bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-World Experience with Brolucizumab Compared to Aflibercept in Treatment-Naïve and Therapy-Refractory Patients with Diabetic Macular Edema
Authors: Rübsam Anne , Hössl Leopold , Rau Saskia , Böker Alexander , Zeitz Oliver , Joussen Antonia M.
Published: March 2024

Background: To report on the outcome of intravitreal brolucizumab compared to aflibercept in patients with diabetic macular edema (DME). Methods: Prospective, observational, study in 35 eyes of 24 patients with a loading dose of five injections of 6 mg brolucizumab every 6 weeks (q6w, treatment-naïve eyes) or a minimum of two injections of brolucizumab q6w after the switch (recalcitrant DME eyes), followed by a treat and extend (T&E) regimen. The results were compared with 40 eyes of 31 DME patients who were treated with aflibercept. The data were obtained from the Berlin Macula Registry. The primary outcome measure was the change in best-corrected visual acuity (BCVA) at week 36. Secondary outcome measures were the change in central retinal thickness (CRT) and the treatment intervals until week 36. Results: BCVA increased significantly in treatment-naïve DME eyes treated with either brolucizumab (+0.12 logMAR, +6.4 letters, p = 0.03) or aflibercept (+0.19 logMAR, +9.5 letters, p = 0.001). In recalcitrant DME eyes, BCVA also increased significantly after switching to brolucizumab (+0.1 logMAR, +5 letters, p = 0.006) or aflibercept (+0.11 logMAR, +5.5 letters, p = 0.02). All treatment-naïve and recalcitrant DME eyes had a significant decrease in CRT after treatment with brolucizumab (p = 0.001 and p < 0.001) or aflibercept (p = 0.0002 and p = 0.03). At week 36, the mean treatment interval for brolucizumab was 11.3 weeks, while for aflibercept, it was 6.5 weeks for treatment-naïve eyes and 9.3 weeks vs. 5.3 weeks for pretreated eyes. Conclusions: In routine clinical practice, patients with treatment-naïve and recalcitrant DME showed a favorable response to brolucizumab and aflibercept therapy, with a reduced injection frequency after brolucizumab treatment.
Comparison of Cervical Biportal Endoscopic Spine Surgery and Anterior Cervical Discectomy and Fusion in Patients with Symptomatic Cervical Disc Herniation
Authors: Jung Seok-Bong , Gunadala Ishant , Kim Nackhwan
Published: March 2024

Background: We aimed to analyze the clinical outcomes and effectiveness of cervical biportal endoscopic spine surgery (C-BESS) and anterior cervical discectomy and fusion (ACDF) in patients with symptomatic cervical disc herniation. Methods: This study was a retrospective chart review of four-year clinical data involving 318 cases of symptomatic cervical disc herniation, with 156 patients undergoing the ACDF and 162 patients receiving the C-BESS. Preoperative and postoperative one-year data were collected. Results: The numeric rating scale and neck disability index showed statistically significant improvement for both ACDF and C-BESS groups. While showing a longer operation time and more blood loss during surgery compared to the ACDF group, the C-BESS group demonstrated a learning effect as the surgeon’s proficiency increased with more cases. There was no significant difference in the postoperative length of hospitalization between the two methods. The subgroup with predominant arm pain revealed the statistical difference in arm pain intensity changes between the two groups (p < 0.001). The rates of complication were 2.6% for the ACDF group and 1.9% for the C-BESS group. Conclusions: C-BESS and ACDF are effective surgical treatments for patients with symptomatic single-level cervical disc herniation in relieving relevant pain intensities and pain-related disabilities.
Investigating the Joint Probability of High Coastal Sea Level and High Precipitation
Authors: Pais Namitha Viona , O’Donnell James , Ravishanker Nalini
Published: March 2024

The design strategies for flood risk reduction in coastal towns must be informed by the likelihood of flooding resulting from both precipitation and coastal storm surge. This paper discusses various bivariate extreme value methods to investigate the joint probability of the exceedance of thresholds in both precipitation and sea level and estimate their dependence structure. We present the results of the dependence structure obtained using the observational record at Bridgeport, CT, a station with long data records representative of coastal Connecticut. Furthermore, we evaluate the dependence structure after removing the effects of harmonics in the sea level data. Through this comprehensive analysis, our study seeks to contribute to the understanding of the joint occurrence of sea level and precipitation extremes, providing insights that are crucial for effective coastal management.
Potential Interactions between Climate Change and Land Use for Forest Issues in the Eastern United States
Authors: Hanberry Brice , Abrams Marc , Nowacki Gregory
Published: March 2024

Applying an interaction framework, we examined whether climate change and combined land use and disturbance changes were synergistic, antagonistic, or neutral for forest issues of wildfires, tree growth, tree species distributions, species invasions and outbreaks, and deer herbivory, focused on the eastern United States generally since the 1800s and the development of instrumental records (1895). Climate largely has not warmed during 1981–2020 compared to 1895–1980, but precipitation has increased. Increased precipitation and land use (encompassing fire exclusion and forestation, with coarse fuel accumulation due to increased tree densities) have interacted synergistically to dampen wildfire frequency in the humid eastern U.S. For overall tree growth, increased precipitation, carbon fertilization, and land use (i.e., young, fast-growing dense stands) likely have been positive, generating a synergistic interaction. Human activities created conditions for expanding native tree species distributions, non-native species invasions, and damaging native species outbreaks. No strong evidence appears to exist for recent climate change or land use influences on deer populations and associated herbivory levels. In the future, a warmer and effectively drier climate may reverse synergistic and neutral interactions with land use, although effects of climate interactions with land use will vary by species. Management can help correct non-climate stressors due to land use and support resilient structures and species against climate change.
Continuity, Resilience, and Change in Rural Settlement Patterns from the Roman to Islamic Period in the Sicani Mountains (Central-Western Sicily)
Authors: Castrorao Barba Angelo , Aleo Nero Carla , Battaglia Giuseppina , Zambito Luca , Virga Ludovica , Messina Alessandra , Cangemi Marco , Bazan Giuseppe
Published: March 2024

This study aims to analyze the dynamics of change in settlement models from the Roman, late antique, and Byzantine periods, focusing on how these transformations influenced the formation of Islamic societies in the rural landscapes of western Sicily. The study is centered around the territory of Corleone in the Sicani Mountains (central-western Sicily). This region, strategically located between the significant cities of Palermo on the Tyrrhenian Sea and Agrigento on the Strait of Sicily, has been pivotal in the communication network spanning from the Roman era to the Middle Ages and beyond. The area has been subject to extensive surveys and excavations, revealing diverse dynamics of continuity, resilience, and innovation in settlement patterns from the Roman to the Islamic periods. Beyond presenting the results of archaeological fieldwork, this study employs GIS-based spatial and statistical analyses and utilizes a range of topographic (elevation, slope, aspect, topographic position index (TPI), and distance to water sources) and ecological factors (vegetation series). These analyses aim to assess the evolving relationships and site positioning within the territory over time. Combining archaeological data with topographic and ecological landscape analysis, this integrated approach elucidates the complex transition dynamics from the Roman settlement system to the Islamic age’s landscape formation in western Sicily’s rural areas. The study thereby contributes to a deeper understanding of the intricate interplay between historical developments and environmental factors in shaping rural settlement patterns.
A Review of Rural Land Capitalization: Current Status and Further Research
Authors: Fan Weiguo , Zhang Yuheng , Chen Nan , Nie Wanqing
Published: March 2024

Land stands as a crucial factor in the production process. The rational allocation of land resources and the enhancement of land use efficiency play pivotal roles in maintaining stable economic development. Various land use types facilitate the capitalization of land resources through activities such as land transfer, land investment, and large-scale land management. Presently, certain regions grapple with challenges characterized by abundant land resources, insufficient utilization of land elements, and a low degree of utilized land capitalization. To address these issues, scholars employ diverse research methods, delving into land capitalization from various perspectives. This paper provides a comprehensive review of the current academic research on land capitalization. It elucidates the conceptual nuances inherent in the process of land capitalization, traces the historical evolution of land capitalization, and establishes a research framework that considers land appreciation, ownership relationships, and functional transformations. By synthesizing and analyzing the existing research on land capitalization, this paper outlines the current status and identifies future research directions. It is concluded that land appropriation, ownership relationships and functional transformations are the three most important elements in the process of land capitalization. The paper proposes objectives for achieving high-quality development while avoiding excessive capitalization and the aim is to propel land capitalization as a catalyst for rural economic development.
Generative-Adversarial-Network-Based Image Reconstruction for the Capacitively Coupled Electrical Impedance Tomography of Stroke
Authors: Ivanenko Mikhail , Wanta Damian , Smolik Waldemar T. , Wróblewski Przemysław , Midura Mateusz
Published: March 2024

This study investigated the potential of machine-learning-based stroke image reconstruction in capacitively coupled electrical impedance tomography. The quality of brain images reconstructed using the adversarial neural network (cGAN) was examined. The big data required for supervised network training were generated using a two-dimensional numerical simulation. The phantom of an axial cross-section of the head without and with impact lesions was an average of a three-centimeter-thick layer corresponding to the height of the sensing electrodes. Stroke was modeled using regions with characteristic electrical parameters for tissues with reduced perfusion. The head phantom included skin, skull bone, white matter, gray matter, and cerebrospinal fluid. The coupling capacitance was taken into account in the 16-electrode capacitive sensor model. A dedicated ECTsim toolkit for Matlab was used to solve the forward problem and simulate measurements. A conditional generative adversarial network (cGAN) was trained using a numerically generated dataset containing samples corresponding to healthy patients and patients affected by either hemorrhagic or ischemic stroke. The validation showed that the quality of images obtained using supervised learning and cGAN was promising. It is possible to visually distinguish when the image corresponds to the patient affected by stroke, and changes caused by hemorrhagic stroke are the most visible. The continuation of work towards image reconstruction for measurements of physical phantoms is justified.
Synthesis of Electrolytic Manganese Slag–Solid Waste-Based Geopolymers: Compressive Strength and Mn Immobilization
Authors: Mi Bao , Zhao Hui , Lu Meng , Zhou Yi , Xue Yongjie
Published: March 2024

The massive stockpiling of electrolytic manganese residue (EMR) has caused serious environmental pollution. In this study, EMR, coal gangue (CG), and fly ash (FA) were used as raw materials to obtain the optimal mix ratio based on Design-Expert mixture design. The effects of activator modulus, liquid–solid (L/S) ratio, and curing temperature on the mechanical properties of geopolymers were investigated. The results showed that the compressive strength of the prepared geopolymer was 12.0 MPa, and the 28d leaching of Mn was 0.123 mg/L under the conditions of EMR:CG:FA = 0.43:0.34:0.23, L/S = 0.9, a curing temperature of 60 °C, and a curing time of 24 h. This indicates that the geopolymer is an environmentally friendly material with high compressive strength. The mineral composition of the geopolymer is mainly hydrated calcium silicate and geopolymer gel. In addition, a more stable new mineral phase, MnSiO3, was generated. The Fourier transform infrared (FTIR) spectrogram showed that the peak at 1100 m−1 was shifted to 1112 cm−1, which indicated that a geopolymerization reaction had occurred. Through scanning electron microscopy (SEM) and energy dispersive spectrum (EDS) analysis, it was identified that the geopolymerization produced a large amount of amorphous gelatinous substances with a relatively dense structure, the major elements being oxygen, silicon, aluminum, calcium, and sodium.
Prompt Optimization in Large Language Models
Authors: Sabbatella Antonio , Ponti Andrea , Giordani Ilaria , Candelieri Antonio , Archetti Francesco
Published: March 2024

Prompt optimization is a crucial task for improving the performance of large language models for downstream tasks. In this paper, a prompt is a sequence of n-grams selected from a vocabulary. Consequently, the aim is to select the optimal prompt concerning a certain performance metric. Prompt optimization can be considered as a combinatorial optimization problem, with the number of possible prompts (i.e., the combinatorial search space) given by the size of the vocabulary (i.e., all the possible n-grams) raised to the power of the length of the prompt. Exhaustive search is impractical; thus, an efficient search strategy is needed. We propose a Bayesian Optimization method performed over a continuous relaxation of the combinatorial search space. Bayesian Optimization is the dominant approach in black-box optimization for its sample efficiency, along with its modular structure and versatility. We use BoTorch, a library for Bayesian Optimization research built on top of PyTorch. Specifically, we focus on Hard Prompt Tuning, which directly searches for an optimal prompt to be added to the text input without requiring access to the Large Language Model, using it as a black-box (such as for GPT-4 which is available as a Model as a Service). Albeit preliminary and based on “vanilla” Bayesian Optimization algorithms, our experiments with RoBERTa as a large language model, on six benchmark datasets, show good performances when compared against other state-of-the-art black-box prompt optimization methods and enable an analysis of the trade-off between the size of the search space, accuracy, and wall-clock time.
Factors Influencing Burnout Syndrome and Depression in Dentists across Various Institutions
Authors: Ciğerim Levent , Orhan Zeynep Dilan , Doğru İbrahim , Kahraman Nazlı Hilal , Hussein Abdalrahim , Baş Hayrettin
Published: March 2024

Background and Objectives: This study aimed to identify the occupational and personal factors influencing burnout syndrome (BS) and depression among dentists in academic faculties, oral and dental health centres (ODHCs), and private clinics. Materials and Methods: This prospective, cross-sectional study was carried out on dentists working in different regions of Turkey. Data were gathered through an online questionnaire hosted on Google Forms. The questionnaire consisted of demographic data and Maslach BS Inventory (MBI) and Beck Depression Inventory (BDI) sections. The demographic data collected included age, height, weight, marital status, blood type, gender, monthly income, income satisfaction, and whether the participant had enough free time. The dentists were divided into three groups, namely, faculty setting, private clinic, and ODHC, according to the institutions at which they worked. Results: The study was composed of 290 dentists, including 172 males and 118 females, with an average age of 36.98 ± 5.56 years. In total, 128 of the dentists worked in faculties, 72 worked in private clinics, and 90 worked in ODHCs. The study found that women exhibited higher EE scores than men (p < 0.05). The comparison of BS and depression scores showed no statistically significant differences between groups based on marital status or blood type (p > 0.05). There was no significant relationship between emotional exhaustion (EE), depersonalisation (DP), personal accomplishment (PA), and depression scores according to age, BMI, and work experience (p < 0.05). It was found that the EE scores of the dentists working in faculties and private clinics were lower than those of the dentists working in ODHCs (p < 0.05). Monthly income was associated with depression (r = −0.35). Conclusions: The findings reveal that dentists employed in ODHCs reported greater levels of EE. These results suggest a pressing need for enhancements in the work environments of dentists, especially in ODHCs.
Steel Sheet Deformation in Clinch-Riveting Joining Process
Authors: Witkowski Waldemar , Mucha Jacek , Boda Łukasz
Published: March 2024

This paper presents the deformation of a joined sheet after the clinch riveting process. The DX51D steel sheet with zinc coating was used. The samples to be joined with clinch riveting technology had a thickness of 1 ± 0.05 mm and 1.5 ± 0.1 mm. The sheet deformation was measured before and after the joining process. The rivet was pressed in the sheets with the same dimension between the rivet axis and three sheet edges: 20, 30, and 40 mm. For fixed segments of the die, from the rivet side close to the rivet, the sheet deformation was greater than that of the area with movable segments. The movement of the die’s sliding element caused more sheet material to flow in the space between the fixed part of the die and movable segments. Hence, the sheet deformation in these places was smaller than for the die’s fixed element—the sheet material was less compressed. For sheet thickness values of 1.5 mm and a width value of 20 mm, the bulk of the sheet was observed. For a sheet width of 20 mm, it was observed that the deformation of the upper and lower sheets in the area of the rivet was greater than for sheet width values of 30 or 40 mm.
Isolation and Characterization of a Novel Virulent Phage ASG01 of Aeromonas salmonicida and Its Cell Wall Hydrolase Activity
Authors: Li Chen , Fang Qiting , Zhang Yangjun , Li Kunyan , Li Yaoguang , Wang Rong , Peng Yuyuan , Zhang Guofan , Xia Liqiu , Hu Shengbiao
Published: March 2024

Aeromonas salmonicida is an important pathogen that causes furunculosis in trout and salmon with high morbidity and mortality, resulting in significant economic losses in aquaculture. Overuse of antibiotics has led to the continuous emergence of drug-resistant strains. Hence, there is an urgent need to find an alternative environmentally friendly antimicrobial agent. In this study, we isolated a virulent phage of A. salmonicida, named ASG01, which belongs to the Myoviridae family and maintains lytic activity at a pH value range from 4 to 12 and in the temperature range from 30 °C to 60 °C. The whole genomic sequence of ASG01 showed 82% similarity to Aeromonas phage pAh6-C. The cell wall hydrolase (Cwh)-encoding gene from the genome of ASG01 was predicted and heterologously expressed. Notably, in the absence of additional phage genes, endogenous expression of Cwh could lyse E. coli cells and greatly inhibit the growth of tested fish pathogenic bacteria. The lytic activity of Cwh was eliminated when the predicted active site was mutated. These results indicate that Cwh of ASG01 possessed excellent lytic activity and a wide antibacterial spectrum, suggesting its potential as an effective enzybiotic.
Characterization of Tableware from Fábrica de Loiça de Sacavém—Linking Analytical and Documental Research
Authors: Coutinho Mathilda L. , Veiga João Pedro , Ruivo Andreia , Pereira da Silva Teresa , Bottura-Scardina Silvia , Lima Maria Margarida R. A. , Pereira Carlos , Dias Ana Carvalho , Dias Luis , Vandenabeele Peter , Roseiro José C.
Published: March 2024

Fábrica de Loiça de Sacavém (ca. 1858–1994) was among the first to produce white earthenware in Portugal, becoming one of the country’s leading ceramic manufacturers during the late 19th to early 20th centuries. Research on white earthenware has accompanied the growing interest in post-industrial archaeology but is still poorly explored compared to more ancient ceramic productions. This study focused on the ceramic body, glazes, and colourants of tableware produced by Fábrica de Loiça de Sacavém during the first 50 years of its activity (1859–1910). A multi-analytical approach was selected to investigate the chemical and mineralogical composition of the ceramic body, glaze, and pigments using optical microscopy, variable-pressure scanning electron microscope energy-dispersive X-ray spectroscopy (VP-SEM-EDS), μ-Raman spectroscopy, μ-X-ray Diffraction (μ-XRD), and reflectance spectroscopy (hyperspectral image analysis). The studied tableware was produced with a Ca-poor siliceous–aluminous white earthenware ceramic body covered with transparent alkali lead or lead borosilicate glaze, and most colourants were complex Cr-based pigments. These results are in agreement with the little documental evidence from this period found in the manufacturer’s archives.
Formation of Intergrowths of Platinum-Group Minerals and Gold from Magmatogenic Ores in Relation to Phase Changes in Pt-Pd-Fe-Cu-Au System
Authors: Okrugin Alexander , Gerasimov Boris
Published: March 2024

The article discusses the features of the chemical composition and the formation of intergrowths of platinum-group minerals, gold, gold-bearing phases, and other ore minerals present in placers collected from the Anabar River in the northeast part of the Siberian platform. Based on an analysis of changes in the phase compositions of these intergrowths of noble metals with other ore minerals on (Pt, Pd)-Fe-Au and Pd-Cu-Au phase equilibrium diagrams, potential trends in the crystallization of natural polymineral alloys from multicomponent low-sulfide metallic liquids are discussed. The similarity of the microstructures of natural and metallurgical alloys indicates that the formation of natural multiphase Au-PGE intergrowths occurred in a similar manner to the crystallization of multicomponent synthetic alloys. The authors suggest that magmatic Au-PGE mineralization occurs during the crystallization of a noble-metal-containing, low-sulfide, Cr-rich oxide melt separated from silicate mafic–ultramafic magma. Magmatic gold–platinum deposits are commonly associated with sulfide or oxide disseminated-schlieren ores in layered mafic–ultramafic intrusions. However, due to the high solubility of gold and platinoids in sulfide minerals, PGMs in sulfide ores occur as isomorphic impurities or as microphases and dispersed inclusions that cannot form placers. Therefore, the authors suggest that magmatic Au-PGE mineralization occurs during the crystallization of an immiscible low-sulfide, high-Cr oxide liquid separated from silicate mafic–ultramafic magma. In the northeast part of the Siberian platform, potential sources for these placers are likely alkaline, high-Ti mafic–ultramafic intrusions, as confirmed by the presence of silicate inclusions in ferroan platinum similar in composition to melteigite.
Preparation and Characterization of Pullulan-Based Packaging Paper for Fruit Preservation
Authors: Dong Hang , Tian Zhongjian
Published: March 2024

Improving the shelf lives of fruits is challenging. The biodegradable polysaccharide pullulan exhibits excellent film-forming ability, gas barrier performance, and natural decomposability, making it an optimal material for fruit preservation. To overcome problems of high cost and film porosity of existing packaging technologies, we aimed to develop pullulan-based packaging paper to enhance the shelf lives of fruits. A thin paper coating comprising a mixture of 15 wt.% pullulan solution at various standard viscosities (75.6, 77.8, and 108.5 mPa·s) with tea polyphenols (15:2) and/or vitamin C (150:1) improved the oxygen transmission rate (120–160 cm3 m−2·24 h·0.1 MPa), water vapor transmission rate (<5.44 g·mm−1 m−2·h·kPa), maximum free radical clearance rate (>87%), and antibacterial properties of base packaging paper. Grapes wrapped with these pullulan-based papers exhibited less weight loss (>4.41%) and improved hardness (>16.4%) after 10 days of storage compared to those of control grapes (wrapped in untreated/base paper). Grapes wrapped with pullulan-based paper had >12.6 wt.% total soluble solids, >1.5 mg/g soluble protein, >0.44 wt.% titratable acidity, and ≥4.5 mg 100 g−1 ascorbic acid. Thus, pullulan-based paper may prolong the shelf life of grapes with operational convenience, offering immense value for fruit preservation.
Characterisation of Modular Polyketide Synthases Designed to Make Pentaene Analogues of Amphotericin B
Authors: Song Yuhao , Hogan Mark , Muldoon Jimmy , Evans Paul , Caffrey Patrick
Published: March 2024

Glycosylated polyene macrolides are important antifungal agents that are produced by many actinomycete species. Development of new polyenes may deliver improved antibiotics. Here, Streptomyces nodosus was genetically re-programmed to synthesise pentaene analogues of the heptaene amphotericin B. These pentaenes are of interest as surrogate substrates for enzymes catalysing unusual, late-stage biosynthetic modifications. The previous deletion of amphotericin polyketide synthase modules 5 and 6 generated S. nodosus M57, which produces an inactive pentaene. Here, the chain-terminating thioesterase was fused to module 16 to generate strain M57-16TE, in which cycles 5, 6, 17 and 18 are eliminated from the biosynthetic pathway. Another variant of M57 was obtained by replacing modules 15, 16 and 17 with a single 15–17 hybrid module. This gave strain M57-1517, in which cycles 5, 6, 15 and 16 are deleted. M57-16TE and M57-1517 gave reduced pentaene yields. Only M57-1517 delivered its predicted full-length pentaene macrolactone in low amounts. For both mutants, the major pentaenes were intermediates released from modules 10, 11 and 12. Longer pentaene chains were unstable. The novel pentaenes were not glycosylated and were not active against Candida albicans. However, random mutagenesis and screening may yet deliver new antifungal producers from the M57-16TE and M57-1517 strains.
Vitamin D Mitigates Hepatic Fat Accumulation and Inflammation and Increases SIRT1/AMPK Expression in AML-12 Hepatocytes
Authors: Chang Eugene
Published: March 2024

Emerging evidence has demonstrated a strong correlation between vitamin D status and fatty liver disease. Aberrant hepatic fat infiltration contributes to oxidant overproduction, promoting metabolic dysfunction, and inflammatory responses. Vitamin D supplementation might be a good strategy for reducing hepatic lipid accumulation and inflammation in non-alcoholic fatty liver disease and its associated diseases. This study aimed to investigate the role of the most biologically active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D), in hepatic fat accumulation and inflammation in palmitic acid (PA)-treated AML-12 hepatocytes. The results indicated that treatment with 1,25(OH)2D significantly decreased triglyceride contents, lipid peroxidation, and cellular damage. In addition, mRNA levels of apoptosis-associated speck-like CARD-domain protein (ASC), thioredoxin-interacting protein (TXNIP), NOD-like receptor family pyrin domain-containing 3 (NLRP3), and interleukin-1β (IL-1β) involved in the NLRP3 inflammasome accompanied by caspase-1 activity and IL-1β expression were significantly suppressed by 1,25(OH)2D in PA-treated hepatocytes. Moreover, upon PA exposure, 1,25(OH)2D-incubated AML-12 hepatocytes showed higher sirtulin 1 (SIRT1) expression and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. A SIRT1 inhibitor alleviated the beneficial effects of 1,25(OH)2D on PA-induced hepatic fat deposition, IL-1β expression, and caspase-1 activity. These results suggest that the favorable effects of 1,25(OH)2D on hepatic fat accumulation and inflammation may be, at least in part, associated with the SIRT1.
An In Vitro Examination of Whether Kratom Extracts Enhance the Cytotoxicity of Low-Dose Doxorubicin against A549 Human Lung Cancer Cells
Authors: Bayu Asep , Rahmawati Siti Irma , Karim Firmansyah , Panggabean Jonathan Ardhianto , Nuswantari Dasilva Primarindu , Indriani Dwi Wahyu , Ahmadi Peni , Witular Rendi , Dharmayanti Ni Luh Putu Indi , Putra Masteria Yunovilsa
Published: March 2024

Doxorubicin is an effective chemotherapeutic agent in the treatment of solid hematological and non-hematological carcinoma. However, its long-term usage could result in side effects, such as cardiomyopathy, chronic heart failure, neurotoxicity and cancer cell resistance. In this study, we reported the sensitivity enhancement of A549 human lung cancer cells on doxorubicin at a low dose (0.1 ppm) in combination with 10–60 ppm of crude and alkaloid extracts derived from the leaves of Kratom (Mitragyna speciosa (Korth.) Havil. Rubiaceae). A549 cancer cell lines were insensitive to the crude extract containing low mitragynine (MG) (4–5%), while these cells were moderately inhibited by the alkaloid extract containing 40–45% MG (IC50 of 48–55 ppm). The alkaloid extract was found to inhibit A549 cancer cells via apoptosis as suggested by the higher relative fluorescence intensity with Annexin compared to that in propidium iodide (PI), i.e., a positive Annexin and a negative PI. The combination of crude extract and doxorubicin sensitized A549 cancer cells to doxorubicin by 1.3 to 2.4 times, while the combination with the alkaloid induced a 2.6- to 3.4-fold increase in sensitivity. The calculated combination index (CI) for doxorubicin with the crude and alkaloid extracts was 0.6 and 0.3, respectively, showing potential synergistic combinations to reduce the level of dosage of doxorubicin used in chemotherapy. In addition, the synergistic enhancement effect of crude extract on the cytotoxic activity of doxorubicin provides insights into the plausibility of non-alkaloids to influence the biological activities of Kratom.
Design, Synthesis, and Biological Evaluation of Novel Coumarin Analogs Targeted against SARS-CoV-2
Authors: Sharma Kirti , Singh Manjinder , Sharma Pratibha , Sharma Sumesh C. , Mujwar Somdutt , Kapoor Mohit , Mishra Krishna Kumar , Wani Tanveer A.
Published: March 2024

SARS-CoV, an RNA virus, is contagious and displays a remarkable degree of adaptability, resulting in intricate disease presentations marked by frequent genetic mutations that can ultimately give rise to drug resistance. Targeting its viral replication cycle could be a potential therapeutic option to counter its viral growth in the human body leading to the severe infectious stage. The Mpro of SARS-CoV-2 is a promising target for therapeutic development as it is crucial for viral transcription and replication. The derivatives of β-diketone and coumarin have already been reported for their antiviral potential and, thus, are considered as a potential scaffold in the current study for the computational design of potential analogs for targeting the viral replication of SARS-CoV-2. In our study, we used novel diketone-hinged coumarin derivatives against the SARS-CoV-2 MPro to develop a broad-spectrum antiviral agent targeting SARS-CoV-2. Through an analysis of pharmacokinetics and docking studies, we identified a list of the top 10 compounds that demonstrated effectiveness in inhibiting the SARS-CoV-2 MPro virus. On the basis of the pharmacokinetics and docking analyses, the top 5 novel coumarin analogs were synthesized and characterized. The thermodynamic stability of compounds KS82 and KS94 was confirmed by their molecular dynamics, and the stability of the simulated system indicated their inhibitory nature. Molecules KS82 and KS94 were further evaluated for their anti-viral potential using Vero E6 cells followed by RT-PCR assay against SARS-CoV-2. The test compound KS82 was the most active with the potential to inhibit SARS-CoV-2 replication in Vero E6 cells. These data indicate that KS82 prevents the attack of the virus and emerges as the primary candidate with promising antiviral properties.
Discovery of Novel 4-Hydroxyquinazoline Derivatives: In Silico, In Vivo and In Vitro Studies Using Primary PARPi-Resistant Cell Lines
Authors: Zhu Lijie , Liu Binzhuo , Jin Feng , Cao Weilong , Xu Guangzhao , Zhang Xinwei , Peng Peng , Gao Dingding , Wang Bin , Feng Kairui
Published: March 2024

A series of novel 4-Hydroxyquinazoline derivatives were designed and synthesized to enhance sensitivity in primary PARPi-resistant cells. Among them, the compound B1 has been found to have superior cytotoxicity in primary PARPi-resistant HCT-15 and HCC1937 cell lines, and dose-dependently suppressed the intracellular PAR formation and enhanced the γH2AX aggregation. Mechanistic study showed that B1 stimulated the formation of intracellular ROS and the depolarization of the mitochondrial membrane, which could increase apoptosis and cytotoxicity. An in vivo study showed that B1 significantly suppressed tumor growth at a dose of 25 mg/kg, and an acute toxicity study confirmed its safety. Molecular docking and dynamics simulations revealed that hydrogen bonding between B1 and ASP766 may be helpful to enhance anti-drug resistance ability. This study suggests that B1 is a potent PARP inhibitor that can overcome PARPi resistance and deserves further investigation.
Asymmetric α-Fluoroalkyl-α-Amino Acids: Recent Advances in Their Synthesis and Applications
Authors: Picois Nathan , Boutahri Yazid , Milbeo Pierre , Zanato Chiara , Lensen Nathalie , Chaume Grégory , Brigaud Thierry
Published: March 2024

Due to the specific properties provided by fluorine atoms to biomolecules, amino acids with fluorinated side chains are of great interest for medicinal chemistry and chemical biology. Among them, α-fluoroalkyl-α-amino acids constitute a unique class of compounds. In this review, we outline the strategies adopted for their syntheses in enantiopure or enantioenriched forms and their incorporation into peptides. We then describe the consequences of the introduction of fluorine atoms in these compounds for the modulation of their hydrophobicity and the control of their conformation. Emerging applications are presented in the areas of enzyme inhibition, medicinal chemistry, hydrolytic stability of peptides, antimicrobial peptides, PET, and 19F NMR probes.
Antibacterial Activities and Underlying Mechanisms of the Compound SYAUP-491 against Xanthomonas oryzae pv. oryzae
Authors: Li Lina , Wang Yuxin , Liu He , Liu Wei , Zhang Xinchen , An Mengnan , Yu Miao , Wu Yuanhua , Li Xinghai , Wang Jianzhong
Published: March 2024

SYAUP-491 is a novel alkyl sulfonamide. In this study, in vivo and in vitro tests were performed along with a proteomic analysis to determine the effects and underlying mechanisms of the antibacterial activity of SYAUP-491 against the causative agent of bacterial leaf blight in rice. The antibacterial test results suggested that SYAUP-491 exhibited significant activities against Xanthomonas oryzae pv. oryzae (Xoo) in vitro and in vivo. The minimal EC50 values reached 6.96 μg/mL and the curative activity reached 74.1%. Detailed studies demonstrated that SYAUP-491 altered membrane permeability and caused morphological changes. Based on proteomics results, SYAUP-491 might inhibit bacterial protein synthesis. SYAUP-491 may disrupt and alter cell membrane permeability and could further act on ribosomes in the bacterial body. Given the above results, SYAUP-491 could serve as a new lead compound in the research of antibacterial control of plant pathogenic bacterial disease.
Phytochemical Profiling and Biological Activities of Rhododendron Subsect. Ledum: Discovering the Medicinal Potential of Labrador Tea Species in the Northern Hemisphere
Authors: Vengrytė Martyna , Raudonė Lina
Published: March 2024

Rhododendron subsect. Ledum is a distinct taxonomic subdivision within the genus Rhododendron, comprising a group of evergreen shrubs and small trees. This review will comprehensively analyse the phytochemical profiles and biological properties of the Rhododendron subsect. Ledum species subsect. Ledum consists of eight plant species indigenous to temperate and subarctic regions of the Northern Hemisphere, collectively known as Labrador tea. Recent investigations have concentrated on the phytochemical constituents of these plants due to limited data, emphasizing their evergreen nature and potential industrial significance. This review summarizes their major phytochemical constituents, including flavonoids, phenolic acids, and terpenoids, and discusses their potential biological activities, such as antioxidant, anti-inflammatory, antimicrobial, antitumor, hypoglycemic, hepatoprotective, neuroprotective, and cardioprotective effects. Traditional uses of these plant species align with scientific findings, emphasizing the significance of these plants in traditional medicine. However, despite promising results, gaps exist in our understanding of specific compounds’ therapeutic effects, necessitating further research for comprehensive validation. This review serves as a valuable resource for researchers, identifying current knowledge, uncertainties, and emerging trends in the study of the Rhododendron subsect. Ledum species.
Advancements in Rice Leaf Development Research
Authors: Gong Xiaoting , Chen Jian , Chen Yanxin , He Ying , Jiang Dagang
Published: March 2024

Rice leaf morphology is a pivotal component of the ideal plant architecture, significantly impacting rice yield. The process of leaf development unfolds through three distinct stages: the initiation of leaf primordia, the establishment and maintenance of polarity, and leaf expansion. Genes regulating leaf morphology encompass transcription factors, hormones, and miRNAs. An in-depth synthesis and categorization of genes associated with leaf development, particularly those successfully cloned, hold paramount importance in unraveling the complexity of rice leaf development. Furthermore, it provides valuable insights into the potential for molecular-level manipulation of rice leaf types. This comprehensive review consolidates the stages of rice leaf development, the genes involved, molecular regulatory pathways, and the influence of plant hormones. Its objective is to establish a foundational understanding of the creation of ideal rice leaf forms and their practical application in molecular breeding.
Salt Water Exposure Exacerbates the Negative Response of Phragmites australis Haplotypes to Sea-Level Rise
Authors: Lynn Austin , Elsey-Quirk Tracy
Published: March 2024

The response of coastal wetlands to sea-level rise (SLR) largely depends on the tolerance of individual plant species to inundation stress and, in brackish and freshwater wetlands, exposure to higher salinities. Phragmites australis is a cosmopolitan wetland reed that grows in saline to freshwater marshes. P. australis has many genetically distinct haplotypes, some of which are invasive and the focus of considerable research and management. However, the relative response of P. australis haplotypes to SLR is not well known, despite the importance of predicting future distribution changes and understanding its role in marsh response and resilience to SLR. Here, we use a marsh organ experiment to test how factors associated with sea level rise—inundation and seawater exposure—affect the porewater chemistry and growth response of three P. australis haplotypes along the northern Gulf of Mexico coast. We planted three P. australis lineages (Delta, European, and Gulf) into marsh organs at five different elevations in channels at two locations, representing a low (Mississippi River Birdsfoot delta; 0–13 ppt) and high exposure to salinity (Mermentau basin; 6–18 ppt) for two growing seasons. Haplotypes responded differently to flooding and site conditions; the Delta haplotype was more resilient to high salinity, while the Gulf type was less susceptible to flood stress in the freshwater site. Survivorship across haplotypes after two growing seasons was 42% lower at the brackish site than at the freshwater site, associated with high salinity and sulfide concentrations. Flooding greater than 19% of the time led to lower survival across both sites linked to high concentrations of acetic acid in the porewater. Increased flood duration was negatively correlated with live aboveground biomass in the high-salinity site (χ2 = 10.37, p = 0.001), while no such relationship was detected in the low-salinity site, indicating that flood tolerance is greater under freshwater conditions. These results show that the vulnerability of all haplotypes of P. australis to rising sea levels depends on exposure to saline water and that a combination of flooding and salinity may help control invasive haplotypes.
Characterization of a New Citrus Mutant Induced by Gamma Irradiation with a Unique Fruit Shape, Gwonje-Early, and Determination of Specific Selection Markers Using Allele-Specific PCR
Authors: Eun Chang-Ho , Ko Jung-Gwon , Kim In-Jung
Published: March 2024

Gamma-ray irradiation is one of the most widely used mutagens worldwide. We previously conducted mutation breeding using gamma irradiation to develop new Citrus unshiu varieties. Among these mutants, Gwonje-early had an ovate shape, a protrusion of the upper part of the fruit, and a large fruit size compared with wild-type (WT) fruits. We investigated the external/internal morphological characteristics and fruit sugar/acid content of Gwonje-early. Additionally, we investigated genome-wide single-nucleotide polymorphisms (SNPs) and insertion/deletion (InDel) variants in Gwonje-early using whole-genome re-sequencing. Functional annotation by Gene Ontology analysis confirmed that InDels were more commonly annotated than SNPs. To identify specific molecular markers for Gwonje-early, allele-specific PCR was performed using homozygous SNPs detected via Gwonje-early genome re-sequencing. The GJ-SNP1 and GJ-SNP4 primer sets were effectively able to distinguish Gwonje-early from the WT and other commercial citrus varieties, demonstrating their use as specific molecular markers for Gwonje-early. These findings also have important implications in terms of intellectual property rights and the variety protection of Gwonje-early. Our results may provide insights into the understanding of morphological traits and the molecular breeding mechanisms of citrus species.
Diagnosing Complex Organisations with Diverse Cultures—Part 2: Application to ASEAN
Authors: Rautakivi Tuomo , Yolles Maurice
Published: March 2024

In this paper, the second part of a two-part series, we explore the cultural stability of the Association of Southeast Asian Nations (ASEAN). The analytical framework adopted, formulated on a background of social cybernetics, uses Mindset Agency Theory (MAT) within a metacybernetic framework. Our exploration involves a thorough investigation of signs pointing to cultural instability, identification of potential pathologies, and the provision of insights into the underlying dynamics within ASEAN. Expanding on the theoretical foundation established in the first part, we explore the notion that regional organisations (ROs) like ASEAN can be viewed as complex adaptive systems with agency. Heterogeneity of RO membership can be both beneficial and detrimental, especially when this delivers cultural diversity. If detrimental, pathologies can arise that affect both ROs’ institutional dynamics and their affiliated regional organisations, a significant interest of this paper. In response to certain cybernetic aspects introduced in part 1 of the research, MAT is shown to be a specialised framework imbued with systemic and reflexive elements. Through this, the analysis sheds light on how an agency’s mindset connects with its behaviour and performance. ROs exhibit coherence in their operations when they successfully achieve adaptive goals. ROs, as agencies defined through a population of state agents, have mutual relationships and are encouraged to pursue shared regional objectives, such as economic growth, social welfare, security, and democracy. However, in highly diverse cultural environments, this poses unique challenges to achieving and maintaining cultural stability. The analysis scrutinises ASEAN’s behaviour, relating it to manifestations of cultural instability, and deduces conditions that encompass an inability to undertake collective action, covert narcissism, and a lack of authority. Employing MAT as a diagnostic tool to comprehend ASEAN’s intricate nature, the paper concludes with practical recommendations aimed at enhancing ASEAN’s cultural health and sustainability. The ultimate vision is to foster a more integrated and proactive regional entity.
Characteristics of Pathogenic Escherichia coli Associated with Diarrhea in Children under Five Years in Northwestern Ethiopia
Authors: Mulu Berihun Mossie , Belete Mequanint Addisu , Demlie Tiliksew Bialfew , Tassew Habtamu , Sisay Tessema Tesfaye
Published: March 2024

Diarrheagenic Escherichia coli (DEC) are the leading cause of infectious diarrhea and pose a significant global, regional, and national burden of disease. This study aimed to investigate the prevalence of six DEC pathotypes in children with diarrhea and determine their antibiotic resistance patterns. Samples from 107 diarrheagenic children were collected and processed for Escherichia coli (E. coli). Single-plex PCR was used to detect target virulence genes as well as characterize and categorize DEC pathotypes. Antibiotic resistance patterns were determined by the Kirby–Bauer disk diffusion method. E. coli was detected in 79 diarrheal stool samples, accounting for 73.8% of the samples collected. Additionally, 49.4% (39 out of 79) of the isolates harbored various typical virulence factors. Results revealed six pathotypes of virulence: enterotoxigenic E. coli (ETEC) (53.8%), enteropathogenic E. coli (EPEC) (12.8%), enteroaggregative E. coli (EAEC) (10.3%), Heteropathotypes (7.8%), Shiga toxin-producing E. coli (STEC), and enterohemorrhagic E. coli (EHEC) (7.7% each). The isolates exhibited high antibiotic resistance against trimethoprim/sulfamethoxazole (82.1%), amoxicillin (79.5%), ampicillin (74.4%), gentamicin (69.2%), and streptomycin (64.1%). An overall occurrence of 84.6% of multiple-drug resistance was observed in the isolates, with resistance ranging from three to four antibiotic classes. Our findings revealed a high level of pathogenic E. coli that were highly resistant to multiple categories of antibiotics among children in the Awi zone. These findings highlight the potential role of pathogenic E. coli in childhood diarrhea in tropical low-resource settings and underscore the need for continued research on the characteristics of pathogenic and antibiotic-resistant strains.