bluuebunny/crossref_metadata_2025 huggingface dataset:
Retrospective quantification of clinical abdominal DCE-MRI using pharmacokinetics-informed deep learning: a proof-of-concept study
Authors: Wu Chaowei , Wang Nan , Gaddam Srinivas , Wang Lixia , Han Hui , Sung Kyunghyun , Christodoulou Anthony G. , Xie Yibin , Pandol Stephen , Li Debiao
Published: September 2023

Introduction

Dynamic contrast-enhanced (DCE) MRI has important clinical value for early detection, accurate staging, and therapeutic monitoring of cancers. However, conventional multi-phasic abdominal DCE-MRI has limited temporal resolution and provides qualitative or semi-quantitative assessments of tissue vascularity. In this study, the feasibility of retrospectively quantifying multi-phasic abdominal DCE-MRI by using pharmacokinetics-informed deep learning to improve temporal resolution was investigated.

Method

Forty-five subjects consisting of healthy controls, pancreatic ductal adenocarcinoma (PDAC), and chronic pancreatitis (CP) were imaged with a 2-s temporal-resolution quantitative DCE sequence, from which 30-s temporal-resolution multi-phasic DCE-MRI was synthesized based on clinical protocol. A pharmacokinetics-informed neural network was trained to improve the temporal resolution of the multi-phasic DCE before the quantification of pharmacokinetic parameters. Through ten-fold cross-validation, the agreement between pharmacokinetic parameters estimated from synthesized multi-phasic DCE after deep learning inference was assessed against reference parameters from the corresponding quantitative DCE-MRI images. The ability of the deep learning estimated parameters to differentiate abnormal from normal tissues was assessed as well.

Results

The pharmacokinetic parameters estimated after deep learning have a high level of agreement with the reference values. In the cross-validation, all three pharmacokinetic parameters (transfer constant Ktrans, fractional extravascular extracellular volume ve, and rate constant kep) achieved intraclass correlation coefficient and R2 between 0.84–0.94, and low coefficients of variation (10.1%, 12.3%, and 5.6%, respectively) relative to the reference values. Significant differences were found between healthy pancreas, PDAC tumor and non-tumor, and CP pancreas.

Discussion

Retrospective quantification (RoQ) of clinical multi-phasic DCE-MRI is possible by deep learning. This technique has the potential to derive quantitative pharmacokinetic parameters from clinical multi-phasic DCE data for a more objective and precise assessment of cancer.
Sex differences in spatial tasks: Considering environmental factors, navigation strategies, and age
Authors: Dahmani Louisa , Idriss Miryam , Konishi Kyoko , West Greg L. , Bohbot Veronique D.
Published: September 2023

Sex differences in navigation have been a topic of investigation for decades and has been subjected to various contradictory findings and debates. The aim of this work was to compare the spatial memory of men and women tested in various different types of spatial tasks, while controlling for navigation strategies and aging. It is generally thought that men outperform women in navigation and that women have higher scores on object location tasks. However, many studies fail to control for different factors that may bias one sex or the other. We aggregated the data of 465 participants (349 young adults, 127 older adults) who took part in various studies conducted in our laboratory, which include both published and original unpublished data, in order to investigate sex differences. In these studies, we used a number of different paradigms: virtual radial arm mazes, a virtual wayfinding task, an object location task, a virtual Morris Water Maze, and the invisible sensor task which is a real-life model of the Morris Water Maze. While our results may seem discordant at first glance, they demonstrate that several factors can impact the performance of men and women on spatial tasks, including spontaneous navigation strategies, environmental characteristics, and age. We replicated findings showing that women favor proximal landmarks compared to men who favor distal landmarks, women have better memory than men for the position of objects in the absence of reference frames, but they will have poorer scores when navigation requires specific angles, distances and polar coordinates. Moreover, we found that in aging, women who avoid the use of landmarks when navigating a radial maze show stronger reliance on these non-spatial strategies than men. On the other hand, women who rely on landmarks, do so to the same extent as men. Our findings highlight the need to carefully take into consideration these factors in order to produce a more harmonious understanding of sex differences in navigation. Finally, the interaction between spontaneous navigation strategies, sex, and age is discussed in terms of its implications for risk of Alzheimer’s disease.
Pharmacokinetic/pharmacodynamic integration of tilmicosin against Pasteurella multocida in a piglet tissue cage model
Authors: Chen Yuqin , Ji Xuan , Zhang Suiling , Wang Wenxiang , Zhang Huilin , Ding Huanzhong
Published: September 2023

Tilmicosin is a semi-synthetic macrolide for veterinary use with strong antibacterial effect on respiratory bacteria. In this study, the pharmacokinetic/pharmacodynamic (PK/PD) integration of tilmicosin againstPasteurella multocida(P. multocida) was evaluated by establishing a piglet tissue cage infection model. Concentration of tilmicosin and bacterial numbers ofP. multocidain the tissue-cage fluid were monitered. After the population ofP. multocidawas equal to or greater than 107 CFU/mL in a tissue cage, piglets received an oral administration of tilmicosin at a dose of 30, 40, 50, and 60 mg/kg b.w., once daily for 3 days, respectively. Bacteria were counted every 24 h after drug administration and at 48 and 72 h after the last administration. A sigmoidal Emaxmodel was used to fit the relationship between PK/PD parameters and the antibacterial effect. AUC24h/MIC was the best PK/PD index that correlated with effectiveness of tilmicosin againstP. multocida. The magnitude of AUC24h/MIC required for continuous 1/3-log, 1/2-log, and 3/4-log reductions were 19.65 h, 23.86 h, and 35.77 h, respectively, during each 24 h treatment period. In this study, when the dosage was >50 mg/kg, the AUC24h/MIC was still >35.77 h in the period of 24–48 h after the last administration due to the slow elimination, that is, tilmicosin exhibited a potent antibacterial effect againstP. multocidaafter three successive daily administrations. The data provide meaningful guidance to optimize regimens of tilmicosin to treat respiratory tract infections caused byP. multocida.
Improved Quality of Life Among Chronic Pancreatitis Patients Undergoing Total Pancreatectomy With Islet Autotransplantation—Single Center Experience With Large Cohort of Patients
Authors: Coluzzi Mariagrazia , Takita Morihito , Saracino Giovanna , Rub Hakim Mohammed Abdul , Darden Carly M. , Testa Giuliano , Beecherl Ernest , Onaca Nicholas , Naziruddin Bashoo
Published: September 2023

Total pancreatectomy with islet autotransplantation (TPIAT) is the treatment of choice to preserve pancreatic endocrine function, alleviate pain, and improve quality of life (QoL) when other strategies are ineffective for chronic pancreatitis (CP) patients. This study utilized pancreatic disease-specific surveys developed by the European Organisation for Research and Treatment of Cancer (EORTC) to conduct a comprehensive, single-center examination of a large cohort of patients to gain understanding of QoL post-TPIAT. Two validated QoL surveys of the EORTC—QLQ-C30 and QLQ-PAN26—were administered in a prospective cohort of CP patients during pre-and post-operative scheduled visits. A total of 116 patients responded to the preoperative survey and were included in this study. The global health scale of QLQ-C30 was significantly improved after TPIAT when compared to baseline with delta scores of 24.26, 20.54, and 26.7 at 1, 2, and 3 years post-TPIAT (p< 0.001). The EORTC-PAN26 revealed significant improvements in symptom scales for pancreatic pain, bloating, digestive symptoms, taste, indigestion, weight loss, body image, and future worries. The comprehensive surveys in such a large cohort expands the QoL criterion in CP patients and indicates significant improvement in QoL post-TPIAT, further validating TPIAT as a treatment option for refractory CP.
Vigilance Data in Organ Donation and Solid Organ Transplantation in Germany: Six Years of Experience 2016–2022
Authors: Böhler Klaus , Rahmel Axel , Barreiros Ana Paula
Published: September 2023

The reporting of serious adverse events (SAE) and serious adverse reactions (SAR) is an essential part of an effective vigilance and surveillance system (V&S) in organ donation and transplantation. All SAE and SAR reported to the German organ procurement organization (DSO) between 2016 and 2022 were analyzed. In case of a possible transmission of a disease to one or more recipients, an assessment of imputability was done according to the grading system of the US Disease Transmission Advisory Committee (DTAC). 543 SAE and SAR cases were reported to the DSO and analyzed in detail. 53 of the 543 reports (9.8%) were proven or probable (P/P) transmissions of infectious diseases, malignancies or other diseases to 75 recipients. Infections were the most frequently reported P/P disease transmission occurrences (30/53, 57%). In case of disease transmission, the mortality of the recipients was high (17/75, 23%), especially when a malignant disease was transmitted (11/22, 50 %). Donor-Derived disease transmission is a rare event (53/8,519; 0.6 %), but when it occurs can lead to significant morbidity and mortality.
Banff Human Organ Transplant Consensus Gene Panel for the Detection of Antibody Mediated Rejection in Heart Allograft Biopsies
Authors: Giarraputo Alessia , Coutance Guillaume , Aubert Olivier , Fedrigo Marny , Mezine Fariza , Zielinski Dina , Mengel Michael , Bruneval Patrick , Duong van Huyen Jean-Paul , Angelini Annalisa , Loupy Alexandre
Published: September 2023

The molecular refinement of the diagnosis of heart allograft rejection based on whole-transcriptome analyses faces several hurdles that greatly limit its widespread clinical application. The targeted Banff Human Organ Transplant gene panel (B-HOT, including 770 genes of interest) has been developed to facilitate reproducible and cost-effective gene expression analysis of solid organ allografts. We aimed to determine in silico the ability of this targeted panel to capture the antibody-mediated rejection (AMR) molecular profile using whole-transcriptome data from 137 heart allograft biopsies (71 biopsies reflecting the entire landscape of histologic AMR, 66 non-AMR control biopsies including cellular rejection and non-rejection cases). Differential gene expression, pathway and network analyses demonstrated that the B-HOT panel captured biologically and clinically relevant genes (IFNG-inducible, NK-cells, injury, monocytes-macrophage, B-cell-related genes), pathways (interleukin and interferon signaling, neutrophil degranulation, immunoregulatory interactions, endothelial activation) and networks reflecting the pathophysiological mechanisms underlying the AMR process previously identified in whole-transcriptome analysis. Our findings support the potential clinical use of the B-HOT-gene panel as a reliable proxy to whole-transcriptome analysis for the gene expression profiling of cardiac allograft rejection.
Export Competence of Cultural Goods: A Structural Gravity Analysis of the BRICS Trade
Authors: Masood Amjad , Hashmi Shujahat Haider , Nazir Muhammad Imran , Khan Basharat
Published: September 2023

The BRICS economies contribute a substantial portion of global trade. However, the share of cultural export in their total exports has been declining over the past two decades. In this context, the current study examines cultural exports of BRICS compared to their aggregate exports using structural gravity model. For empirical estimation, we apply Poisson Pseudo-Maximum Likelihood High Dimensional Fixed Effects (PPMLHDFE) estimator for annual bilateral exports data. The results show that, as compared to non-cultural aggregate exports, exports of creative industries are more sensitive to geographical distance between countries. Nevertheless, positive effect of the similarity between trading partners in terms of language commonality, colonial relationship and shared border is more pronounced in case of cultural exports. Furthermore, we find that while the regional trade agreements promote exports in general, they remain inconsequential in case of cultural exports of BRICS. Additionally, the study uses cultural exports as a proxy for cultural proximity and finds that bilateral cultural exports facilitate the exports of non-cultural exports.
Optimal Integration of Flexible Alternating Current Transmission Systems in Electrical Distribution Grids Using a Mixed-Integer Convex Model
Authors: Gil-González Walter , Montoya Oscar Danilo , Trujillo-Rodríguez César Leonardo
Published: September 2023

This research addresses the efficient integration and sizing of flexible alternating current transmission systems (FACTS) in electrical distribution networks via a convex optimization approach. The exact mixed-integer nonlinear programming (MINLP) model associated with FACTS siting and sizing aims for the minimization of the expected annual operating costs of the network (i.e., energy losses and FACTS purchasing costs). The constraints of this problem include power equilibrium equalities, voltage regulation bounds, and device capacities, among others. Due to the power equilibrium constraints per node and period, the MINLP model is a non-convex optimization problem. To transform the exact MINLP model into a mixed-integer convex one, the approximation of the product between two variables in the complex domain is relaxed through its hyperbolic equivalent, which generates a set of convex cones. The main advantage of the proposed mixed-integer convex model is that it ensures the global optimum of the problem, even when considering objective multiplexes. Numerical simulations in the IEEE 33-, 69-, and 85-bus grids demonstrate the effectiveness and robustness of FACTS integration via the proposed convex approach in comparison with the exact solution of the MINLP model in the GAMS software as well as with combinatorial optimization algorithms (i.e., the black widow optimizer and the vortex search algorithm). All simulations were carried out in MATLAB with Yalmip optimization and the Gurobi and Mosek solvers. The simulation results show that, for a fixed operation of the FACTS devices (i.e., a VAR compensator) during the day, the annual operating costs are reduced by 12.63%, 13.97%, and 26.53% for the IEEE 33-, 69-, and 85-bus test systems, respectively, while for the operation variable, the reductions are by 14.24%, 15.79%, and 30.31%, respectively.
Special Issue “Neural Network for Traffic Forecasting”
Authors: Jiang Weiwei
Published: September 2023

Traffic forecasting is an important research topic in intelligent transportation systems and smart cities [...]
Elevating Univariate Time Series Forecasting: Innovative SVR-Empowered Nonlinear Autoregressive Neural Networks
Authors: Borrero Juan D. , Mariscal Jesus
Published: September 2023

Efforts across diverse domains like economics, energy, and agronomy have focused on developing predictive models for time series data. A spectrum of techniques, spanning from elementary linear models to intricate neural networks and machine learning algorithms, has been explored to achieve accurate forecasts. The hybrid ARIMA-SVR model has garnered attention due to its fusion of a foundational linear model with error correction capabilities. However, its use is limited to stationary time series data, posing a significant challenge. To overcome these limitations and drive progress, we propose the innovative NAR–SVR hybrid method. Unlike its predecessor, this approach breaks free from stationarity and linearity constraints, leading to improved model performance solely through historical data exploitation. This advancement significantly reduces the time and computational resources needed for precise predictions, a critical factor in univariate economic time series forecasting. We apply the NAR–SVR hybrid model in three scenarios: Spanish berry daily yield data from 2018 to 2021, daily COVID-19 cases in three countries during 2020, and the daily Bitcoin price time series from 2015 to 2020. Through extensive comparative analyses with other time series prediction models, our results substantiate that our novel approach consistently outperforms its counterparts. By transcending stationarity and linearity limitations, our hybrid methodology establishes a new paradigm for univariate time series forecasting, revolutionizing the field and enhancing predictive capabilities across various domains as highlighted in this study.
Reddit CrosspostNet—Studying Reddit Communities with Large-Scale Crosspost Graph Networks
Authors: Sawicki Jan , Ganzha Maria , Paprzycki Marcin , Watanobe Yutaka
Published: September 2023

As the largest open social medium on the Internet, Reddit is widely studied in the scientific literature. Due to its structured form and division into topical subfora (subreddits), conducted research often concerns connections and interactions between users and/or whole, subreddit-structure-based communities. Overall, the relations between communities are most often studied by applying graph networks, with various creation algorithms. In this work, a novel approach is proposed to build and understand the structure of Reddit. It is based on crossposts—posts that appeared on one subreddit and then were crossposted to another. After capturing one year of crossposts, a directed weighted graph network, using seven million posts from over 10,000 of the most popular subreddits, has been created. Using graph network algorithms, its characteristics are captured and compared to similar studies. We identify the information “sinks” and “sources”—the most active crossposting subreddits. Moreover, we obtained graph network metrics: the degree (modeled with the Power Law), clustering, community detection algorithms, and connected components structure network are compared to previous studies on Reddit network(s), yielding consistent, but also novel results. Finally, the relations between extensively studied subreddits (e.g., r/AITA, r/Parenting, r/politics) and new ones, which were not accounted for in previous research, opening new paths for data-driven studies, are summarized.
The Association between Adolescents’ Experiences of Close Relatives Having Severe Health Conditions and Their Own Mental Health—A Population-Based School Study
Authors: Tiikkaja Sanna , Tindberg Ylva
Published: September 2023

Adolescents with close relatives having severe health conditions or who have died (RSHC) are vulnerable, and this has long-term influences on their lives and health. This study investigated how adolescents with RSHC experiences reported having poor mental health and protective factors and the combined influence of these compared to their peers who had not had these experiences. A cross-sectional school-based survey among students aged 15–18 years (N = 3410) in Sörmland, Sweden, was used to analyse the association between poor mental health and experiences from having one or several RSHC experiences with physical illness, mental illness, or substance abuse/gambling disorder, as well as having relatives who have died. Logistic regression models were performed, adjusting for background factors, and protective factors against poor mental health related to school, home relations, safety in everyday life, and lifestyle were assessed. Adolescents with one RSHC experience had an OR of 1.45 (95% CI: 1.23–1.72) for poor mental health, and those with several RSHC experiences had an OR of 2.35 (95% CI: 1.94–2.84) compared to those with no RSHC experiences. The greatest OR for poor mental health was seen among adolescents with the combination of several RSHC experiences and few protective factors against poor mental health (18.83; 95% CI: 11.86–29.91). Adolescents with RSHC experiences have increased odds of poor mental health compared to adolescents without these experiences, especially those with several RSHC experiences and few protective factors. When meeting adolescents with RSHC experiences, supporting their key protective factors may play an important role in improving mental health.
Risk Assessment Method for UAV’s Sense and Avoid System Based on Multi-Parameter Quantification and Monte Carlo Simulation
Authors: Fitrikananda Bona P. , Jenie Yazdi Ibrahim , Sasongko Rianto Adhy , Muhammad Hari
Published: September 2023

The rise in Unmanned Aerial Vehicle (UAV) usage has opened exciting possibilities but has also introduced risks, particularly in aviation, with instances of UAVs flying dangerously close to commercial airplanes. The potential for accidents underscores the urgent need for effective measures to mitigate mid-air collision risks. This research aims to assess the effectiveness of the Sense and Avoid (SAA) system during operation by providing a rating system to quantify its parameters and operational risk, ultimately enabling authorities, developers, and operators to make informed decisions to reach a certain level of safety. Seven parameters are quantified in this research: the SAA’s detection range, field of view, sensor accuracy, measurement rate, system integration, and the intruder’s range and closing speed. While prior studies have addressed these parameter quantifications separately, this research’s main contribution is the comprehensive method that integrates them all within a simple five-level risk rating system. This quantification is complemented by a risk assessment simulator capable of testing a UAV’s risk rating within a large sample of arbitrary flight traffic in a Monte Carlo simulation setup, which ultimately derives its maximum risk rating. The simulation results demonstrated safety improvements using the SAA system, shown by the combined maximum risk rating value. Among the contributing factors, the detection range and sensor accuracy of the SAA system stand out as the primary drivers of this improvement. This conclusion is consistent even in more regulated air traffic imposed with five or three mandatory routes. Interestingly, increasing the number of intruders to 50 does not alter the results, as the intruders’ probability of being detected remains almost the same. On the other hand, improving SAA radar capability has a more significant effect on risk rating than enforcing regulations or limiting intruders.
The Impact of Cultivation Systems on Weed Suppression and the Canopy Architecture of Spring Barley
Authors: Wacławowicz Roman , Giemza Magdalena , Pytlarz Elżbieta , Wenda-Piesik Anna
Published: September 2023

Under the pro-environmental principles of agricultural production, soil cultivation and organic fertilization are of particular importance as strategical elements in reducing weed infestation in the context of sustainable agriculture. The aim of this study was to determine the effect of long-term practices that are used in regenerative agriculture (reducing soil tillage, cover crop management, and mineral nitrogen fertilization) on canopy weed infestation and the elements of spring barley architecture. Understanding the impact of the studied factors influences decision-making regarding weed infestation control, and thus may contribute to a reduction in herbicide use. A two-factor field experiment was conducted using the split-plot method. The main factors were four cultivation methods: 1. conventional tillage without a cover crop, 2. conventional tillage + cover crop, 3. reduced tillage + cover crop, and 4. no tillage + cover crop. The subplot factor was differentiated via nitrogen fertilization, at 40, 80, or 120 kg N∙ha−1. The research covered canopy weed infestation and the parameters of spring barley canopy architecture. The species composition; the number and weight of weeds; and, for barley, the leaf area index (LAI), density, length, and tillers were determined. The test results were statistically analyzed (ANOVA) in a series of experiments while using Tukey’s test for a significance level of p = 0.05. Additionally, simple linear regression analysis, principal component analysis (PCA), and data clustering (CA) were utilized. The study showed that simplified tillage contributed to reducing the number of weeds in the barley tillering stage, while also contributing to an increase in weed infestation during grain harvest. Plowing in the cover crop did not reduce the presence of undesirable plants in the canopy, while increasing doses of nitrogen fertilization contributed to a reduction in the number of weeds without affecting their mass. Weed infestation was also affected by meteorological conditions. Increased rainfall in the early stages of barley development benefits the number of weeds, especially in terms of traditional cultivation. Simplified tillage resulted in a reduction in barley density, height, and LAI, as well as an increase in the branching of the tested cereal. A significant negative correlation was also found between the weed infestation of the barley canopy and the characteristics of the canopy architecture. The PCA showed that the highest tillering of barley was provided at the lowest intensity of weed infestation. In turn, the CA indicated that the significantly higher LAI that resulted from a higher density and length of barley was attributed to the simplified cultivation treatments and the practice of direct sowing. It is a comprehensive method that can favor barley growth and development conditions while weakening weed infestation potential.
Distribution Characteristics and Factors Influencing Culturable Bacterial Bioaerosols on a Dairy Farm in Northern China
Authors: Ru Lin , Ding Luyu , Deng Shuhui , Li Qifeng , Zhao Wanying , Wang Rong , Li Jiawei , Lu Yujian , Yao Chunxia
Published: September 2023

Studying the distribution characteristics of bioaerosols and their interaction with the environment is crucial for dairy farms. The distribution of aerosols differs in dairy farming from farming of other livestock, and their sensitivity to environmental factors varies across sites. Field experiments were conducted in an intensive commercial dairy farm in Northern China to investigate the horizontal and vertical distribution of culturable bacterial bioaerosols. Concentration levels and particle size ranges were analyzed, and the impact of multiple environmental factors on culturable bacterial bioaerosols was assessed. Significant variations in culturable bacterial bioaerosol concentrations were observed across eight functional zones, ranging from 1.14 × 103 to 7.35 × 103 CFU/m3. Culturable bacterial bioaerosols exhibited consistent carrier distribution patterns across six different size ranges. Vertical analysis revealed significantly higher culturable bacterial bioaerosol concentrations at a 1 m height compared to 4 m (p < 0.05), while similar size distributions were observed at different heights of the same sampling location. The top three environmental factors influencing culturable bacterial bioaerosol concentrations were PM100 concentration, wind direction, and air temperature. This study provides insights into the distribution characteristics of culturable bacterial bioaerosols on dairy farms and their response to environmental factors. The findings serve as a reference for evaluating bioaerosol emissions and establishing daily disinfection management measures on dairy farms.
Alleviation of Stripe Rust Disease in Wheat Seedlings Using Three Different Species of Trichoderma spp.
Authors: Mourad Amira M. I. , Börner Andreas , Esmail Samar M.
Published: September 2023

Wheat stripe rust (WSR) caused by Puccinia striiformis F. tritici Erikss. (Pst) is one of the serious diseases that affect wheat planting areas around the world. Many efforts have been made to control such a serious disease including using fungicides and breeding highly resistant genotypes. However, due to Pst’s ability to produce new races that overcome these fungicides and break the resistance in the highly resistant genotypes, looking for other effective ways to restrict this disease is urgently required. One of the highly effective ways of controlling crop diseases is using biological control. In this study, the efficiency of three different Trichoderma species (Trichoderma asperellum T34, Trichoderma harzianum (TH), and Trichoderma verdinium (TV)) was tested in a set of 34 wheat genotypes at the seedling stage. The evaluation was conducted in two experiments with two different temperature regimes. In each experiment, four treatments were applied, namely, control, T34, TV, and TH. High genetic variation was found among all genotypes in each experiment and under each Trichoderma treatment. Notably, the symptoms of WSR were affected by temperature under all treatments except T34, which had a stable performance in the two experiments. The 34 studied genotypes were highly diverse, related to ten different countries, and consisted of durum and bread wheat. Out of the three studied Trichoderma species, T34 was able to improve WSR resistance in all the studied genotypes suggesting its effectiveness in inducing the resistance and producing a priming response in different wheat genetic backgrounds. The results of this study provided very useful information on the effectiveness of Trichoderma spp. in controlling WSR.
Peptide Stapling Applied to Antimicrobial Peptides
Authors: Lourenço Ana Laura Pereira , Rios Thuanny Borba , da Silva Állan Pires , Franco Octávio Luiz , Ramada Marcelo Henrique Soller
Published: September 2023

Antimicrobial peptides (AMPs) are considered a promising therapeutic approach against multi-drug resistant microorganisms. Besides their advantages, there are limitations to be overcome so that these molecules can become market competitive. One of the biggest limitations is proteolytic susceptibility, which could be overcome by structural modifications such as cyclization, especially for helix-constraining strategies. Over the years, many helix stabilization techniques have arisen, such as lactam-bridging, triazole-based, N-alkylation and all-hydrocarbon stapling. All-hydrocarbon stapling takes advantage of modified amino acid residues and olefinic cross-linking to constrain peptide helices. Despite being a well-established strategy and presenting efficient stability results, there are different limitations especially related to toxicity. In this review, recent studies on stapled AMPs for antimicrobial usage are explored with the aim of understanding the future of these molecules as putative antimicrobial agents.
A Systematic Review on the Clinical Pharmacokinetics of Cephalexin in Healthy and Diseased Populations
Authors: Kanan Mohammed , Atif Shahd , Mohammed Faisal , Balahmar Yara , Adawi Yasir , AlSaleem Revan , Farhan Ahmed , Alghoribi Manayer , Mohammed Saud , Alshanbari Raghad , Fahad Malak , Kallab Rana , Mohammed Reem , Alassaf Dimah , Hazza Ashwag
Published: September 2023

Cephalexin is a first-generation β-lactam antibiotic used in adults and pediatrics to treat various streptococcal and staphylococcal infections. This review aims to summarize and evaluate all the pharmacokinetic (PK) data on cephalexin by screening out all pertinent studies in human beings following the per oral (PO) route. By employing different online search engines such as Google Scholar, PubMed, Cochrane Central, and Science Direct, 23 studies were retrieved, among which nine were in healthy subjects, five in diseased ones, and the remaining were drug–drug, drug–food, and bioequivalence-related. These studies were included only based on the presence of plasma concentration-time profiles or PK parameters, i.e., maximum plasma concentration (Cmax), half-life (t1/2) area under the curve from time 0-infinity (AUC0–∞), and clearance (CL/F). A dose-proportional increase in AUC0–∞ and Cmax can be portrayed in different studies conducted in the healthy population. In comparison to cefaclor, Cmax was recorded to be 0.5 folds higher for cephalexin in the case of renal impairment. An increase in AUC0–∞ was seen in cephalexin on administration with probenecid, i.e., 117 µg.h/mL vs. 68.1 µg.h/mL. Moreover, drug–drug interactions with omeprazole, ranitidine, zinc sulfate, and drug–food interactions for cephalexin and other cephalosporins have also been depicted in different studies with significant changes in all PK parameters. This current review has reported all accessible studies containing PK variables in healthy and diseased populations (renal, dental, and osteoarticular infections, continuous ambulatory peritoneal dialysis) that may be favorable for health practitioners in optimizing doses among the latter.
Deploying a Novel Approach to Prepare Silver Nanoparticle Bellamya bengalensis Extract Conjugate Coating on Orthopedic Implant Biomaterial Discs to Prevent Potential Biofilm Formation
Authors: Qamer Shafqat , Che-Hamzah Fahrudin , Misni Norashiqin , Joseph Narcisse M. S. , Al-Haj Nagi A. , Amin-Nordin Syafinaz
Published: September 2023

This study is based on the premise of investigating antibacterial activity through a novel conjugate of silver nanoparticles (AgNPs) and antimicrobial peptides (AMPs) in line with a green synthesis approach by developing antimicrobial-coated implants to prevent bacterial resistance. The AMPs were obtained from Bellamya Bengalensis (BB), a freshwater snail, to prepare the nanocomposite conjugate, e.g., AgNPs@BB extract, by making use of UV-Visible spectroscopy. The antimicrobial assessment of AgNPs@BB extract conjugate was performed using the Resazurin Microtiter Assay Method (REMA), followed by the use of three biocompatible implant materials (titanium alloys, Ti 6AL-4V stainless steel 316L, and polyethylene). Finally, the coating was analyzed under confocal microscopy. The results revealed a significant reduction of biofilm formation on the surfaces of implants coated with conjugate (AgNPs@BB extract) in comparison to uncoated implants. For the MTT assay, no significant changes were recorded for the cells grown on the AgNPs/AMP++ sample in high concentrations. Staphylococcus epidermidis, however, showed more prominent growth on all implants in comparison to Staphylococcus aureus. It is evident from the results that Staphylococcus epidermidis is more susceptible to AgNPs@BB extract, while the minimum inhibitory concentration (MIC) value of AgNPs@BB extract conjugates and biosynthesized AgNPs was also on the higher side. This study indicates that AgNPs@BB extract carries antibacterial activity, and concludes that an excessive concentration of AgNPs@BB extract may affect the improved biocompatibility. This study recommends using robust, retentive, and antimicrobial coatings of AgNPs@BB extract for implantable biocompatible materials in accordance with the novel strategy of biomaterial applications.
Lyophilized Lipid Liquid Crystalline Nanoparticles as an Antimicrobial Delivery System
Authors: Awad Muhammed , Barnes Timothy J. , Prestidge Clive A.
Published: September 2023

Lipid liquid crystalline nanoparticles (LCNPs) are unique nanocarriers that efficiently deliver antimicrobials through biological barriers. Yet, their wide application as an antimicrobial delivery system is hindered by their poor stability in aqueous dispersions. The production of dried LCNP powder via lyophilization is a promising approach to promote the stability of LCNPs. However, the impact of the process on the functionality of the loaded hydrophobic cargoes has not been reported yet. Herein, we investigated the potential of lyophilization to produce dispersible dry LCNPs loaded with a hydrophobic antimicrobial compound, gallium protoporphyrin (GaPP). The effect of lyophilization on the physicochemical characteristics and the antimicrobial activity of rehydrated GaPP-LCNPs was studied. The rehydrated GaPP-LCNPs retained the liquid crystalline structure and were monodisperse (PDI: 0.27 ± 0.02), with no significant change in nanoparticle concentration despite the minor increase in hydrodynamic diameter (193 ± 6.5 compared to 173 ± 4.2 prior to freeze-drying). Most importantly, the efficacy of the loaded GaPP as an antimicrobial agent and a photosensitizer was not affected as similar MIC values were obtained against S. aureus (0.125 µg/mL), with a singlet oxygen quantum yield of 0.72. These findings indicate the suitability of lyophilization to produce a dry form of LCNPs and pave the way for future studies to promote the application of LCNPs as an antimicrobial delivery system.
BcWRKY22 Activates BcCAT2 to Enhance Catalase (CAT) Activity and Reduce Hydrogen Peroxide (H2O2) Accumulation, Promoting Thermotolerance in Non-Heading Chinese Cabbage (Brassica campestris ssp. chinensis)
Authors: Wang Haiyan , Gao Zhanyuan , Chen Xiaoshan , Li Entong , Li Ying , Zhang Changwei , Hou Xilin
Published: September 2023

WRKY transcription factors (TFs) participate in plant defense mechanisms against biological and abiotic stresses. However, their regulatory role in heat resistance is still unclear in non-heading Chinese cabbage. Here, we identified the WRKY-IIe gene BcWRKY22(BraC09g001080.1), which is activated under high temperatures and plays an active role in regulating thermal stability, through transcriptome analysis. We further discovered that the BcWRKY22 protein is located in the nucleus and demonstrates transactivation activity in both the yeast and plant. Additionally, our studies showed that the transient overexpression of BcWRKY22 in non-heading Chinese cabbage activates the expression of catalase 2 (BcCAT2), enhances CAT enzyme activity, and reduces Hydrogen Peroxide (H2O2) accumulation under heat stress conditions. In addition, compared to its wild-type (WT) counterparts, Arabidopsis thaliana heterologously overexpresses BcWRKY22, improving thermotolerance. When the BcWRKY22 transgenic root was obtained, under heat stress, the accumulation of H2O2 was reduced, while the expression of catalase 2 (BcCAT2) was upregulated, thereby enhancing CAT enzyme activity. Further analysis revealed that BcWRKY22 directly activates the expression of BcCAT2 (BraC08g016240.1) by binding to the W-box element distributed within the promoter region of BcCAT2. Collectively, our findings suggest that BcWRKY22 may serve as a novel regulator of the heat stress response in non-heading Chinese cabbage, actively contributing to the establishment of thermal tolerance by upregulating catalase (CAT) activity and downregulating H2O2 accumulation via BcCAT2 expression.
Selenium-Fortified Kombucha–Pollen Beverage by In Situ Biosynthesized Selenium Nanoparticles with High Biocompatibility and Antioxidant Activity
Authors: Tritean Naomi , Dima Ștefan-Ovidiu , Trică Bogdan , Stoica Rusăndica , Ghiurea Marius , Moraru Ionuț , Cimpean Anisoara , Oancea Florin , Constantinescu-Aruxandei Diana
Published: September 2023

Biogenic selenium nanoparticles (SeNPs) have been shown to exhibit increased bioavailability. Fermentation of pollen by a symbiotic culture of bacteria and yeasts (SCOBY/Kombucha) leads to the release of pollen content and enhances the prebiotic and probiotic effects of Kombucha. The aim of this study was to fortify Kombucha beverage with SeNPs formed in situ by Kombucha fermentation with pollen. Response Surface Methodology (RSM) was used to optimize the biosynthesis of SeNPs and the pollen-fermented Kombucha beverage. SeNPs were characterized by Transmission electron microscopy energy-dispersive X-ray spectroscopy (TEM-EDX), Fourier-transform infrared spectroscopy (FTIR), Dynamic light scattering (DLS), and Zeta potential. The pollen-fermented Kombucha beverage enriched with SeNPs was characterized by measuring the total phenolic content, antioxidant activity, soluble silicon, saccharides, lactic acid, and the total content of Se0. The polyphenols were identified by liquid chromatography–mass spectrometry (LC-MS). The pollen and the bacterial (nano)cellulose were characterized by scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDX), FTIR, and X-Ray diffraction (XRD). We also assessed the in vitro biocompatibility in terms of gingival fibroblast viability and proliferation, as well as the antioxidant activity of SeNPs and the pollen-fermented Kombucha beverage enriched with SeNPs. The results highlight their increased biological performance in this regard.
Pharmacological Evaluation of Newly Synthesized Cannabidiol Derivates on H9c2 Cells
Authors: Szőke Kitti , Kajtár Richárd , Gyöngyösi Alexandra , Czompa Attila , Fésüs Adina , Lőrincz Eszter Boglárka , Petróczi Ferenc Dániel , Herczegh Pál , Bak István , Borbás Anikó , Bereczki Ilona , Lekli István
Published: September 2023

Cannabidiol (CBD) is a nonpsychoactive phytocannabinoid that can be found in Cannabis sativa and possesses numerous pharmacological effects. Due to these promising effects, CBD can be used in a wide variety of diseases, for instance cardiovascular diseases. However, CBD, like tetrahydrocannabinol (THC), has low bioavailability, poor water solubility, and a variable pharmacokinetic profile, which hinders its therapeutic use. Chemical derivatization of CBD offers us potential ways to overcome these issues. We prepared three new CBD derivatives substituted on the aromatic ring by Mannich-type reactions, which have not been described so far for the modification of cannabinoids, and studied the protective effect they have on cardiomyocytes exposed to oxidative stress and hypoxia/reoxygenation (H/R) compared to the parent compound. An MTT assay was performed to determine the viability of rat cardiomyocytes treated with test compounds. Trypan blue exclusion and lactate dehydrogenase (LDH) release assays were carried out to study the effect of the new compounds in cells exposed to H2O2 or hypoxia/reoxygenation (H/R). Direct antioxidant activity was evaluated by a total antioxidant capacity (TAC) assay. To study antioxidant protein levels, HO-1, SOD, catalase, and Western blot analysis were carried out. pIC50 (the negative log of the IC50) values were as follows: CBD1: 4.113, CBD2: 3.995, CBD3: 4.190, and CBD: 4.671. The newly synthesized CBD derivatives prevented cell death induced by H/R, especially CBD2. CBD has the largest direct antioxidant activity. The levels of antioxidant proteins were increased differently after pretreatment with synthetic CBD derivatives and CBD. Taken together, our newly synthesized CBD derivatives are able to decrease cytotoxicity during oxidative stress and H/R. The compounds have similar or better effects than CBD on H9c2 cells.
Melatonin Restores Autophagic Flux by Activating the Sirt3/TFEB Signaling Pathway to Attenuate Doxorubicin-Induced Cardiomyopathy
Authors: Ma Yanyan , Ma Jipeng , Lu Linhe , Xiong Xiang , Shao Yalan , Ren Jun , Yang Jian , Liu Jiankang
Published: September 2023

Doxorubicin (DOX) chemotherapy in cancer patients increases the risk of the occurrence of cardiac dysfunction and even results in congestive heart failure. Despite the great progress of pathology in DOX-induced cardiomyopathy, the underlying molecular mechanisms remain elusive. Here, we investigate the protective effects and the underlying mechanisms of melatonin in DOX-induced cardiomyopathy. Our results clearly show that oral administration of melatonin prevented the deterioration of cardiac function caused by DOX treatment, which was evaluated by left ventricular ejection fraction and fractional shortening as well as cardiac fibrosis. The ejection fraction and fractional shortening in the DOX group were 49.48% and 25.5%, respectively, while melatonin treatment increased the ejection fraction and fractional shortening to 60.33 and 31.39 in wild-type mice. Cardiac fibrosis in the DOX group was 3.97%, while melatonin reduced cardiac fibrosis to 1.95% in wild-type mice. Sirt3 is a mitochondrial deacetylase and shows protective effects in diverse cardiovascular diseases. Therefore, to test whether Sirt3 is a key factor in protection, Sirt3 knockout mice were used, and it was found that the protective effects of melatonin in DOX-induced cardiomyopathy were partly abolished. Further analysis revealed that Sirt3 and its downstream molecule TFEB were downregulated in response to DOX treatment, while melatonin administration was able to significantly enhance the expressions of Sirt3 and TFEB. Our in vitro study demonstrated that melatonin enhanced lysosomal function by increasing the Sirt3-mediated increase at the TFEB level, and the accumulation of autolysosomes induced by DOX treatment was attenuated. Thus, autophagic flux disrupted by DOX treatment was restored by melatonin supplementation. In summary, our results demonstrate that melatonin protects the heart against DOX injury by the restoration of autophagic flux via the activation of the Sirt3/TFEB signaling pathway.
Phytoconstituent Profiles Associated with Relevant Antioxidant Potential and Variable Nutritive Effects of the Olive, Sweet Almond, and Black Mulberry Gemmotherapy Extracts
Authors: Aleya Amina , Mihok Emőke , Pecsenye Bence , Jolji Maria , Kertész Attila , Bársony Péter , Vígh Szabolcs , Cziaky Zoltán , Máthé Anna-Beáta , Burtescu Ramona Flavia , Oláh Neli-Kinga , Neamțu Andreea-Adriana , Turcuș Violeta , Máthé Endre
Published: September 2023

The extracts of whole plants or specific organs from different plant species are gaining increasing attention for their phytotherapy applications. Accordingly, we prepared standardized gemmotherapy extracts (GTEs) from young shoots/buds of olive (Olea europaea), sweet almond (Prunus amygdalus), and black mulberry (Morus nigra), and analyzed the corresponding phytonutrient profiles. We identified 42, 103, and 109 phytonutrients in the olive, almond, and black mulberry GTEs, respectively, containing amino acids, vitamins, polyphenols, flavonoids, coumarins, alkaloids, iridoids, carboxylic acids, lignans, terpenoids, and others. In order to assess the physiological effects generated by the GTEs, we developed a translational nutrition model based on Drosophila melanogaster and Cyprinus carpio. The results indicate that GTEs could influence, to a variable extent, viability and ATP synthesis, even though both are dependent on the specific carbohydrate load of the applied diet and the amino acid and polyphenol pools provided by the GTEs. It seems, therefore, likely that the complex chemical composition of the GTEs offers nutritional properties that cannot be separated from the health-promoting mechanisms that ultimately increase viability and survival. Such an approach sets the paves the way for the nutritional genomic descriptions regarding GTE-associated health-promoting effects.