bluuebunny/crossref_metadata_2025 huggingface dataset:
Laser Rescanning for Enhancing Mechanical Properties of Laser-Directed Energy-Deposited High-Manganese Steels
Authors: Park Young Keun , Nam Hyun Ji , Park Yong Ho , Lee Wookjin
Published: January 2024

This study investigates the effects of laser deposition and laser rescanning (LR) on the microstructure and mechanical properties of high-manganese steel (HMnS) deposited by laser-directed energy deposition (L-DED) comprising 24 wt.% Mn. Four types of laser deposition and LR strategies were investigated: unidirectional L-DED scanning without laser rescanning, L-DED scanning with 90° alterations in the laser scanning path on each layer without laser rescanning, unidirectional L-DED with laser rescanning in the same direction, and L-DED with laser rescanning with 90° alterations in the laser scanning path. The L-DED-processed HMnS had only a few small pores and exhibited a microstructure without any serious defects such as cracks. Additionally, a strong fibrous texture along the <101>/building direction of the fully austenite phase was found. The mechanical properties (microhardness and tensile strength) of HMnS were improved by the LR with a grain refinement effect and fine solidification cell size due to the significantly faster solidification rate in LR than that in L-DED.
Identification of Cellulose-Degrading Bacteria and Assessment of Their Potential Value for the Production of Bioethanol from Coconut Oil Cake Waste
Authors: Fu Zihuan , Zhong Longbin , Tian Yan , Bai Xinpeng , Liu Jing
Published: January 2024

Bioconversion of lignocellulosic biomass is a highly promising alternative to rapidly reduce reliance on fossil fuels and greenhouse gas emissions. However, the use of lignocellulosic biomass is limited by the challenges of efficient degradation strategies. Given this need, Bacillus tropicus (B. tropicus) with cellulose degradation ability was isolated and screened from rotten dahlia. The strain efficiently utilized coconut oil cake (COC) to secrete 167.3 U/mL of cellulase activity. Electron microscopy results showed significant changes in the structure and properties of cellulose after treatment with B. tropicus, which increased the surface accessibility and the efficiency of the hydrolysis process. The functional group modification observed by Fourier transform infrared spectroscopy indicated the successful depolymerization of COC. The X-ray diffraction pattern showed that the crystallinity index increased from 44.8% to 48.2% due to the hydrolysis of the amorphous region in COC. The results of colorimetry also reveal an efficient hydrolysis process. A co-culture of B. tropicus and Saccharomyces cerevisiae was used to produce ethanol from COC waste, and the maximum ethanol yield was 4.2 g/L. The results of this work show that B. tropicus can be used to prepare biotechnology value-added products such as biofuels from lignocellulosic biomass, suggesting promising utility in biotechnology applications.
A Microcosm Experiment Reveals the Temperature-Sensitive Release of Mucochytrium quahogii (=QPX) from Hard Clams and Pallial Fluid as a Stable QPX Reservoir
Authors: Geraci-Yee Sabrina , Collier Jackie L. , Allam Bassem
Published: January 2024

Mucochytrium quahogii, also known as QPX or Quahog Parasite Unknown, is the causative agent of QPX disease in the hard clam (Mercenaria mercenaria). Host–pathogen–environment interactions between M. quahogii, the hard clam, and temperature were explored in a microcosm experiment. Hard clams were housed in individual tanks with sterile seawater under two temperature regimes: low (13 °C) temperature, which is thought to be optimal for QPX disease development, and high (20 °C) temperature, which has been shown to promote “healing” of QPX-infected clams. Hard clam tissue, pallial fluid, seawater, and shell biofilms were collected and assayed for M. quahogii. The release of M. quahogii from naturally infected live hard clams into seawater was detected only in the low temperature treatment, suggesting that temperature influences the release of potentially infectious cells. M. quahogii was commonly found in hard clam pallial fluid, even after 9 weeks in the lab, suggesting pallial fluid is a stable reservoir of M. quahogii within its primary host and that M. quahogii is not a transient component of the hard clam microbiota. Overall, results support a host-specific relationship and that M. quahogii is a commensal member of the hard clam microbiota, supporting its classification as an opportunistic pathogen.
Detection of mcr-1-1 Positive Enteropathogenic Escherichia coli Isolates Associated with Post-Weaning Diarrhoea in an Organic Piglet-Producing Farm in Austria
Authors: Renzhammer René , Schwarz Lukas , Cabal Rosel Adriana , Ruppitsch Werner , Fuchs Andreas , Simetzberger Erwin , Ladinig Andrea , Loncaric Igor
Published: January 2024

Postweaning diarrhoea (PWD) is a frequent multifactorial disease occurring in swine stocks worldwide. Since pathogenic Escherichia (E.) coli play a pivotal role in the pathogenesis of PWD and porcine E. coli are often resistant to different antibiotics, colistin is frequently applied to treat piglets with PWD. However, the application of colistin to livestock has been associated with the emergence of colistin resistance. This case report describes the detection of the colistin resistance gene mcr-1-1 in two E. coli isolated from piglets with PWD in an Austrian organic piglet-producing farm, which was managed by two farmers working as nurses in a hospital. Both mcr-1-positive E. coli were further analysed by Illumina short-read-sequencing, including assemblies and gene prediction. Both isolates belonged to the same clonal type and were positive for eaeH and espX5, which are both virulence genes associated with enteropathogenic E. coli (EPEC). Due to the detection of mcr-1-positive EPEC and based on the results of the antimicrobial resistance testing, the veterinarian decided to apply gentamicin for treatment instead of colistin, leading to improved clinical signs. In addition, after replacing faba beans with whey, PWD was solely observed in 2/10 weaned batches in the consecutive months.
Characterisation of Putative Outer Membrane Proteins from Leptospira borgpetersenii Serovar Hardjo-Bovis Identifies Novel Adhesins and Diversity in Adhesion across Genomospecies Orthologs
Authors: Kamaruzaman Intan Noor Aina , Staton Gareth James , Ainsworth Stuart , Carter Stuart D. , Evans Nicholas James
Published: January 2024

Leptospirosis is a zoonotic bacterial disease affecting mammalian species worldwide. Cattle are a major susceptible host; infection with pathogenic Leptospira spp. represents a public health risk and results in reproductive failure and reduced milk yield, causing economic losses. The characterisation of outer membrane proteins (OMPs) from disease-causing bacteria dissects pathogenesis and underpins vaccine development. As most leptospire pathogenesis research has focused on Leptospira interrogans, this study aimed to characterise novel OMPs from another important genomospecies, Leptospira borgpetersenii, which has global distribution and is relevant to bovine and human diseases. Several putative L. borgpetersenii OMPs were recombinantly expressed, refolded and purified, and evaluated for function and immunogenicity. Two of these unique, putative OMPs (rLBL0972 and rLBL2618) bound to immobilised fibronectin, laminin and fibrinogen, which, together with structural and functional data, supports their classification as leptospiral adhesins. A third putative OMP (rLBL0375), did not exhibit saturable adhesion ability but, together with rLBL0972 and the included control, OmpL1, demonstrated significant cattle milk IgG antibody reactivity from infected cows. To dissect leptospire host–pathogen interactions further, we expressed alleles of OmpL1 and a novel multi-specific adhesin, rLBL2618, from a variety of genomospecies and surveyed their adhesion ability, with both proteins exhibiting divergences in extracellular matrix component binding specificity across synthesised orthologs. We also observed functional redundancy across different L. borgspetersenii OMPs which, together with diversity in function across genomospecies orthologs, delineates multiple levels of plasticity in adhesion that is potentially driven by immune selection and host adaptation. These data identify novel leptospiral proteins which should be further evaluated as vaccine and/or diagnostic candidates. Moreover, functional redundancy across leptospire surface proteins together with identified adhesion divergence across genomospecies further dissect the complex host–pathogen interactions of a genus responsible for substantial global disease burden.
Three Rounds of Read Correction Significantly Improve Eukaryotic Protein Detection in ONT Reads
Authors: Safar Hussain A. , Alatar Fatemah , Mustafa Abu Salim
Published: January 2024

Background: Eukaryotes’ whole-genome sequencing is crucial for species identification, gene detection, and protein annotation. Oxford Nanopore Technology (ONT) is an affordable and rapid platform for sequencing eukaryotes; however, the relatively higher error rates require computational and bioinformatic efforts to produce more accurate genome assemblies. Here, we evaluated the effect of read correction tools on eukaryote genome completeness, gene detection and protein annotation. Methods: Reads generated by ONT of four eukaryotes, C. albicans, C. gattii, S. cerevisiae, and P. falciparum, were assembled using minimap2 and underwent three rounds of read correction using flye, medaka and racon. The generates consensus FASTA files were compared for total length (bp), genome completeness, gene detection, and protein-annotation by QUAST, BUSCO, BRAKER1 and InterProScan, respectively. Results: Genome completeness was dependent on the assembly method rather than on the read correction tool; however, medaka performed better than flye and racon. Racon significantly performed better than flye and medaka in gene detection, while both racon and medaka significantly performed better than flye in protein-annotation. Conclusion: We show that three rounds of read correction significantly affect gene detection and protein annotation, which are dependent on assembly quality in preference to assembly completeness.
Antimony’s Significance as a Critical Metal: The Global Perspective and the Greek Deposits
Authors: Kanellopoulos Christos , Sboras Sotiris , Voudouris Panagiotis , Soukis Konstantinos , Moritz Robert
Published: January 2024

Antimony is widely acknowledged as a critical raw material of worldwide significance, based on its recognition by many countries. According to current projections, there is an anticipated increase in the demand for antimony in the forthcoming years. An issue of significant concern within the supply chain, which poses a substantial obstacle to sustainable development, is the global unequal allocation of abundant antimony resources. Most nations exhibited a high degree of dependence on a few countries for their net imports of antimony, resulting in a notable disruption and raising concerns regarding the supply chain. In most countries, antimony exploration and exploitation have been paused for a long period due to financial constraints associated with operations and environmental concerns. Nowadays, identifying additional antimony reserves, particularly in countries that heavily rely on new technologies and use significant amounts of antimony, is imperative and presents a pressing endeavor. Greece is recognized as one of the European Union member states with identified antimony deposits and a historical record of antimony exploitation. A thorough description, examination, and re-assessment of all existing data on the deposits and occurrences of antimony in Greece is presented. Most of Greece’s antimony deposits are related to hydrothermal processes, controlled by specific tectonic structures, and associated with Cenozoic magmatism. They are classified either as simple Sb-deposits, where the primary ore is a stibnite mineral, or complex polymetallic deposits with varying contents that include antimony minerals.
Machine Learning-Based Uranium Prospectivity Mapping and Model Explainability Research
Authors: Kong Weihao , Chen Jianping , Zhu Pengfei
Published: January 2024

Sandstone-hosted uranium deposits are indeed significant sources of uranium resources globally. They are typically found in sedimentary basins and have been extensively explored and exploited in various countries. They play a significant role in meeting global uranium demand and are considered important resources for nuclear energy production. Erlian Basin, as one of the sedimentary basins in northern China, is known for its uranium mineralization hosted within sandstone formations. In this research, machine learning (ML) methodology was applied to mineral prospectivity mapping (MPM) of the metallogenic zone in the Manite depression of the Erlian Basin. An ML model of 92% accuracy was implemented with the random forest algorithm. Additionally, the confusion matrix and receiver operating characteristic curve were used as model evaluation indicators. Furthermore, the model explainability research with post hoc interpretability algorithms bridged the gap between complex opaque (black-box) models and geological cognition, enabling the effective and responsible use of AI technologies. The MPM results shown in QGIS provided vivid geological insights for ML-based metallogenic prediction. With the favorable prospective targets delineated, geologists can make decisions for further uranium exploration.
Organosolv Treatment of Red Grape Pomace for Effective Recovery of Antioxidant Polyphenols and Pigments Using a Ternary Glycerol/Ethanol/Water System under Mild Acidic Conditions
Authors: Geropoulou Maria , Yiagtzi Elissavet , Chatzimitakos Theodoros , Palaiogiannis Dimitrios , Makris Dimitris P.
Published: January 2024

The purpose of this investigation was (i) the development of a novel, green tertiary solvent system, composed of water, ethanol and glycerol, and (ii) the implementation of an organosolv treatment of red grape pomace (RGP) for the efficient production of polyphenol-containing extracts with enhanced antioxidant properties. The treatment developed was performed under mild acidic conditions, imparted by the addition of citric acid, and it was first evaluated on the basis of severity, establishing linear models that described the correlation between treatment performance and combined severity factors. To solicit treatment optimization, response surface methodology was implemented, considering solvent acidity and residence time as the treatment variables. The optimized treatment afforded maximum total polyphenol (166 ± 6 mg GAE g−1 DM), total pigment (4.4 ± 0.2 mg MvE g−1 DM) and total flavanol (31.5 mg CtE g−1 DM) yields and extracts with particularly enhanced antioxidant activity. This might be attributed to specific constituents with high antioxidant potency, such as catechin, determined in the extract using high-performance liquid chromatography. Thus, the treatment developed is proposed as a highly efficient process to generate RGP extracts enriched in polyphenolic compounds, with enhanced antioxidant activity. Such extracts might then be valorized as food additives, to provide antioxidant protection and/or pigmentation.
Profiling of Volatile Compounds in ‘Muscat Hamburg’ Contaminated with Aspergillus carbonarius before OTA Biosynthesis Based on HS-SPME-GC-MS and DLLME-GC-MS
Authors: Guo Yayun , Wang Zhe , He Yi , Gao Huanhuan , Shi Hongmei
Published: January 2024

Aspergillus carbonarius is known to produce the carcinogenic ochratoxin A (OTA) in grapes. The metabolism process before OTA biosynthesis influences the content and composition of the volatile compounds in grapes. In this study, a self-established method based on QuEChERS coupled with high-performance liquid chromatography–fluorescence detection (HPLC-FLD) was used to determine the OTA levels during a seven-day contamination period. The results showed that OTA was detected on the second day after contamination with A. carbonarius. Thus, the first day was considered as the critical sampling timepoint for analyzing the volatiles in grapes before OTA biosynthesis. Additionally, the volatile compounds in grapes were analyzed using headspace solid-phase microextraction gas chromatography–mass spectrometry (HS-SPME-GC-MS) and dispersive liquid–liquid microextraction gas chromatography–mass spectrometry (DLLME-GC-MS). The corresponding data were evaluated via multivariate data analysis using projection methods, including PCA and OPLS-DA. The results indicated significant differences in the nine volatile compounds in grapes contaminated with A. carbonarius before OTA biosynthesis. The results of the Pearson correlation analysis showed positive correlations between ethyl acetate, styrene, 1-hexanol and OTA; (E)-2-hexenal and nerolic acid were negatively correlated with OTA. Overall, these findings provide a theoretical basis for the early prediction of OTA formation in grape and grape products using GC-MS technology.
Conversion of PET Bottle Waste into a Terephthalic Acid-Based Metal-Organic Framework for Removing Plastic Nanoparticles from Water
Authors: Chinglenthoiba Chingakham , Mahadevan Gomathi , Zuo Jiawei , Prathyumnan Thiruchelvam , Valiyaveettil Suresh
Published: January 2024

Micro- and nanoparticles of plastic waste are considered emerging pollutants with significant environmental and health impacts at high concentrations or prolonged exposure time. Here we report the synthesis and characterization of a known metal-organic framework (MOF) using terephthalic acid (TPA) recovered from the hydrolysis of polyethylene terephthalate (PET) bottle waste. This approach adds value to the existing large amounts of bottle waste in the environment. Fully characterized zinc-TPA MOF (MOF-5) was used for the extraction and removal of engineered polyvinyl chloride (PVC) and polymethylmethacrylate (PMMA) nanoparticles from water with a high efficiency of 97% and 95%, respectively. Kinetic and isotherm models for the adsorption of polymer nanoparticles (PNPs) on the MOF surface were investigated to understand the mechanism. The Qmax for PVC and PMMA NPs were recorded as 56.65 mg/g and 33.32 mg/g, respectively. MOF-5 was characterized before and after adsorption of PNPs on the surface of MOF-5 using a range of techniques. After adsorption, the MOF-5 was successfully regenerated and reused for the adsorption and removal of PNPs, showing consistent results for five adsorption cycles with a removal rate of 83–85%. MOF-5 was characterized before and after adsorption of PNPs on the surface using a range of techniques. The MOF-5 with PNPs on the surface was successfully regenerated and reused for the adsorption and removal of polymer nanoparticles, showing consistent results for five extraction cycles. As a proof of concept, MOF-5 was also used to remove plastic particles from commercially available body scrub gel solutions. Such methods and materials are needed to mitigate the health hazards caused by emerging micro- and nanoplastic pollutants in the environment.
Influence of Soil Type and Temperature on Nitrogen Mineralization from Organic Fertilizers
Authors: de Jesus Hanna Ibiapina , Cassity-Duffey Kate , Dutta Bhabesh , da Silva Andre Luiz Biscaia Ribeiro , Coolong Timothy
Published: January 2024

Organic vegetable producers in Georgia, USA, utilize a range of amendments to supply nitrogen (N) for crop production. However, differences in soil type, fertilizers and environmental conditions can result in variability in N mineralization rates among commonly utilized organic fertilizers in the region. In this study, the effects of temperature on N mineralization from three commercial organic fertilizers [feather meal (FM), pelleted poultry litter (PPL) and a mixed organic fertilizer (MIX)] in two soil types from Georgia, USA (Cecil sandy clay loam and Tifton loamy sand) were evaluated for 120 d. Net N mineralization (Net Nmin) varied with soil type, fertilizer and temperature. After 120 d, Net Nmin from the FM fertilizer ranged between 41% and 77% of total organic N applied, the MIX fertilizer ranged between 26% and 59% and the PPL fertilizer ranged between 0% and 22% across all soil types and temperatures. Incubation at higher temperatures (20 °C and 30 °C) impacted Net Nmin of FM fertilizer in the Tifton series soil. Temperature and soil type had a relatively minor impact on the potentially mineralizable N of the PPL and MIX fertilizers after 120 d of incubation; however, both factors impacted the rate of fertilizer release shortly after application, which could impact the synchronicity of N availability and plant uptake. Temperature-related differences in the mineralization of organic fertilizers may not be large enough to influence a grower’s decisions regarding N fertilizer inputs for vegetable crop production in the two soils. However, organic fertilizer source will likely play a significant role in N availability during the cropping season.
Antioxidant Minerals Modified the Association between Iron and Type 2 Diabetes in a Chinese Population
Authors: Xu Teng , Wan Sitong , Shi Jiaxin , Xu Tiancheng , Wang Langrun , Guan Yiran , Luo Junjie , Luo Yongting , Sun Mingyue , An Peng , He Jingjing
Published: January 2024

Inconsistent findings exist regarding the relationship between heme iron intake and type 2 diabetes (T2D) among Western and Eastern populations. Easterners tend to consume a plant-based diet which is abundant in antioxidant minerals. To examine the hypothesis that antioxidant mineral may modify the relationship between iron and T2D, we performed a case–control study by measuring the serum mineral levels in 2198 Chinese subjects. A total of 2113 T2D patients and 2458 controls were invited; 502 T2D patients and 1696 controls were finally analyzed. In the total population, high serum iron showed a positive association with T2D odds (odds ratio [OR] = 1.27 [1.04, 1.55]); high magnesium (OR = 0.18 [0.14, 0.22]), copper (OR = 0.27 [0.21, 0.33]), zinc (OR = 0.37 [0.30, 0.46]), chromium (OR = 0.61 [0.50, 0.74]), or selenium concentrations (OR = 0.39 [0.31, 0.48]) were inversely associated with T2D odds. In contrast, in individuals with higher magnesium (>2673.2 µg/dL), zinc (>136.7 µg/dL), copper (>132.1 µg/dL), chromium (>14.0 µg/dL), or selenium concentrations (>16.8 µg/dL), serum iron displayed no association with T2D (p > 0.05). Serum copper and magnesium were significant modifiers of the association between iron and T2D in individuals with different physiological status (p < 0.05). Our findings support the idea that consuming a diet rich in antioxidant minerals is an effective approach for preventing T2D.
Effect of Pre-, Pro-, and Synbiotics on Biomarkers of Systemic Inflammation in Children: A Scoping Review
Authors: Kadia Benjamin Momo , Allen Stephen John
Published: January 2024

Systemic inflammation plays a central role in many diseases and is, therefore, an important therapeutic target. In a scoping review, we assessed the evidence base for the anti-inflammatory effects of pre-, pro-, and synbiotics in children. Of the 1254 clinical trials published in English in Ovid Medline and Cochrane Library PubMed from January 2003 to September 2022, 29 were included in the review. In six studies of healthy children (n = 1552), one reported that fructo-oligosaccharides added to infant formula significantly reduced pro-inflammatory biomarkers, and one study of a single-strain probiotic reported both anti- and pro-inflammatory effects. No effects were seen in the remaining two single-strain studies, one multi-strain probiotic, and one synbiotic study. In 23 studies of children with diseases (n = 1550), prebiotics were tested in 3, single-strain in 16, multi-strain probiotics in 6, and synbiotics in 2 studies. Significantly reduced inflammatory biomarkers were reported in 7/10 studies of atopic/allergic conditions, 3/5 studies of autoimmune diseases, 1/2 studies of preterm infants, 1 study of overweight/obesity, 2/2 studies of severe illness, and 2/3 studies of other diseases. However, only one or two of several biomarkers were often improved; increased pro-inflammatory biomarkers occurred in five of these studies, and a probiotic increased inflammatory biomarkers in a study of newborns with congenital heart disease. The evidence base for the effects of pre-, pro-, and synbiotics on systemic inflammation in children is weak. Further research is needed to determine if anti-inflammatory effects depend on the specific pre-, pro-, and synbiotic preparations, health status, and biomarkers studied.
Sex-Dependent Variations in Hypothalamic Fatty Acid Profile and Neuropeptides in Offspring Exposed to Maternal Obesity and High-Fat Diet
Authors: Baqueiro Mayara da Nóbrega , Simino Laís Angélica de Paula , Costa João Paulo , Panzarin Carolina , Reginato Andressa , Torsoni Marcio Alberto , Ignácio-Souza Letícia , Milanski Marciane , Ross Michael G. , Coca Kelly Pereira , Desai Mina , Torsoni Adriana Souza
Published: January 2024

Maternal obesity and/or high-fat diet (HF) consumption can disrupt appetite regulation in their offspring, contributing to transgenerational obesity and metabolic diseases. As fatty acids (FAs) play a role in appetite regulation, we investigated the maternal and fetal levels of FAs as potential contributors to programmed hyperphagia observed in the offspring of obese dams. Female mice were fed either a control diet (CT) or HF prior to mating, and fetal and maternal blood and tissues were collected at 19 days of gestation. Elevated levels of linoleic acid were observed in the serum of HF dams as well as in the serum of their fetuses. An increased concentration of eicosadienoic acid was also detected in the hypothalamus of female HF-O fetuses. HF-O male fetuses showed increased hypothalamic neuropeptide Y (Npy) gene expression, while HF-O female fetuses showed decreased hypothalamic pro-opiomelanocortin (POMC) protein content. Both male and female fetuses exhibited reduced hypothalamic neurogenin 3 (NGN-3) gene expression. In vitro experiments confirmed that LA contributed to the decreased gene expression of Pomc and Ngn-3 in neuronal cells. During lactation, HF female offspring consumed more milk and had a higher body weight compared to CT. In summary, this study demonstrated that exposure to HF prior to and during gestation alters the FA composition in maternal serum and fetal serum and hypothalamus, particularly increasing n-6, which may play a role in the switch from POMC to NPY neurons, leading to increased weight gain in the offspring during lactation.
Therapeutic Evaluation of Bifidobacterium animalis subsp. lactis MH-02 as an Adjunctive Treatment in Patients with Reflux Esophagitis: A Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Gan Lihong , Wang Yufan , Huang Shenan , Zheng Li , Feng Qi , Liu Hui , Liu Peng , Zhang Kaige , Chen Tingtao , Fang Nian
Published: January 2024

Proton pump inhibitors (PPIs) are currently routinely used for the treatment of reflux esophagitis (RE); however, with frequent symptom recurrence after discontinuation and limited clinical improvement in accompanying gastrointestinal symptoms. This study aims to explore the adjuvant therapeutic effect of Bifidobacterium supplement for RE patients. A total of 110 eligible RE patients were recruited and randomly assigned to the placebo and probiotic groups. All patients were treated with rabeprazole tablets and simultaneously received either Bifidobacterium animalis subsp. lactis MH-02 or placebo for 8 weeks. Patients who achieved clinical remission then entered the next 12 weeks of follow-up. RDQ, GSRS scores, and endoscopy were performed to assess clinical improvement, and changes in intestinal microbiota were analyzed with high-throughput sequencing. Our results revealed that MH-02 combined therapy demonstrated an earlier time to symptom resolution (50.98% vs. 30.61%, p = 0.044), a significant reduction in the GSRS score (p = 0.0007), and a longer mean time to relapse (p = 0.0013). In addition, high-throughput analyses showed that MH-02 combined therapy increased the α (p = 0.001) diversity of gut microbiota and altered microbial composition by beta diversity analysis, accompanied with significantly altered gut microbiota taxa at the genus level, where the abundance of some microbial genera including Bifidobacterium, Clostridium, and Blautia were increased, while the relative abundance of Streptococcus and Rothia were decreased (p < 0.05). Collectively, these results support the beneficial effects of MH-02 as a novel complementary strategy in RE routine treatment.
Brazilian Front-of-Package Labeling: A Product Compliance Analysis 12 Months after Implementation of Regulations
Authors: Senda Marcos Vinícius Garcia , Raposo António , Teixeira-Lemos Edite , Chaves Cláudia , Alturki Hmidan A. , Alsharari Zayed D. , Romão Bernardo
Published: January 2024

This study investigated the presence of front-of-package labeling on food products in major retailers in Brazil after its implementation in 2022. Carried out from May to October 2023, we analyzed 2145 products of brands present in five Brazilian states. A total of 541 products presented front-of-package warnings. The categories varied in their adherence to front-of-package labeling, highlighting a prevalence of combined warnings, such as high in added sugar and high in saturated fat on sweet biscuits and chocolates. Sausages showed a high prevalence of high in sodium and high in saturated fat warnings. Beverages stood out as high in added sugar, while fats, dairy products, frozen preparations, seasonings, and sauces presented diversity in the warnings. Other products, such as panettone, showed a high presence of alerts. The study demonstrated the widespread presence of front-of-package labeling on ultra-processed products highly consumed by the Brazilian population. Considering the alarming presence of these foods in the Brazilian diet, it is concluded that front-of-package nutrition labeling is crucial to inform and raise awareness among consumers, allowing healthier choices and potentially contributing to a reduction in chronic diseases and the costs associated with treatment in the health system.
The Trimeric Autotransporter Adhesin EmaA and Infective Endocarditis
Authors: Mintz Keith P. , Danforth David R. , Ruiz Teresa
Published: January 2024

Infective endocarditis (IE), a disease of the endocardial surface of the heart, is usually of bacterial origin and disproportionally affects individuals with underlying structural heart disease. Although IE is typically associated with Gram-positive bacteria, a minority of cases are caused by a group of Gram-negative species referred to as the HACEK group. These species, classically associated with the oral cavity, consist of bacteria from the genera Haemophilus (excluding Haemophilus influenzae), Aggregatibacter, Cardiobacterium, Eikenella, and Kingella. Aggregatibacter actinomycetemcomitans, a bacterium of the Pasteurellaceae family, is classically associated with Aggressive Periodontitis and is also concomitant with the chronic form of the disease. Bacterial colonization of the oral cavity serves as a reservoir for infection at distal body sites via hematological spreading. A. actinomycetemcomitans adheres to and causes disease at multiple physiologic niches using a diverse array of bacterial cell surface structures, which include both fimbrial and nonfimbrial adhesins. The nonfimbrial adhesin EmaA (extracellular matrix binding protein adhesin A), which displays sequence heterogeneity dependent on the serotype of the bacterium, has been identified as a virulence determinant in the initiation of IE. In this chapter, we will discuss the known biochemical, molecular, and structural aspects of this protein, including its interactions with extracellular matrix components and how this multifunctional adhesin may contribute to the pathogenicity of A. actinomycetemcomitans.
Comprehensive Analysis of HIV-1 Integrase Resistance-Related Mutations in African Countries
Authors: Branda Francesco , Giovanetti Marta , Sernicola Leonardo , Farcomeni Stefania , Ciccozzi Massimo , Borsetti Alessandra
Published: January 2024

The growing emergence of non-nucleoside reverse transcriptase inhibitor (NNRTI) HIV drug resistance in sub-Saharan Africa (SSA) led to the World Health Organization (WHO) recommending, in 2018, a transition to dolutegravir (DTG) as a first-line antiretroviral therapy (ART) in SSA. The broad HIV-1 genetic diversity in SSA could shape DTG effectiveness and the pattern of drug resistance mutations (DRMs) in this region. This study evaluated HIV-1 integrase (IN) DRMs and conserved regions among published groups M, N, O, and P HIV-1 sequences spanning forty years of the HIV epidemic during the transition of DTG-based ART. Overall, we found low levels of integrase strand transfer inhibitor (INSTI)-DRMs (<1%) across HIV groups between the years 1983 and 2023; however, it was unexpected to detect DRMs at statistically significantly higher frequencies in pre-INSTI (1983–2007) than in the INSTI (2008–2023) era. The variability of accessory INSTI-DRMs depended on the HIV subtypes, with implications for susceptibility to DTG. Our findings provide new perspectives on the molecular epidemiology and drug resistance profiles of INSTIs in SSA, emphasizing the need for ongoing surveillance and customized treatment approaches to address the continent’s varied HIV subtypes and changing resistance patterns.
Deleting the C84L Gene from the Virulent African Swine Fever Virus SY18 Does Not Affect Its Replication in Porcine Primary Macrophages but Reduces Its Virulence in Swine
Authors: Yang Jinjin , Zhu Rongnian , Zhang Yanyan , Zhou Xintao , Yue Huixian , Li Qixuan , Ke Junnan , Wang Yu , Miao Faming , Chen Teng , Zhang Fei , Zhang Shoufeng , Qian Aidong , Hu Rongliang
Published: January 2024

(1) Background: African swine fever (ASF) is a highly contagious disease that causes high pig mortality. Due to the absence of vaccines, prevention and control are relatively challenging. The pathogenic African swine fever virus (ASFV) has a complex structure and encodes over 160 proteins, many of which still need to be studied and verified for their functions. In this study, we identified one of the unknown functional genes, C84L. (2) Methods: A gene deficient strain was obtained through homologous recombination and several rounds of purification, and its replication characteristics and virulence were studied through in vitro and in vivo experiments, respectively. (3) Results: Deleting this gene from the wild-type virulent strain SY18 did not affect its replication in porcine primary macrophages but reduced its virulence in pigs. In animal experiments, we injected pigs with a 102 TCID50, 105 TCID50 deletion virus, and a 102 TCID50 wild-type strain SY18 intramuscularly. The control group pigs reached the humane endpoint on the ninth day (0/5) and were euthanized. Two pigs in the 102 TCID50(2/5) deletion virus group survived on the twenty-first day, and one in the 105 TCID50(1/5) deletion virus group survived. On the twenty-first day, the surviving pigs were euthanized, which was the end of the experiment. The necropsies of the survival group and control groups’ necropsies showed that the surviving pigs’ liver, spleen, lungs, kidneys, and submaxillary lymph nodes did not show significant lesions associated with the ASFV. ASFV-specific antibodies were first detected on the seventh day after immunization; (4) Conclusions: This is the first study to complete the replication and virulence functional exploration of the C84L gene of SY18. In this study, C84L gene was preliminarily found not a necessary gene for replication, gene deletion strain SY18ΔC84L has similar growth characteristics to SY18 in porcine primary alveolar macrophages. The C84L gene affects the virulence of the SY18 strain.
NK Cell Levels Correlate with Disease Activity in Patients with Multiple Sclerosis on Ocrelizumab/Rituximab Therapy
Authors: Dal Bello Simone , Lorenzut Simone , Saccomano Emma , Tereshko Yan , Gigli Gian Luigi , Pucillo Carlo Ennio , Valente Mariarosaria
Published: January 2024

Background: Recently, research on the pathogenesis of multiple sclerosis (MS) has focused on the role of B lymphocytes and the possibility of using specific drugs, such as Ocrelizumab and Rituximab, directed toward these cells to reduce inflammation and to slow disease progression. Objective: We aimed to evaluate the effect of Ocrelizumab/Rituximab on laboratory immune parameters and identify the predictors of treatment responses. Methods: A retrospective single-center study was conducted among patients who received infusion therapy with an anti-CD20 drug to treat MS. Results: A total of 64 patients met the inclusion criteria, with 277 total cycles of therapy studied. Compared with the baseline values, anti-CD20 infusions resulted in absolute-value and percentage decreases in B lymphocyte levels and increased the absolute and percentage levels of NK cells 3 and 5 months after therapy (p < 0.001). After multivariate logistic regression analysis, a reduced percentage level of NK cells 3 months after infusion could predict disease activity 6 months after Ocrelizumab/Rituximab administration (p = 0.041). Conclusions: Lower percentage levels of NK cells 3 months after anti-CD20 infusion correlate with the presence of disease activity 6 months after therapy, confirming a possible protective role of NK cells in MS.
A New Intervention for Implementation of Pharmacogenetics in Psychiatry: A Description of the PSY-PGx Clinical Study
Authors: Pelgrim Teuntje A. D. , Philipsen Alexandra , Young Allan H. , Juruena Mario , Jimenez Ester , Vieta Eduard , Jukić Marin , Van der Eycken Erik , Heilbronner Urs , Moldovan Ramona , Kas Martien J. H. , Jagesar Raj R. , Nöthen Markus M. , Hoffmann Per , Shomron Noam , Kilarski Laura L. , van Amelsvoort Thérèse , Campforts Bea ,   The PSY-PGx Consortium, van Westrhenen Roos
Published: January 2024

(1) Background Pharmacological treatment for psychiatric disorders has shown to only be effective in about one-third of patients, as it is associated with frequent treatment failure, often because of side effects, and a long process of trial-and-error pharmacotherapy until an effective and tolerable treatment is found. This notion emphasizes the urgency for a personalized medicine approach in psychiatry. (2) Methods This prospective patient- and rater-blinded, randomized, controlled study will investigate the effect of dose-adjustment of antidepressants escitalopram and sertraline or antipsychotics risperidone and aripiprazole according to the latest state-of-the-art international dosing recommendations for CYP2C19 and CYP2D6 metabolizer status in patients with mood, anxiety, and psychotic disorders. A total sample of N = 2500 will be recruited at nine sites in seven countries (expected drop-out rate of 30%). Patients will be randomized to a pharmacogenetic group or a dosing-as-usual group and treated over a 24-week period with four study visits. The primary outcome is personal recovery using the Recovery Assessment Scale as assessed by the patient (RAS-DS), with secondary outcomes including clinical effects (response or symptomatic remission), side effects, general well-being, digital phenotyping, and psychosocial functioning. (3) Conclusions This is, to our knowledge, the first international, multi-center, non-industry-sponsored randomized controlled trial (RCT) that may provide insights into the effectiveness and utility of implementing pharmacogenetic-guided treatment of psychiatric disorders, and as such, results will be incorporated in already available dosing guidelines.
Determination of the Cannabinoid CB1 Receptor’s Positive Allosteric Modulator Binding Site through Mutagenesis Studies
Authors: Green Hayley M. , Fellner Daniel M. J. , Finlay David B. , Furkert Daniel P. , Glass Michelle
Published: January 2024

Positive allosteric modulators (PAMs) of the cannabinoid CB1 receptor (CB1) offer potential therapeutic advantages in the treatment of neuropathic pain and addiction by avoiding the adverse effects associated with orthosteric CB1 activation. Here, molecular modeling and mutagenesis were used to identify residues central to PAM activity at CB1. Six putative allosteric binding sites were identified in silico, including novel sites previously associated with cholesterol binding, and key residues within each site were mutated to alanine. The recently determined ZCZ011 binding site was found to be essential for allosteric agonism, as GAT228, GAT229 and ZCZ011 all increased wild-type G protein dissociation in the absence of an orthosteric ligand; activity that was abolished in mutants F191A3.27 and I169A2.56. PAM activity was demonstrated for ZCZ011 in the presence of the orthosteric ligand CP55940, which was only abolished in I169A2.56. In contrast, the PAM activity of GAT229 was reduced for mutants R220A3.56, L404A8.50, F191A3.27 and I169A2.56. This indicates that allosteric modulation may represent the net effect of binding at multiple sites, and that allosteric agonism is likely to be mediated via the ZCZ011 site. This study underlines the need for detailed understanding of ligand receptor interactions in the search for pure CB1 allosteric modulators.
Nano-Formulations for Pulmonary Delivery: Past, Present, and Future Perspectives
Authors: Peng Siyuan , Wang Wenhao , Zhang Rui , Wu Chuanbin , Pan Xin , Huang Zhengwei
Published: January 2024

With the development of nanotechnology and confronting the problems of traditional pharmaceutical formulations in treating lung diseases, inhalable nano-formulations have attracted interest. Inhalable nano-formulations for treating lung diseases allow for precise pulmonary drug delivery, overcoming physiological barriers, improving aerosol lung deposition rates, and increasing drug bioavailability. They are expected to solve the difficulties faced in treating lung diseases. However, limited success has been recorded in the industrialization translation of inhalable nano-formulations. Only one relevant product has been approved by the FDA to date, suggesting that there are still many issues to be resolved in the clinical application of inhalable nano-formulations. These systems are characterized by a dependence on inhalation devices, while the adaptability of device formulation is still inconclusive, which is the most important issue impeding translational research. In this review, we categorized various inhalable nano-formulations, summarized the advantages of inhalable nano-formulations over conventional inhalation formulations, and listed the inhalable nano-formulations undergoing clinical studies. We focused on the influence of inhalation devices on nano-formulations and analyzed their adaptability. After extensive analysis of the drug delivery mechanisms, technical processes, and limitations of different inhalation devices, we concluded that vibrating mesh nebulizers might be most suitable for delivering inhalable nano-formulations, and related examples were introduced to validate our view. Finally, we presented the challenges and outlook for future development. We anticipate providing an informative reference for the field.
Effect of Drug Loading in Mesoporous Silica on Amorphous Stability and Performance
Authors: Bavnhøj Christoffer G. , Knopp Matthias M. , Löbmann Korbinian
Published: January 2024

The encapsulation of drugs within mesoporous silica (MS) has for several years been a subject of research. Previous studies proposed that drug loadings up to the monomolecular loading capacity (MLC) are the optimal choice for maintaining the drug in an amorphous form, whereas filling the pores above the monolayer and up to the pore filling capacity (PFC) may introduce some physical instabilities. The aim of this study was to assess the effect of drug loading in MS-based amorphous formulations on the stability of the amorphous form of the drug as well as the dissolution. In particular, the following drug loadings were investigated: below MLC, at MLC, between MLC and PFC and at PFC. The drug-loaded MS formulations were analyzed directly after preparation and after 18 months of storage under accelerated conditions (40 °C in both dry and humid conditions). The MLC and PFC for the drug celecoxib (CEL) on the MS ParteckSLC500 (SLC) were determined at 33.5 wt.% and 48.4 wt.%, respectively. This study found that SLC can effectively preserve the amorphous form of the drug for 18 months, provided that the loading is below the PFC (<48.4 wt.%) and no humidity is present. On the other hand, drug loading at the PFC showed recrystallization even when stored under dry conditions. Under humid conditions, however, all samples, regardless of drug loading, showed recrystallization upon storage. In terms of dissolution, all freshly prepared formulations showed supersaturation. For drug loadings below PFC, a degree of supersaturation (DS) around 15 was measured before precipitation was observed. For drug loadings at PFC, the DS was found to be lower and only 6-times compared to the crystalline solubility. Lastly, for those samples that remained amorphous during storage for 18 months, the release profiles were found to be the same as the freshly loaded samples, with similar Cmax, Tmax and dissolution rate.
In Vitro and Biological Evaluation of Oral Fast-Disintegrating Films Containing Ranitidine HCl and Syloid® 244FP-Based Ternary Solid Dispersion of Flurbiprofen
Authors: Rashid Aisha , Irfan Muhammad , Kamal Yousaf , Asghar Sajid , Khalid Syed Haroon , Hussain Ghulam , Alshammari Abdulrahman , Albekairi Thamer H. , Alharbi Metab , Khan Hafeez Ullah , Chauhdary Zunera , Vandamme Thierry F. , Khan Ikram Ullah
Published: January 2024

Flurbiprofen (FBP), a nonsteroidal anti-inflammatory drug (NSAID), is commonly used to treat the pain of rheumatoid arthritis, but in prolonged use it causes gastric irritation and ulcer. To avoid these adverse events of NSAIDs, the simultaneous administration of H2 receptor antagonists such as ranitidine hydrochloride (RHCl) is obligatory. Here, we developed composite oral fast-disintegrating films (ODFs) containing FBP along with RHCl to provide a gastroprotective effect as well as to enhance the solubility and bioavailability of FBP. The ternary solid dispersion (TSD) of FBP was fabricated with Syloid® 244FP and poloxamer® 188 using the solvent evaporation technique. The synthesized FBP-TSD (coded as TSD) was loaded alone (S1) and in combination with plain RHCl (S2) in the composite ODFs based on hydroxypropyl methyl cellulose E5 (HPMC E5). The synthesized composite ODFs were evaluated by in vitro (thickness, folding endurance, tensile strength, disintegration, SEM, FTIR, XRD and release study) and in vivo (analgesic, anti-inflammatory activity, pro-inflammatory cytokines and gastroprotective assay) studies. The in vitro characterization revealed that TSD preserved its integrity and was effectively loaded in S1 and S2 with optimal compatibility. The films were durable and flexible with a disintegration time ≈15 s. The release profile at pH 6.8 showed that the solid dispersion of FBP improved the drug solubility and release when compared with pure FBP. After in vitro studies, it was observed that the analgesic and anti-inflammatory activity of S2 was higher than that of pure FBP and other synthesized formulations (TSD and S1). Similarly, the level of cytokines (TNF-α and IL-6) was also markedly reduced by S2. Furthermore, a gastroprotective assay confirmed that S2 has a higher safety profile in comparison to pure FBP and other synthesized formulations (TSD and S1). Thus, composite ODF (S2) can effectively enhance the FBP solubility and its therapeutic efficacy, along with its gastroprotective effect.