effective platform for the covalent immobilization of unmodified single-stranded DNA, using glutaraldehyde as a cross-linking agent. The immobilized DNA capture probe was hybridized in the presence of miRNA-222 as a complementary sequence. The target was evaluated based on the electrochemical response of the released guanine, using hydrochloride acid as a hydrolysis agent. Differential pulse voltammetry technique and screen-printed electrodes modified with COOH-functionalized carbon black were used to monitor the released guanine response before and after hybridization. The functionalized carbon black provided an important signal amplification of guanine compared to the other studied nanomaterials. Under optimal conditions (6 M HCl at 65 °C for 90 min), an electrochemical-based label-free genosensor assay exhibited a linear range between 1 nM and 1 µM of miRNA-222, with a detection limit of 0.2 nM of miRNA-222. The developed sensor was successfully used to quantify miRNA-222 in a human serum sample.
Dissolution of Molybdenum in Hydrogen Peroxide: A Thermodynamic, Kinetic and Microscopic Study of a Green Process for 99mTc Production
Authors: Cicconi Flavio , Ubaldini Alberto , Fiore Angela , Rizzo Antonietta , Cataldo Sebastiano , Agostini Pietro , Pietropaolo Antonino , Salvi Stefano , Cuzzola Vincenzo ,   on behalf of the SRF Collaboration
Published: February 2023

99mTc-based radiopharmaceuticals are the most commonly used medical radioactive tracers in nuclear medicine for diagnostic imaging. Due to the expected global shortage of 99Mo, the parent radionuclide from which 99mTc is produced, new production methods should be developed. The SORGENTINA-RF (SRF) project aims at developing a prototypical medium-intensity D-T 14-MeV fusion neutron source specifically designed for production of medical radioisotopes with a focus on 99Mo. The scope of this work was to develop an efficient, cost-effective and green procedure for dissolution of solid molybdenum in hydrogen peroxide solutions compatible for 99mTc production via the SRF neutron source. The dissolution process was extensively studied for two different target geometries: pellets and powder. The first showed better characteristics and properties for the dissolution procedure, and up to 100 g of pellets were successfully dissolved in 250–280 min. The dissolution mechanism on the pellets was investigated by means of scanning electron microscopy and energy-dispersive X-ray spectroscopy. After the procedure, sodium molybdate crystals were characterized via X-ray diffraction, Raman and infrared spectroscopy and the high purity of the compound was established by means of inductively coupled plasma mass spectroscopy. The study confirmed the feasibility of the procedure for production of 99mTc in SRF as it is very cost-effective, with minimal consumption of peroxide and controlled low temperature.
Oscillatoria limnetica Mediated Green Synthesis of Iron Oxide (Fe2O3) Nanoparticles and Their Diverse In Vitro Bioactivities
Authors: Haris Muhammad , Fatima Namra , Iqbal Javed , Chalgham Wadie , Mumtaz Abdul Samad , El-Sheikh Mohamed A. , Tavafoghi Maryam
Published: February 2023

Iron oxide nanoparticles (Fe2O3-NPs) were synthesized using Oscillatoria limnetica extract as strong reducing and capping agents. The synthesized iron oxide nanoparticles IONPs were characterized by UV-visible spectroscopy, Fourier transform infrared (FTIR), X-ray diffractive analysis (XRD), scanning electron microscope (SEM), and Energy dispersive X-ray spectroscopy (EDX). IONPs synthesis was confirmed by UV-visible spectroscopy by observing the peak at 471 nm. Furthermore, different in vitro biological assays, which showed important therapeutic potentials, were performed. Antimicrobial assay of biosynthesized IONPs was performed against four different Gram-positive and Gram-negative bacterial strains. E. coli was found to be the least suspected strain (MIC: 35 µg/mL), and B. subtilis was found to be the most suspected strain (MIC: 14 µg/mL). The maximum antifungal assay was observed for Aspergillus versicolor (MIC: 27 µg mL). The cytotoxic assay of IONPs was also studied using a brine shrimp cytotoxicity assay, and LD50 value was reported as 47 µg/mL. In toxicological evaluation, IONPs was found to be biologically compatible to human RBCs (IC50: >200 µg/mL). The antioxidant assay, DPPH 2,2-diphenyl-1-picrylhydrazyly was recorded at 73% for IONPs. In conclusion, IONPs revealed great biological potential and can be further recommended for in vitro and in vivo therapeutic purposes.