bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhancing the Yield, Quality and Antioxidant Content of Lettuce through Innovative and Eco-Friendly Biofertilizer Practices in Hydroponics
Authors: Dasgan Hayriye Yildiz , Yilmaz Dilek , Zikaria Kamran , Ikiz Boran , Gruda Nazim S.
Published: November 2023

Hydroponics is a contemporary agricultural system providing precise control over growing conditions, potentially enhancing productivity. Biofertilizers are environmentally friendly, next-generation fertilizers that augment product yield and quality in hydroponic cultivation. In this study, we investigated the effect of three bio-fertilizers in a hydroponic floating system, microalgae, plant growth-promoting rhizobacteria (PGPR) and arbuscular mycorrhizal fungi (AMF), combined with a 50% reduction in mineral fertilizer, on lettuce yield and quality parameters including antioxidants: vitamin C, total phenols and flavonoids. The treatments tested were: 100% mineral fertilizer (control 1), 50% mineral fertilizer (control 2), 50% mineral fertilizer with microalgae, 50% mineral fertilizer with PGPR and 50% mineral fertilizer with AMF. The research was conducted during the winter months within a controlled environment of a glasshouse in a Mediterranean climate. The PGPR comprised three distinct bacterial strains, while the AMF comprised nine different mycorrhizal species. The microalgae consisted of only a single species, Chlorella vulgaris. AMF inoculation occurred once during seed sowing, while the introduction of PGPR and microalgae occurred at 10-day intervals into the root medium. Our findings revealed that the treatment with PGPR resulted in the highest growth parameters, including the lettuce circumference, stem diameter and fresh leaf weight. The 100% mineral fertilizer and PGPR treatments also yielded the highest lettuce production. Meanwhile, the treatment with AMF showed the highest total phenol and flavonoid content, which was statistically similar to that of the PGPR treatment. Furthermore, the PGPR recorded the maximum range of essential nutrients, including nitrogen (N), potassium (K), iron (Fe), zinc (Zn) and copper (Cu). Thus, the inclusion of PGPR holds promise for optimizing the lettuce growth and nutrient content in hydroponic systems. In conclusion, PGPR has the potential to enhance nutrient availability in a floating hydroponic system, reducing the dependence on chemical fertilizers. This mitigates environmental pollution and fosters sustainable agriculture.
Performance Evaluation of Different Stilling Basins Downstream of Barrage Using FLOW-3D Scour Models
Authors: Zaffar Muhammad Waqas , Haasan Ishtiaq , Ghumman Abdul Razzaq
Published: November 2023

The present study investigated the performance of three different stilling basins, i.e., modified United State Bureau of Reclamation (USBR) Type III, USBR Type II, and wedge-shaped baffle blocks (WSBB), using FLOW-3D scour models. Field data of the riverbed profile are employed to validate the present models. After comparison, the results of statistical indices, i.e., coefficient of determination (R2) and Nash–Sutcliffe model efficiency coefficient (NSE), indicated that the Renormalization Group (RNG-K-ϵ) showed good agreement with the field data, with R2 and NSE values of 0.9094 and 0.896, respectively. Validated models are used to simulate velocity field and local bed shear stress (BSS) and scour for design and flood discharges of 28.30 m3/s/m and 17.5 m3/s/m, respectively. At 28.30 m3/s/m, the results indicated that the riverbed downstream of the remodeled basin was completely exposed, while, at 17.5 m3/s/m, the net change in bed reached 85%. At 28.30 m3/s/m, the net change at the centerline of models reached 51% and 67% in USBR Type III and WSBB basins, respectively. At 17.5 m3/s/m, compared to Type II and III basins, the WSBB basin indicated less BSS, which significantly reduced the scour. Conclusively, the Type II basin showed less energy dissipation for the studied flows, while the WSBB basin improved flow fields downstream of the barrage.
Oral Health-Related Quality of Life among Adolescents in the First 6 Months of Fixed Orthodontic Therapy
Authors: Fahd Cláudia Gonçalves , Castro Gustavo Garcia , Costa Ana Carla Souza , Costa Cyrene Piazera Silva , Carvalho Ceci Nunes , Pinzan-Vercelino Célia Regina Maio , Ferreira Meire Coelho
Published: November 2023

Clarification on disabilities that may arise during orthodontic treatment allows patients to have more realistic expectations. This prospective study assessed the impact of fixed orthodontic therapy on adolescents’ quality of life over 6 months. A total of 78 adolescents aged 11–17 years were included. Quality of life was measured using the Child Perceptions Questionnaire (CPQ11–14, short form) at five moments: before treatment (T0), one week (T1), one month (T2), three months (T3), and six months (T4) after treatment initiation. Multiple and pairwise comparisons were conducted for CPQ11–14 scores (Friedman and Wilcoxon test; effect size). Changes in the quality of life were assessed as mean differences (T0–T1 and T0–T4) in total and domain scores (Kruskal–Wallis and Mann–Whitney test) (α = 5%). Significant differences were observed between T0 and T4 in the oral symptoms’ domain (p < 0.001), and between T0 and T1, T2, T3, and T4 for emotional well-being (p < 0.001 for all). Significant differences in impact were also found between T0 and T2, T3, and T4 with regard to social well-being (p = 0.004, =0.049, and <0.001, respectively). Orthodontic therapy positively impacted the emotional and social aspects of adolescents’ quality of life. Negative effects were primarily related to pain, mouth sores, and difficulty biting or chewing. Understanding the symptoms and feelings of orthodontic patients aids professionals in decision-making.
UK Nurses Delivering Physical Activity Advice: What Are the Challenges and Possible Solutions? A Qualitative Study
Authors: Raghavan Anoop , Vishnubala Dane , Iqbal Adil , Hunter Ruth , Marino Katherine , Eastwood David , Nykjaer Camilla , Pringle Andy
Published: November 2023

There are a multitude of health benefits gained from regular physical activity (PA). Currently, PA advice implementation from NHS nurses is inadequate despite their ever-increasing role in lifestyle and preventive medicine. By assessing their knowledge of current PA guidance, this study proposed to investigate the issues with regular PA advice being given and expand upon nurses’ proposed barriers and solutions. A qualitative approach using semi structured interviews was undertaken between March and August 2023 involving 13 NHS nurses. Thematic analysis was undertaken using Braun and Clarke’s six step approach. Four themes and fifteen subthemes emerged as barriers and solutions in delivering PA advice. Intrinsic barriers included a lack of nurse knowledge on the topic and PA being seen as an afterthought. Extrinsic barriers included time pressures and a lack of staff engagement. Solutions involved increasing staff awareness of guidelines through teaching, policy, encouraging staff to be active and optimising PA advice delivery through a piecemeal approach and utilising online and visual resources. This study displayed an insight into nurses’ thoughts on their consultations with patients regarding PA, and proposed several barriers and solutions. Further work is needed to improve nurses’ PA knowledge and to assess the proposed strategies to improve its delivery.
Precision Recruitment and Engagement of Individuals at Risk for Diabetes and Hypertension in Clinical Trials (PREDHICT): A Randomized Trial for an E-Persuasive Mobile Application to Inform Decision Making about Clinical Trials
Authors: Seixas Azizi , Richards Shannique , Moore Jesse Q. , Izeogu Chigozirim , Hollimon Laronda A. , Jin Peng , Jean-Louis Girardin
Published: November 2023

The primary objective of this randomized trial was to test the effectiveness of the PREDHiCT digital application, which provides educational and supportive navigation to increase willingness to participate in a future clinical trial. The second objective was to test whether PREDHiCT increased clinical trial literacy or enhanced psychological facilitators of clinical trial participation, such as altruism. To test these two objectives, we conducted a 1-month remote decentralized trial with 100 participants who either have a personal or family history of cardiometabolic health conditions, such as hypertension, diabetes, and obesity. Results indicated significant changes in altruism (mean: −2.94 vs. 0.83; p-value = 0.011) and clinical trial literacy (mean: 0.55 vs. 2.59; p-value = 0.001) from baseline to 1-month follow-up between the control and intervention groups. Additionally, participants exposed to personalized clinical trial navigation had greater clinical trial literacy at the end of the study relative to the individuals in the control arm of the study. Our findings indicate that tailored education, navigation, and access to clinical trials—three unique features of our PREDHiCT app—increased altruism and clinical trial literacy but not willingness to participate in a trial.
Research on Approximate Spatial Keyword Group Queries Based on Differential Privacy and Exclusion Preferences in Road Networks
Authors: Zhang Liping , Li Jing , Li Song
Published: November 2023

A new spatial keyword group query method is proposed in this paper to address the existing issue of user privacy leakage and exclusion of preferences in road networks. The proposed query method is based on the IGgram-tree index and minimum hash set. To deal with this problem effectively, this paper proposes a query method based on the IGgram-tree index and minimum hash set. The IGgram-tree index is proposed for the first time to deal with the approximate keyword query problem in the road network. This index significantly improves the efficiency of calculating the road network distance and querying approximate keywords. Considering that spatial keyword group queries are caused by NP-hard problems with high time complexity, this paper proposes a data structure that uses the minimum hash set, which can efficiently search for the result set. To address the problem that the traditional spatial keyword group query does not consider user privacy leakage and the limitations of existing privacy protection techniques, this method proposes a differential privacy-based allocation method to better protect the privacy of data. The theoretical study and experimental analysis show that the proposed method can better handle the approximate spatial keyword group query problem based on its use of differential privacy and exclusion preferences in road networks.
Dynamic Interplay of Metabolic and Transcriptional Responses in Shrimp during Early and Late Infection Stages of Enterocytozoon hepatopenaei (EHP)
Authors: Zhang Leiting , Zhang Sheng , Qiao Yi , Cao Xiaohui , Cheng Jie , Meng Qingguo , Shen Hui
Published: November 2023

Enterocytozoon hepatopenaei (EHP) is a microsporidian parasite that infects Litopenaeus vannamei, causing severe hepatopancreatic microsporidiosis (HPM) and resulting in significant economic losses. This study utilizes a combined analysis of transcriptomics and metabolomics to unveil the dynamic molecular interactions between EHP and its host, the Pacific white shrimp, during the early and late stages of infection. The results indicate distinct immunological, detoxification, and antioxidant responses in the early and late infection phases. During early EHP infection in shrimp, immune activation coincides with suppression of genes like Ftz-F1 and SEPs, potentially aiding parasitic evasion. In contrast, late infection shows a refined immune response with phagocytosis-enhancing down-regulation of Ftz-F1 and a resurgence in SEP expression. This phase is characterized by an up-regulated detoxification and antioxidant response, likely a defense against the accumulated effects of EHP, facilitating a stable host–pathogen relationship. In the later stages of infection, most immune responses return to baseline levels, while some immune genes remain active. The glutathione antioxidant system is suppressed early on but becomes activated in the later stages. This phenomenon could facilitate the early invasion of EHP while assisting the host in mitigating oxidative damage caused by late-stage infection. Notably, there are distinctive events in polyamine metabolism. Sustained up-regulation of spermidine synthase and concurrent reduction in spermine levels suggest a potential role of polyamines in EHP development. Throughout the infection process, significant differences in genes such as ATP synthase and hexokinase highlight the continuous influence on energy metabolism pathways. Additionally, growth-related pathways involving amino acids such as tryptophan, histidine, and taurine are disrupted early on, potentially contributing to the growth inhibition observed during the initial stages of infection. In summary, these findings elucidate the dynamic interplay between the host, Litopenaeus vannamei, and the parasite, EHP, during infection. Specific phase differences in immune responses, energy metabolism, and antioxidant processes underscore the intricate relationship between the host and the parasite. The disruption of polyamine metabolism offers a novel perspective in understanding the proliferation mechanisms of EHP. These discoveries significantly advance our comprehension of the pathogenic mechanisms of EHP and its interactions with the host.
Medication-Related Osteonecrosis of the Jaw: A Systematic Review and a Bioinformatic Analysis
Authors: Laputková Galina , Talian Ivan , Schwartzová Vladimíra
Published: November 2023

The objective was to evaluate the current evidence regarding the etiology of medication-related osteonecrosis of the jaw (MRONJ). This study systematically reviewed the literature by searching PubMed, Web of Science, and ProQuest databases for genes, proteins, and microRNAs associated with MRONJ from the earliest records through April 2023. Conference abstracts, letters, review articles, non-human studies, and non-English publications were excluded. Twelve studies meeting the inclusion criteria involving exposure of human oral mucosa, blood, serum, saliva, or adjacent bone or periodontium to anti-resorptive or anti-angiogenic agents were analyzed. The Cochrane Collaboration risk assessment tool was used to assess the quality of the studies. A total of 824 differentially expressed genes/proteins (DEGs) and 22 microRNAs were extracted for further bioinformatic analysis using Cytoscape, STRING, BiNGO, cytoHubba, MCODE, and ReactomeFI software packages and web-based platforms: DIANA mirPath, OmicsNet, and miRNet tools. The analysis yielded an interactome consisting of 17 hub genes and hsa-mir-16-1, hsa-mir-21, hsa-mir-23a, hsa-mir-145, hsa-mir-186, hsa-mir-221, and hsa-mir-424. A dominance of cytokine pathways was observed in both the cluster of hub DEGs and the interactome of hub genes with dysregulated miRNAs. In conclusion, a panel of genes, miRNAs, and related pathways were found, which is a step toward understanding the complexity of the disease.
COVID-19 in Children: Molecular Profile and Pathological Features
Authors: Nasyrov Ruslan A. , Ivanov Dmitry O. , Krasnogorskaya Olga L. , Timchenko Vladimir N. , Fedotova Elena P. , Chepelev Alexander S. , Galichina Veronika A. , Sidorova Nadezhda A. , Anichkov Nikolai M.
Published: November 2023

Although the World Health Organization has declared the end of the COVID-19 pandemic, doctors continue to register new cases of the disease among both adults and children. Unfortunately, the course of COVID-19 in children can have a severe form, with death being a potential outcome. The absence of published works discussing the pathological morphology of COVID-19 in children prevents the objective analysis of the disease’s pathogenesis, including among the adult population. In this vein, the objective of our study is to identify the morphological features of the lungs’ involvement and evaluate virus–host interactions in the case of COVID-19 in patients at a pediatric medical practice. We present the results of the study of the lungs of three children who died due to COVID-19, highlighting the predominant involvement of their respiratory organs at different stages of the disease (5, 21, and 50 days). This article presents data obtained from histopathological and immunohistochemical investigations, taking into account the results of clinical and laboratory indicators and intravital and postmortem SARS-CoV-2 PCR investigations. The common finding of all of the examined COVID-19 cases is the involvement of the endothelium in microcirculation vessels, which are considered to be a primary target of various pathogenic influencing factors. We also discuss both the significance of apoptosis as a result of virus–host interactions and the most likely cause of endothelium cell destruction. The results of this study could be useful for the development of endothelium-protective therapy to prevent the progression of disseminated intravascular coagulation syndrome.
TRPC6 Deletion Enhances eNOS Expression and Reduces LPS—Induced Acute Lung Injury
Authors: Wang Mengyuan , Zhang Xingfang , Guo Juan , Yang Shangze , Yang Fang , Chen Xingjuan
Published: November 2023

Acute lung injury (ALI) is characterized by endothelial barrier disruption and associated inflammatory responses, and transient receptor potential cation channel 6 (TRPC6)—mediated Ca2+ influx is critical for endothelial hyperpermeability. In this study, we investigated the role of TRPC6 in LPS—induced ALI, analyzed gene expression in WT and TRPC6-/- lungs using RNA sequencing, and explored the effects of TRPC6 in the LPS—induced hyperpermeability in human umbilical vein endothelial cells (HUVECs) to elucidate the underlying mechanisms. Intratracheal instillation of LPS caused edema in the mouse lungs. Deletion of TRPC6 reduced LPS—induced lung edema and decreased cell infiltration. RNA sequencing analysis suggested that downregulated cell adhesion molecules in TRPC6-/- lungs may be responsible for their resistance to LPS—induced injury. In addition, downregulation of TRPC6 significantly alleviated the LPS—induced decrease in eNOS expression in lung tissue as well as in HUVECs. Moreover, inhibition of TRPC6 with the channel antagonist larixyl led to a decrease in LPS—induced hyperpermeability and ROS production in HUVECs, which could be reversed by blocking eNOS. Our findings suggest that inhibition of TRPC6 ameliorates LPS—induced ALI, which may be achieved by acting on the cell adhesion molecule signaling pathway and participating in the regulation of eNOS levels in endothelial cells.
CRISPR-Cas9 Mediated Stable Expression of Exogenous Proteins in the CHO Cell Line through Site-Specific Integration
Authors: Huang Zhipeng , Habib Arslan , Zhao Guoping , Ding Xiaoming
Published: November 2023

Chinese hamster ovary (CHO) cells are a popular choice in biopharmaceuticals because of their beneficial traits, including high-density suspension culture, safety, and exogenously produced proteins that closely resemble natural proteins. Nevertheless, a decline in the expression of exogenous proteins is noted as culture time progresses. This is a consequence of foreign gene recombination into chromosomes by random integration. The current investigation employs CRISPR-Cas9 technology to integrate foreign genes into a particular chromosomal location for sustained expression. Results demonstrate the successful integration of enhanced green fluorescent protein (EGFP) and human serum albumin (HSA) near base 434814407 on chromosome NC_048595.1 of CHO-K1 cells. Over 60 successive passages, monoclonal cell lines were produced that consistently expressed all relevant external proteins without discernible variation in expression levels. In conclusion, the CHO-K1 cell locus, NC_048595.1, proves an advantageous locus for stable exogenous protein expression. This study provides a viable approach to establishing a CHO cell line capable of enduring reliable exogenous protein expression.
Acetylcholine-Binding Protein Affinity Profiling of Neurotoxins in Snake Venoms with Parallel Toxin Identification
Authors: Palermo Giulia , Schouten Wietse M. , Alonso Luis Lago , Ulens Chris , Kool Jeroen , Slagboom Julien
Published: November 2023

Snakebite is considered a concerning issue and a neglected tropical disease. Three-finger toxins (3FTxs) in snake venoms primarily cause neurotoxic effects since they have high affinity for nicotinic acetylcholine receptors (nAChRs). Their small molecular size makes 3FTxs weakly immunogenic and therefore not appropriately targeted by current antivenoms. This study aims at presenting and applying an analytical method for investigating the therapeutic potential of the acetylcholine-binding protein (AChBP), an efficient nAChR mimic that can capture 3FTxs, for alternative treatment of elapid snakebites. In this analytical methodology, snake venom toxins were separated and characterised using high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS) and high-throughput venomics. By subsequent nanofractionation analytics, binding profiling of toxins to the AChBP was achieved with a post-column plate reader-based fluorescence-enhancement ligand displacement bioassay. The integrated method was established and applied to profiling venoms of six elapid snakes (Naja mossambica, Ophiophagus hannah, Dendroaspis polylepis, Naja kaouthia, Naja haje and Bungarus multicinctus). The methodology demonstrated that the AChBP is able to effectively bind long-chain 3FTxs with relatively high affinity, but has low or no binding affinity towards short-chain 3FTxs, and as such provides an efficient analytical platform to investigate binding affinity of 3FTxs to the AChBP and mutants thereof and to rapidly identify bound toxins.
Radiation and Immune Checkpoint Inhibitors: Combination Therapy for Treatment of Hepatocellular Carcinoma
Authors: Chami Perla , Diab Youssef , Khalil Danny N. , Azhari Hassan , Jarnagin William R. , Abou-Alfa Ghassan K. , Harding James J. , Hajj Joseph , Ma Jennifer , El Homsi Maria , Reyngold Marsha , Crane Christopher , Hajj Carla
Published: November 2023

The liver tumor immune microenvironment has been thought to possess a critical role in the development and progression of hepatocellular carcinoma (HCC). Despite the approval of immune checkpoint inhibitors (ICIs), such as programmed cell death receptor 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T lymphocyte associated protein 4 (CTLA-4) inhibitors, for several types of cancers, including HCC, liver metastases have shown evidence of resistance or poor response to immunotherapies. Radiation therapy (RT) has displayed evidence of immunosuppressive effects through the upregulation of immune checkpoint molecules post-treatment. However, it was revealed that the limitations of ICIs can be overcome through the use of RT, as it can reshape the liver immune microenvironment. Moreover, ICIs are able to overcome the RT-induced inhibitory signals, effectively restoring anti-tumor activity. Owing to the synergetic effect believed to arise from the combination of ICIs with RT, several clinical trials are currently ongoing to assess the efficacy and safety of this treatment for patients with HCC.
Prognostic Value of Galectin-3 after Left Atrial Appendage Occlusion for Predicting Peri-Device Leakage
Authors: Haertel Franz , Lustermann Paul , Hamadanchi Ali , Gruen Katja , Bogoviku Jurgen , Aftanski Pawel , Westphal Julian , Baez Laura , Franz Marcus , Schulze P. Christian , Moebius-Winkler Sven
Published: November 2023

Echocardiographic detection of residual peri-device leakage (PDL) after percutaneous left atrial appendage occlusion (LAAO) is crucial for managing anticoagulation. Galectin-3, a protein involved in tissue–foreign body interactions, may hold significance in understanding PDL and cardiac tissue remodeling after LAAO. This study aimed to analyze galectin-3 serum levels in relation to PDL using a novel echo-morphological classification. LAAO eligible patients were included in the study. Galectin-3 serum levels were measured before LAAO, at 45 days (45D), and at 6 months (6M) after the procedure. Transesophageal echocardiography was used to assess LAAO success. A new echo-morphological classification categorized the degree of LAAO into three different types (A: homogenous echodensity, indicating completely thrombosed device; B: inhomogeneous echolucencies (<50% of device); and C: partially thrombosed device with echolucencies > 50%). Among 47 patients, complete LAAO was achieved in 60% after 45D and in 74% after 6M. We observed a significant increase and distribution of serum levels of galectin-3 [ng/mL] after 45D among the three types (baseline: 13.1 ± 5.8 ng/mL; 45D: 16.3 ± 7.2 ng/mL (Type A) vs. 19.2 ± 8.6 ng/mL (Type B) vs. 25.8 ± 9.4 ng/mL (Type C); p = 0.031), followed by a drop in galectin-3 for Types A and B after 6M toward and below the baseline levels (6M: 8.9 ± 3.1 ng/mL (Type A) vs. 12.4 ± 5.5 ng/mL (Type B)), whereas Type C persisted in showing elevated galectin-3 levels compared to all other types (6M: 17.5 ± 4.5 ng/mL (Type C); p < 0.01). Increased galectin-3 serum levels after LAAO likely reflect the transition from thrombus formation to fibrotic scar development in the LAA lumen. Successful occlusion is associated with a time-restricted decrease in galectin-3 levels after 6 months, while relevant PDL leads to persistently elevated levels, making galectin-3 a potential predictor of occlusion success.
CXCR2-Blocking Has Context-Sensitive Effects on Rat Glioblastoma Cell Line Outgrowth (S635) in an Organotypic Rat Brain Slice Culture Depending on Microglia-Depletion (PLX5622) and Dexamethasone Treatment
Authors: Falter Johannes , Lohmeier Annette , Eberl Petra , Stoerr Eva-Maria , Koskimäki Janne , Falter Lena , Rossmann Jakob , Mederer Tobias , Schmidt Nils Ole , Proescholdt Martin
Published: November 2023

In glioblastoma (GBM), the interplay of different immune cell subtypes, cytokines, and/or drugs shows high context-dependencies. Interrelations between the routinely applied dexamethasone (Dex) and microglia remain elusive. Here, we exploited rat organotypic brain slice co-cultures (OBSC) to examine the effects on a rat GBM cell line (S635) outgrowth resulting from the presence of Dex and pretreatment with the colony-stimulating factor receptor 1 (CSF1-R) inhibitor PLX5622: in native OBSC (without PLX5622-pretreatment), a diminished S635 spheroid outgrowth was observable, whereas Dex-treatment enhanced outgrowth in this condition compared to PLX5622-pretreated OBSC. Screening the supernatants of our model with a proteome profiler, we found that CXCL2 was differentially secreted in a Dex- and PLX5622-dependent fashion. To analyze causal interrelations, we interrupted the CXCL2/CXCR2-axis: in the native OBSC condition, CXCR2-blocking resulted in increased outgrowth, in combination with Dex, we found potentiated outgrowth. No effect was found in the PLX5622-pretreated. Our method allowed us to study the influence of three different factors—dexamethasone, PLX5622, and CXCL2—in a well-controlled, simplified, and straight-forward mechanistic manner, and at the same time in a more realistic ex vivo scenario compared to in vitro studies. In our model, we showed a GBM outgrowth enhancing synergism between CXCR2-blocking and Dex-treatment in the native condition, which was levelled by PLX5622-pretreatment.
Channel Formation in Cry Toxins: An Alphafold-2 Perspective
Authors: Torres Jaume , Surya Wahyu , Boonserm Panadda
Published: November 2023

Bacillus thuringiensis (Bt) strains produce pore-forming toxins (PFTs) that attack insect pests. Information for pre-pore and pore structures of some of these Bt toxins is available. However, for the three-domain (I-III) crystal (Cry) toxins, the most used Bt toxins in pest control, this crucial information is still missing. In these Cry toxins, biochemical data have shown that 7-helix domain I is involved in insertion in membranes, oligomerization and formation of a channel lined mainly by helix α4, whereas helices α1 to α3 seem to have a dynamic role during insertion. In the case of Cry1Aa, toxic against Manduca sexta larvae, a tetrameric oligomer seems to precede membrane insertion. Given the experimental difficulty in the elucidation of the membrane insertion steps, we used Alphafold-2 (AF2) to shed light on possible oligomeric structural intermediates in the membrane insertion of this toxin. AF2 very accurately (<1 Å RMSD) predicted the crystal monomeric and trimeric structures of Cry1Aa and Cry4Ba. The prediction of a tetramer of Cry1Aa, but not Cry4Ba, produced an ‘extended model’ where domain I helices α3 and α2b form a continuous helix and where hydrophobic helices α1 and α2 cluster at the tip of the bundle. We hypothesize that this represents an intermediate that binds the membrane and precedes α4/α5 hairpin insertion, together with helices α6 and α7. Another Cry1Aa tetrameric model was predicted after deleting helices α1 to α3, where domain I produced a central cavity consistent with an ion channel, lined by polar and charged residues in helix α4. We propose that this second model corresponds to the ‘membrane-inserted’ structure. AF2 also predicted larger α4/α5 hairpin n-mers (14 ≤n ≤ 17) with high confidence, which formed even larger (~5 nm) pores. The plausibility of these models is discussed in the context of available experimental data and current paradigms.
Graphdiyne and Nitrogen-Doped Graphdiyne Nanotubes as Highly Efficient Electrocatalysts for Oxygen Reduction Reaction
Authors: Liu Tongchang , Hao Xinmeng , Liu Jiaqi , Zhang Pengfei , Chang Jiaming , Shang Hong , Liu Xuanhe
Published: November 2023

Electrocatalysts with high efficiency and low cost are always urgently needed for oxygen reduction reaction (ORR). As a new carbon allotrope, graphdiyne (GDY) has received much attention due to its unique chemical structure containing sp- and sp2-hybridized carbons, and intrinsic electrochemical activity ascribed to its inherent conductivity. Herein, we prepared two graphdiyne materials named GDY nanotube and nitrogen-doped GDY (NGDY) nanotube via cross-coupling reactions on the surface of Cu nanowires. As metal-free catalysts, their electrocatalytic activities for ORR were demonstrated. The results showed that the NGDY nanotube presents more excellent electrochemical performance than that of the GDY nanotube, including more positive potential and faster kinetics and charge transfer process. The improvement can be ascribed to the greater number of structural electrocatalytic active sites from nitrogen atoms as well as the hollow nanotube morphology, which is beneficial to the adsorption of oxygen and acceleration of the catalytic reaction. This work helps develop high-quality graphdiyne-based electrocatalysts with well-defined chemical structures and morphologies for various electrochemical reactions.
Melatonin Ameliorates Neuropsychiatric Behaviors, Gut Microbiome, and Microbiota-Derived Metabolites in Rats with Chronic Sleep Deprivation
Authors: Li Bingcong , Hsieh Yin-Ru , Lai Wen-De , Tung Te-Hsuan , Chen Yu-Xuan , Yang Chia-Hui , Fang Yu-Chiao , Huang Shih-Yi
Published: November 2023

With the increasing prevalence of sleep deprivation (SD)-related disorders, the effective treatment of sleep disorders has become a critical health research topic. Thus, we hypothesized and investigated the effectiveness of a 3-week melatonin intervention on neuropsychiatric behavioral responses mediated throughout melatonin receptors, gut microbiota, and lipid metabolites in rats with chronic SD. Eighteen 6-week-old Wistar rats were used and divided into the control grup (C, n = 6), SD group (n = 6), and melatonin-supplemented group (SDM, n = 6). During weeks 0 to 6, animals were provided with the AIN-93M diet and free access to water. Four-week chronic SD was conducted from weeks 7 to 10. Exogenous melatonin administration (10 mg/kg BW) was injected intraperitoneally 1 h before the daily administration of SD for 3 weeks in the SDM group. SD rats exhibited anxiety-like behavior, depression-like behavior, and cognitive impairment. Exogenous melatonin administration ameliorated neuropsychiatric behaviors induced by chronic SD. Analysis of fecal metabolites indicated that melatonin may influence brain messaging through the microbiota–gut–brain axis by increasing the production of short-chain fatty acids (SCFA) and decreasing the production of secondary bile acids (SBA). Four-week SD reduced the cerebral cortex expression of MT1, but not in the colon. Chronic SD led to anxiety and depression-like behaviors and cognitive decline, as well as the reduced intestinal level of SCFAs and the enhanced intestinal level of SBAs in rats. In this work, we confirmed our hypothesis that a 3-week melatonin intervention on neuropsychiatric behavioral response mediated throughout melatonin receptors, gut microbiota, and lipid metabolites in rats with chronic SD.
The Future of HER2-Targeted Treatment for Osteosarcoma: Lessons from the Negative Trastuzumab Deruxtecan Results
Authors: Nakano Kenji
Published: November 2023

Human epidermal growth factor receptor 2 (HER2), coded by the proto-oncogene ERBB, is known to be mutated or amplified in various malignant diseases, and many HER2-targeted therapies (including monoclonal antibodies and low-molecular-weight tyrosine kinase inhibitors) have been investigated. HER2 overexpression is observed in ~30% of patients with osteosarcoma, and HER2-targeted therapy for osteosarcoma has also been investigated, along with the prognostic and/or predictive value of HER2. An effective HER2-targeted therapy for osteosarcoma has not been established, however. An antibody–drug conjugate (ADC), i.e., trastuzumab deruxtecan (T-DXd), has been approved for the treatment of HER2-positive malignant diseases such as breast cancer and gastric cancer. T-DXd showed promising efficacy in a tumor-agnostic clinical trial, but even T-DXd did not demonstrate sufficient efficacy against HER2-positive osteosarcoma. In this review, the underlying reasons/mechanisms for the failure of HER2-targeted treatments for osteosarcoma (including T-DXd) are discussed, and the potential and future direction of HER2-targeted therapy is described.
Quantitative Proteomics of Maternal Blood Plasma in Isolated Intrauterine Growth Restriction
Authors: Starodubtseva Natalia L. , Tokareva Alisa O. , Volochaeva Maria V. , Kononikhin Alexey S. , Brzhozovskiy Alexander G. , Bugrova Anna E. , Timofeeva Angelika V. , Kukaev Evgenii N. , Tyutyunnik Victor L. , Kan Natalia E. , Frankevich Vladimir E. , Nikolaev Evgeny N. , Sukhikh Gennady T.
Published: November 2023

Intrauterine growth restriction (IUGR) remains a significant concern in modern obstetrics, linked to high neonatal health problems and even death, as well as childhood disability, affecting adult quality of life. The role of maternal and fetus adaptation during adverse pregnancy is still not completely understood. This study aimed to investigate the disturbance in biological processes associated with isolated IUGR via blood plasma proteomics. The levels of 125 maternal plasma proteins were quantified by liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM MS) with corresponding stable isotope-labeled peptide standards (SIS). Thirteen potential markers of IUGR (Gelsolin, Alpha-2-macroglobulin, Apolipoprotein A-IV, Apolipoprotein B-100, Apolipoprotein(a), Adiponectin, Complement C5, Apolipoprotein D, Alpha-1B-glycoprotein, Serum albumin, Fibronectin, Glutathione peroxidase 3, Lipopolysaccharide-binding protein) were found to be inter-connected in a protein–protein network. These proteins are involved in plasma lipoprotein assembly, remodeling, and clearance; lipid metabolism, especially cholesterol and phospholipids; hemostasis, including platelet degranulation; and immune system regulation. Additionally, 18 proteins were specific to a particular type of IUGR (early or late). Distinct patterns in the coagulation and fibrinolysis systems were observed between isolated early- and late-onset IUGR. Our findings highlight the complex interplay of immune and coagulation factors in IUGR and the differences between early- and late-onset IUGR and other placenta-related conditions like PE. Understanding these mechanisms is crucial for developing targeted interventions and improving outcomes for pregnancies affected by IUGR.
Positive Influence of Oxalate and Cyanate on the Supercapacitance Performance of V/Co 2D-Nanolayered Structures
Authors: Saber Osama , Ansari Sajid Ali , Parveen Nazish , Shaalan Nagih M. , Osama Aya , Osama Mostafa
Published: November 2023

Two-dimensional (2D) nanolayered and nanohybrid structures, which are composed of different species of organic anions and multi-valence inorganic cations, are considered favorable in the field of energy storage for use as supercapacitors. In this study, host–guest interactions were used to build a series of these nanohybrids. The host was the layered double hydroxides of vanadium–cobalt (V/Co) nanolayers with different molar ratios. Cyanate was used as a guest to design a V/Co supercapacitor with a 2D-nanolayered structure. In addition, oxalate was used as a new additive to improve the performance of the V/Co supercapacitor. X-ray diffraction, infrared spectroscopy, thermal analyses, and scanning electron microscopy confirmed the formation of the nanolayered structures of cyanate-V/Co. In the case of the oxalate-V/Co nanostructures, a new phase of cobalt oxalate was produced and combined with the nanolayered structure to build a 3D porous structure. A three-assembly electrode system was used to study the electrochemical supercapacitive behavior of the cyanate-V/Co and oxalate-V/Co nanolayered structures. The results indicated that the OXVC-20 electrode possessed the highest specific capacitance as compared to that of the OXVC-16 and CNOVC electrodes. An excellent stability performance of up to 91% after various charge–discharge cycles was detected for the optimum case. Because of the positive effect of oxalate on the supercapacitance performance of the V/Co supercapacitor, it is suggested as a new track for building active electrodes for high-performance supercapacitor applications.
Synthesis, Structural, and Quantum Chemical Analysis of Neutral and Cationic Ruthenium(II) Complexes with Nicotinate-Polyethylene Glycol Ester Ligands
Authors: Dimić Dušan , Eichhorn Thomas , Milenković Dejan , Kaluđerović Goran N.
Published: November 2023

Ruthenium(II/III)-based compounds have gained significant interest due to the biocompatibility of ruthenium, its similarity to iron, and the possibility for structural diversification through the choice of ligands. In this contribution, two novel ligands, (2-(2-methoxyethoxy)ethyl nicotinate hydrochloride) and (2-[2-(2-methoxyethoxy)ethoxy]ethyl nicotinate hydrochloride) (pyCOO(CH2CH2O)nCH3: L2, n = 2; L3, n = 3), were synthesized and characterized via ESI-HRMS, as well as IR and NMR spectroscopies. Their structures were optimized at the B3LYP/6-311++G(d,p) level of theory, and NMR chemical shifts were predicted, along with the most important intramolecular interactions. Additionally, two neutral complexes of the general formula [RuCl2(η6-p-cym) (L-κN)] (L = L2: 2; L3: 3) and two cationic complexes of the general formula [RuCl(η6-p-cym)(L-κN)2][PF6] (L = L1: 4; L2: 5) were obtained and characterized. The optimization of the structures was performed at the B3LYP/6-31+G(d,p)(H,C,N,O,Cl)/LanL2DZ(Ru) level of theory. Structural features were described, and intramolecular stabilization interactions were outlined.
Diagnostic Evaluation of Pulmonary Hypertension: A Comprehensive Approach for Primary Care Physicians
Authors: Anand Suneesh , Sadek Ahmed , Vaidya Anjali , Oliveros Estefania
Published: November 2023

Pulmonary hypertension (PH) is a disorder involving a heterogeneous group of medical conditions encompassing several cardiopulmonary illnesses. Implementing new diagnostic criteria for PH in conjunction with multimodality diagnostic tools is crucial for accurate and early recognition of this life-threatening form of right heart failure. This should streamline early referrals to accredited PH centers, with a goal to rapidly institute targeted therapy in order to optimize prognosis.
Prospective Clinical Evaluation of the Singularity™ Air Laryngeal Mask in Adult Patients
Authors: Martins Joana , Beutel Bernhard , Ettlin Nadja , Nickel Norbert , Wüthrich Roman , Sandoz Roman , Borisov Angel , Welter JoEllen , Dullenkopf Alexander
Published: November 2023

A laryngeal mask is one of the most widely used airway management devices. The SingularityTM Air is a second-generation laryngeal mask whose shaft angle can be adjusted after insertion. Since the device’s performance has been assessed on mannequins only, this study aimed to evaluate SingularityTM Air’s effectiveness in the clinical setting. The prospective single-center cohort study included 100 adults undergoing elective surgery under general anesthesia and suitable for airway securing with a laryngeal mask. The primary endpoint was the oropharyngeal leak pressure, and the secondary endpoints were the ease of insertion and the patient’s comfort. Laryngeal mask insertion was successful in 97%, and mechanical ventilation was possible in 96% of patients. After insertion, the median (IQR) oropharyngeal leak pressure was 25 (18–25) cm H2O, which remained stable at 25 (25–25) cm H2O after 20 min. The median (IQR) time for successful manual bag ventilation was 42 (34–50) seconds. Nineteen patients complained of side effects (e.g., sore throat, difficulty swallowing), but none persisted. The SingularityTM Air performed well in a clinical setting, and its oropharyngeal leak pressure was comparable to that of other masks reported in the literature. The time for successful manual ventilation was slightly longer, and patients reported more temporary side effects.
Using Multi-Modal Electronic Health Record Data for the Development and Validation of Risk Prediction Models for Long COVID Using the Super Learner Algorithm
Authors: Jin Weijia , Hao Wei , Shi Xu , Fritsche Lars G. , Salvatore Maxwell , Admon Andrew J. , Friese Christopher R. , Mukherjee Bhramar
Published: November 2023

Background: Post-Acute Sequelae of COVID-19 (PASC) have emerged as a global public health and healthcare challenge. This study aimed to uncover predictive factors for PASC from multi-modal data to develop a predictive model for PASC diagnoses. Methods: We analyzed electronic health records from 92,301 COVID-19 patients, covering medical phenotypes, medications, and lab results. We used a Super Learner-based prediction approach to identify predictive factors. We integrated the model outputs into individual and composite risk scores and evaluated their predictive performance. Results: Our analysis identified several factors predictive of diagnoses of PASC, including being overweight/obese and the use of HMG CoA reductase inhibitors prior to COVID-19 infection, and respiratory system symptoms during COVID-19 infection. We developed a composite risk score with a moderate discriminatory ability for PASC (covariate-adjusted AUC (95% confidence interval): 0.66 (0.63, 0.69)) by combining the risk scores based on phenotype and medication records. The combined risk score could identify 10% of individuals with a 2.2-fold increased risk for PASC. Conclusions: We identified several factors predictive of diagnoses of PASC and integrated the information into a composite risk score for PASC prediction, which could contribute to the identification of individuals at higher risk for PASC and inform preventive efforts.
Clinical Characteristics of Individuals with Interstitial Lung Diseases and Indication of End-of-Life Care
Authors: Krinski Gabriela , Bertin Larissa Dragonetti , Pimpão Heloise Angélico , Silva Humberto , Tavares Brunna Luiza , Lunardelli Leonardo , Alves do Prado Geovana , Pitta Fabio , Camillo Carlos Augusto
Published: November 2023

End-of-life care (EOLC) is palliative support provided in the last 6 months to 1 year of a patient’s life. Although there are established criteria for its indication, few studies describe the clinical and functional characteristics of individuals with interstitial lung diseases (ILD) in EOLC. ILD individuals underwent various assessments, including lung function, exercise capacity (6 min walk test), physical activity in daily life (PADL), peripheral muscle strength, maximal respiratory pressures, body composition, quality of life (SGRQ-I), symptoms of anxiety and depression, dyspnea (MRC scale), and sleep quality. Fifty-eight individuals were included and divided into two groups according to the indication for commencing EOLC (ILD with an indication of EOLC (ILD-EOLC) or ILD without an indication of EOLC (ILD-nEOLC). There were differences between the groups, respectively, for steps/day (2328 [1134–3130] vs. 5188 [3863–6514] n/day, p = 0.001), time spent/day carrying out moderate-to-vigorous physical activities (1 [0.4–1] vs. 10 [3–19] min/day, p = 0.0003), time spent/day in standing (3.8 [3.2–4.5] vs. 4.8 [4.1–6.7] h/day, p = 0.005), and lying positions (5.7 [5.3–6.9] vs. 4.2 [3.6–5.1] h/day, p = 0.0004), the sit-to-stand test (20 ± 4 vs. 26 ± 7 reps, p = 0.01), 4 m gait speed (0.92 ± 0.21 vs. 1.05 ± 0.15 m/s, p = 0.02), quadriceps muscle strength (237 [211–303] vs. 319 [261–446] N, p = 0.005), SGRQ-I (71 ± 15 vs. 50 ± 20 pts, p = 0.0009), and MRC (4 [3–5] vs. 2 [2–3] pts, p = 0.001). ILD individuals with criteria for commencing EOLC exhibit reduced PADL, functional performance, peripheral muscle strength, quality of life, and increased dyspnea.
Antibody–Drug Conjugates in HR+ Breast Cancer: Where Are We Now and Where Are We Heading?
Authors: De Santis Pierluigi , Sanna Valeria , Perrone Martina , Guarini Chiara , Santoro Anna Natalizia , Laface Carmelo , Carrozzo Daniela , Oliva Gaia Rachele , Fancellu Alessandro , Fedele Palma
Published: November 2023

Hormone receptor-positive (HR+) breast cancer (BC) accounts for about 60–70% of all diagnosed BCs, and endocrine therapy has long been the hallmark of systemic treatment for this tumor subtype. However, the therapeutic paradigm of luminal BC has been overcome due to recent evidence of antibody–drug conjugate (ADC) activity (such as trastuzumab deruxtecan and sacituzumab govitecan) in pretreated metastatic HR+ BC patients. Therefore, nowadays, the identification of patients who can benefit more from this approach represents a new challenge, as does the management of new toxicities and the integration of these drugs into the therapeutic algorithm of HR+ metastatic BC patients.