bluuebunny/crossref_metadata_2025 huggingface dataset:
Managing Super Pests: Interplay between Pathogens and Symbionts Informs Biocontrol of Whiteflies
Authors: Yan Weili , Wang Saixian , Liu Jialei , Zhai Dan , Lu Hang , Li Jingjing , Bai Rune , Lei Caiyan , Song Luyang , Zhao Chenchen , Yan Fengming
Published: May 2024

Bemisia tabaci is distributed globally and incurs considerable economic and ecological costs as an agricultural pest and viral vector. The entomopathogenic fungus Metarhizium anisopliae has been known for its insecticidal activity, but its impacts on whiteflies are understudied. We investigated how infection with the semi-persistently transmitted Cucurbit chlorotic yellows virus (CCYV) affects whitefly susceptibility to M. anisopliae exposure. We discovered that viruliferous whiteflies exhibited increased mortality when fungus infection was present compared to non-viruliferous insects. High throughput 16S rRNA sequencing also revealed significant alterations of the whitefly bacterial microbiome diversity and structure due to both CCYV and fungal presence. Specifically, the obligate symbiont Portiera decreased in relative abundance in viruliferous whiteflies exposed to M. anisopliae. Facultative Hamiltonella and Rickettsia symbionts exhibited variability across groups but dominated in fungus-treated non-viruliferous whiteflies. Our results illuminate triangular interplay between pest insects, their pathogens, and symbionts—dynamics which can inform integrated management strategies leveraging biopesticides This work underscores the promise of M. anisopliae for sustainable whitefly control while laying the groundwork for elucidating mechanisms behind microbe-mediated shifts in vector competence.
Community-Acquired Solitary Brain Abscesses Caused by Hypervirulent Klebsiella pneumoniae in a Healthy Adult
Authors: Hwang Joo-Hee , Park Jung Soo , Bae Tae Won , Hwang Jeong-Hwan , Lee Jaehyeon
Published: May 2024

A 42-year-old man was admitted to the emergency room complaining of fever and headache. His cerebrospinal fluid showed a cloudy appearance, and his white blood cell count was elevated at 2460/mm3, with a predominance of neutrophils (81%), and abnormal protein and glucose levels (510.7 mg/dL and 5 mg/dL, respectively). A lobulated lesion with rim enhancement, suggestive of abscess, was detected through magnetic resonance imaging. Klebsiella pneumoniae was detected in nasopharyngeal swab and blood cultures. The capsular serotype of K. pneumoniae was K2 and the sequence type determined by multilocus sequence typing was 23. The hypervirulent phenotype was associated with multiple virulent genes, including rmpA, rmpA2, entB, ybtS, kfu, iucA, iutA, iroB mrkD, allS, peg-344, peg-589, and peg-1631. After six weeks of receiving appropriate antibiotics and exhibiting clinical resolution of the brain abscesses, the patient was discharged. We present the first reported case of a healthy community-dwelling adult with solitary brain abscesses, and no other invasive abscesses, related to hypervirulent K. pneumoniae.
Widespread Circulation of Tick-Borne Viruses in Virginia—Evidence of Exposure to Heartland, Bourbon, and Powassan Viruses in Wildlife and Livestock
Authors: Garba Ahmed , Riley Jennifer , Lahmers Kevin K. , Eastwood Gillian
Published: May 2024

Emerging tick-borne viruses such as Powassan virus (POWV), Bourbon virus (BRBV), and Heartland virus (HRTV), whilst rare, can cause severe health problems in humans. While limited clinical cases have been reported thus far in Virginia, the presence of tick-borne viruses poses a serious health threat, and the extent of their prevalence in Virginia is unknown. Here, we sought evidence of POWV, BRBV, and HRTV exposure in Virginia via a serological assessment of wildlife and livestock. Wildlife in Virginia were found to be seropositive against POWV (18%), BRBV (8%), and HRTV (5%), with western and northern regions of the state having a higher prevalence. Multiple wildlife species were shown to have been exposed to each virus examined. To a lesser extent, cattle also showed exposure to tick-borne viruses, with seroprevalences of 1%, 1.2%, and 8% detected in cattle against POWV, BRBV, and HRTV, respectively. Cross-reactivity against other known circulating mosquito-borne flaviviruses was ruled out. In conclusion, there is widespread exposure to tick-borne viruses in western and northern Virginia, with exposure to a diverse range of animal populations. Our study provides the first confirmation that HRTV is circulating in the Commonwealth. These findings strengthen the existing evidence of emerging tick-borne viruses in Virginia and highlight the need for public health vigilance to avoid tick bites.
Salvage Therapy with Rezafungin for Candida parapsilosis Spondylodiscitis: A Case Report from Expanded Access Program
Authors: Viceconte Giulio , Buonomo Antonio Riccardo , Esposito Nunzia , Cattaneo Letizia , Somma Teresa , Scirocco Maria Michela , Mainolfi Ciro Gabriele , Gentile Ivan
Published: May 2024

Candida spp. spondylodiscitis is a rare condition for which treatment options are often limited. A further obstacle is the duration of therapy, which should be administered for up to twelve months. In view of the long duration of therapy, azoles are, so far, the only oral treatment strategy that can be given as home therapy. In the case of resistance or reduced susceptibility to azoles, there are not enough comfortable treatment opportunities with adequate bone penetration and limited toxicity. We report the first case of the successful use of rezafungin for spondylodiscitis due to Candida parapsilosis with reduced susceptibility to azoles. A 68-year-old patient, affected by paraplegia and short bowel syndrome, was diagnosed with Candida parapsilosis spondylodiscitis, confirmed with a culture on vertebral biopsy after an 18-FDG PET/CT scan. He received 200 mg of rezafungin weekly for 26 weeks, after 10 weeks of previous antifungal treatment that was not well tolerated with voriconazole plus liposomal amphotericin B. He had a full clinical, radiologic, and biochemical response to the therapy with rezafungin, with no adverse effects. Rezafungin can be a promising therapy for Candida osteomyelitis, especially when first line therapies are ineffective, poorly tolerated, or contraindicated.
Examining Sound, Light, and Vibrations as Tools to Manage Microbes and Support Holobionts, Ecosystems, and Technologies
Authors: Dietert Rodney R. , Dietert Janice M.
Published: May 2024

The vast array of interconnected microorganisms across Earth’s ecosystems and within holobionts has been called the “Internet of Microbes.” Bacteria and archaea are masters of energy and information collection, storage, transformation, and dissemination using both “wired” and wireless (at a distance) functions. Specific tools affecting microbial energy and information functions offer effective strategies for managing microbial populations within, between, and beyond holobionts. This narrative review focuses on microbial management using a subset of physical modifiers of microbes: sound and light (as well as related vibrations). These are examined as follows: (1) as tools for managing microbial populations, (2) as tools to support new technologies, (3) as tools for healing humans and other holobionts, and (4) as potential safety dangers for microbial populations and their holobionts. Given microbial sensitivity to sound, light, and vibrations, it is critical that we assign a higher priority to the effects of these physical factors on microbial populations and microbe-laden holobionts. We conclude that specific sound, light, and/or vibrational conditions are significant therapeutic tools that can help support useful microbial populations and help to address the ongoing challenges of holobiont disease. We also caution that inappropriate sound, light, and/or vibration exposure can represent significant hazards that require greater recognition.
Analysis of Aetiological Agents in Infectious Endocarditis in the Central Military Emergency University Hospital “Dr. Carol Davila” Bucharest
Authors: Anton Corina-Ioana , Ștefan Ion , Dumitrache Simona Mihaela , Ștefan Alexia-Teodora , Răduț Diana , Nistor Claudiu-Eduard , Ranetti Aurelian-Emil , Adella-Sîrbu Carmen , Ioniță-Radu Florentina
Published: May 2024

Background: Infective endocarditis (IE) is a pathological condition caused by various microbial agents that can lead to severe complications affecting the heart. Accurate diagnosis is crucial for the effective management of patients with IE. Blood culture is the gold standard for identifying the primary infectious agents, which is a key factor in diagnosing IE using the modified Duke criteria. Objective: The main objective of this study was to investigate the distribution of the etiological agents of IE and the most common secondary diagnoses associated with it. Method: A total of 152 patients aged 23–95 years with a diagnosis of IE and proven etiology (through blood cultures or serological tests) were included in this study. Results: The most common etiological agent identified through blood tests was Enterococcus faecalis, which was detected in 39 patients (23.5%). Staphylococcus aureus was the second most common agent and was identified in 33 patients (19.9%), followed by Staphylococcus epidermidis, which was identified in 12 patients (13.1%). Nine patients (5.8%) had high levels of anti-Coxiella burnetti IgG phase I and II antibodies. Conclusions: IE is a leading cause of death in the Department of Infectious Diseases. Early and accurate diagnosis, along with interdisciplinary treatment, can significantly increase the chances of patient survival. Currently, Enterococcus faecalis and Staphylococcus aureus are the dominant etiological agents of IE, highlighting the need to revise protocols for prophylaxis, diagnosis, and initial treatment of this condition.
Molecular Detection and Characterization of Rickettsia Species in Ixodid Ticks from Selected Regions of Namibia
Authors: Mbiri Pricilla , Matomola Ophelia Chuma , Muleya Walter , Mhuulu Lusia , Diegaardt Azaria , Noden Bruce Howard , Changula Katendi , Chimwamurombe Percy , Matos Carolina , Weiss Sabrina , Nepolo Emmanuel , Chitanga Simbarashe
Published: May 2024

Rickettsial pathogens are among the emerging and re-emerging vector-borne zoonoses of public health importance. Reports indicate human exposure to Rickettsial pathogens in Namibia through serological surveys, but there is a lack of data on infection rates in tick vectors, hindering the assessment of the relative risk to humans. Our study sought to screen Ixodid ticks collected from livestock for the presence of Rickettsia species in order to determine infection rates in ticks and to determine the Rickettsia species circulating in the country. We collected and pooled Hyalomma and Rhipicephalus ticks from two adjacent regions of Namibia (Khomas and Otjozondjupa) and observed an overall minimum Rickettsia infection rate of 8.6% (26/304), with an estimated overall pooled prevalence of 9.94% (95% CI: 6.5–14.3). There were no statistically significant differences in the estimated pooled prevalence between the two regions or tick genera. Based on the nucleotide sequence similarity and phylogenetic analysis of the outer membrane protein A (n = 9) and citrate synthase (n = 12) genes, BLAST analysis revealed similarity between Rickettsia africae (n = 2) and Rickettsia aeschlimannii (n = 11), with sequence identities ranging from 98.46 to 100%. Our initial study in Namibia indicates that both zoonotic R. africae and R. aeschlimannii are in circulation in the country, with R. aeschlimannii being the predominant species.
Factors Influencing Microbial Contamination of Groundwater: A Systematic Review of Field-Scale Studies
Authors: Bagordo Francesco , Brigida Silvia , Grassi Tiziana , Caputo Maria Clementina , Apollonio Francesca , De Carlo Lorenzo , Savino Antonella Francesca , Triggiano Francesco , Turturro Antonietta Celeste , De Donno Antonella , Montagna Maria Teresa , De Giglio Osvalda
Published: May 2024

Pathogenic microorganisms released onto the soil from point or diffuse sources represent a public health concern. They can be transported by rainwater that infiltrates into subsoil and reach the groundwater where they can survive for a long time and contaminate drinking water sources. As part of the SCA.Re.S. (Evaluation of Health Risk Related to the Discharge of Wastewater on the Soil) project, we reviewed a selection of field-scale studies that investigated the factors that influenced the fate of microorganisms that were transported from the ground surface to the groundwater. A total of 24 studies published between 2003 and 2022 were included in the review. These studies were selected from the PubMed and Web of Science databases. Microbial contamination of groundwater depends on complex interactions between human activities responsible for the release of contaminants onto the soil, and a range of environmental and biological factors, including the geological, hydraulic, and moisture characteristics of the media traversed by the water, and the characteristics and the viability of the microorganisms, which in turn depend on the environmental conditions and presence of predatory species. Enterococci appeared to be more resistant in the underground environment than thermotolerant coliforms and were suggested as a better indicator for detecting microbial contamination of groundwater.
Blood Group Variations in COVID-19 Convalescent Plasma and Regular Blood Donors: A Comparative Analysis in the Serbian Population
Authors: Grujić Jasmina , Budakov-Obradović Zorana , Klašnja Jelena , Dinić Radovan , Dolinaj Vladimir , Cabezas-Cruz Alejandro , Banović Pavle
Published: May 2024

This research explores the association between ABO blood groups and susceptibility to SARS-CoV-2 infection, analyzing Convalescent COVID-19 plasma (CCP) donors (n = 500) and healthy whole blood donors (BDs) (n = 9678) during the pandemic (1 May 2020 to 30 April 2021). A comparison is made with pre-pandemic BDs (n = 11,892) from 1 May 2018 to 30 April 2019. Significant differences in blood group distribution are observed, with blood group A individuals being three times more likely to be CCP donors. Conversely, blood groups B, O, and AB are less associated with CCP donation. Notably, blood group O is more prevalent among regular BDs, suggesting potential resistance to SARS-CoV-2 infection. This study underscores variations in blood group distribution during the pandemic compared to pre-pandemic periods. The findings support previous research indicating a link between blood group antigens and viral susceptibility, including SARS-CoV-2. Understanding these associations has implications for public health strategies, with potential for predicting COVID-19 outcomes and transmission patterns. Further research is crucial to explore molecular and immunological mechanisms, providing valuable insights for targeted preventive strategies and personalized healthcare in managing the impact of COVID-19.
Efficacy of the Combined Intrastromal Injection of Voriconazole and Amphotericin B in Recalcitrant Fungal Keratitis
Authors: Moramarco Antonio , Grendele Arianna , Iannetta Danilo , Ottoboni Simone , Gregori Giulia , di Geronimo Natalie , Ortalli Margherita , Lazzarotto Tiziana , Fontana Luigi
Published: May 2024

This study aims to report the efficacy of a combined intrastromal injection in optimizing the outcome of severe mycotic keratitis. Herein, we report a case series of 20 consecutive patients with positive fungal cultures not responding to topical antifungal treatment. Patients received cycles of intrastromal injections of voriconazole (50 µg/0.1 mL) and amphotericin B (2.5 µg/0.1 mL); all patients continued their topical antifungal therapy. The organisms isolated were Fusarium (n = 5), Aspergillus (n = 4), Candida (n = 4), Rhodotorula (n = 2), Penicillium (n = 2), Alternaria (n = 1), Bipolaris (n = 1), and Curvularia (n = 1). The size of the infiltrate varied from 6.5 to 1.5 mm. At presentation, the best corrected visual acuity (BCVA, namely, the best visual acuity achieved with glasses, if needed) was less than 20/400 in all patients, improving to better than 20/400 in eleven patients. Seven patients required surgical intervention; four of them underwent penetrating keratoplasty (PK) à chaud one month after the first intrastromal injection. Patients who underwent surgery achieved a BCVA of 20/40 or better. Combined intrastromal injections before therapeutic penetrating keratoplasty (TPK) effectively reduced ulcer size and graft diameter, preventing infection recurrence. Our results highlight the efficacy of combined intrastromal injections in optimizing outcomes for severe mycotic keratitis undergoing TPK.
Influence of Compost Amendments on Soil and Human Gastrointestinal Bacterial Communities during a Single Gardening Season
Authors: Bu Sihan , Beavers Alyssa W. , Sugino Kameron Y. , Keller Sarah F. , Alaimo Katherine , Comstock Sarah S.
Published: May 2024

To measure associations between gardening with different compost amendments and the human gut microbiota composition, gardeners (n = 25) were provided with one of three types of compost: chicken manure (CM), dairy manure and plant material (DMP), or plant-based (P). Stool samples were collected before gardening (T1), after compost amendment (T2), and at peak garden harvest (T3). Compost and soil samples were collected. DNA was extracted, 16S rRNA libraries were established, and libraries were sequenced by Illumina MiSeq. Sequences were processed using mothur, and data were analyzed in R software version 4.2.2. Fast expectation-maximization microbial source tracking analysis was used to determine stool bacteria sources. At T2/T3, the gut microbiotas of P participants had the lowest Shannon alpha diversity, which was also the trend at T1. In stool from T2, Ruminococcus 1 were less abundant in the microbiotas of those using P compost as compared to those using CM or DMP. At T2, Prevotella 9 had the highest abundance in the microbiotas of those using CM compost. In participants who used CM compost to amend their gardening plots, a larger proportion of the human stool bacteria were sourced from CM compared to soil. Soil exposure through gardening was associated with a small but detectable change in the gardeners’ gut microbiota composition. These results suggest that human interactions with soil through gardening could potentially impact health through alterations to the gut microbiota.
Selective Removal of Arsenic and Antimony from Pb-Ag Sulfide Concentrates by Alkaline Leaching: Thermodynamic and Kinetic Studies
Authors: Blanco-Vino Walter , Zamora Gerardo , Ordóñez Javier I.
Published: May 2024

Arsenic and antimony are impurities that reduce the economic value of concentrates due to the environmental problems they cause. The removal of these impurities by hydrometallurgical means has been highly studied for sulfide copper concentrates using different leaching agents in an alkaline medium (NaClO, H2O2, NaOH, Na2S, NaHS, and S). For a lead–silver concentrate consisting of galena, sphalerite, and pyrite, it was possible to selectively reduce the arsenic content from 1.10% to 0.55% and antimony from 2.41 to 1.04% through the digestion-leaching technique that uses elemental sulfur as a leaching agent in alkaline medium. The adequate powdered sulfur and sodium hydroxide dosage were 336 and 342 kg/t, respectively. The process was carried out at 120 °C with a liquid/solid ratio of 2 in digestion and 5.67 in leaching; the appropriate digestion and leaching time were 20 and 30 min, respectively. The thermodynamics and kinetics of this process turned out to be very complex due to the great variety of simultaneous leaching and precipitation reactions. The digestion process exhibited a mixed kinetic control, where diffusion through the boundary layer and the chemical reaction were the controlling steps with an activation energy of 11.05 kcal/mol.
Phenolic Compounds Profile and Antioxidant Capacity of Plant-Based Protein Supplements
Authors: Sawicki Tomasz , Jabłońska Monika , Danielewicz Anna , Przybyłowicz Katarzyna E.
Published: May 2024

The study aimed to determine the phenolic content and antioxidant capacity of five protein supplements of plant origin. The content and profile of phenolics were determined using the UHPLC-DAD-MS method, while antioxidant capacity (ABTS and DPPH assays) and total phenolic content (TPC) were evaluated using spectrophotometric tests. In the analyzed proteins, twenty-five polyphenols were detected, including eleven phenolic acids, thirteen flavonoids, and one ellagitannin. Hemp protein revealed the highest individual phenolics content and TPC value (1620 μg/g and 1.79 mg GAE/g, respectively). Also, hemp protein showed the highest antioxidant activity determined via ABTS (9.37 μmol TE/g) and DPPH (9.01 μmol TE/g) assays. The contents of p-coumaric acid, m-coumaric acid, kaempferol, rutin, isorhamnetin-3-O-rutinoside, kaempferol-3-O-rutinoside, and TPC value were significantly correlated with antioxidant activity assays. Our findings indicate that plant-based protein supplements are a valuable source of phenols and can also be used in research related to precision medicine, nutrigenetics, and nutrigenomics. This will benefit future health promotion and personalized nutrition in the prevention of chronic diseases.
Strategies, Achievements, and Potential Challenges of Plant and Microbial Chassis in the Biosynthesis of Plant Secondary Metabolites
Authors: Han Taotao , Miao Guopeng
Published: May 2024

Diverse secondary metabolites in plants, with their rich biological activities, have long been important sources for human medicine, food additives, pesticides, etc. However, the large-scale cultivation of host plants consumes land resources and is susceptible to pest and disease problems. Additionally, the multi-step and demanding nature of chemical synthesis adds to production costs, limiting their widespread application. In vitro cultivation and the metabolic engineering of plants have significantly enhanced the synthesis of secondary metabolites with successful industrial production cases. As synthetic biology advances, more research is focusing on heterologous synthesis using microorganisms. This review provides a comprehensive comparison between these two chassis, evaluating their performance in the synthesis of various types of secondary metabolites from the perspectives of yield and strategies. It also discusses the challenges they face and offers insights into future efforts and directions.
A New Quinazolinone Alkaloid along with Known Compounds with Seed-Germination-Promoting Activity from Rhodiola tibetica Endophytic Fungus Penicillium sp. HJT-A-6
Authors: Xiao Dongliang , Wang Yan , Gao Congcong , Zhang Xuemei , Feng Weixing , Lu Xuan , Feng Baomin
Published: May 2024

A new quinazolinone alkaloid named peniquinazolinone A (1), as well as eleven known compounds, 2-(2-hydroxy-3-phenylpropionamido)-N-methylbenzamide (2), viridicatin (3), viridicatol (4), (±)-cyclopeptin (5a/5b), dehydrocyclopeptin (6), cyclopenin (7), cyclopenol (8), methyl-indole-3-carboxylate (9), 2,5-dihydroxyphenyl acetate (10), methyl m-hydroxyphenylacetate (11), and conidiogenone B (12), were isolated from the endophytic Penicillium sp. HJT-A-6. The chemical structures of all the compounds were elucidated by comprehensive spectroscopic analysis, including 1D and 2D NMR and HRESIMS. The absolute configuration at C-13 of peniquinazolinone A (1) was established by applying the modified Mosher’s method. Compounds 2, 3, and 7 exhibited an optimal promoting effect on the seed germination of Rhodiola tibetica at a concentration of 0.01 mg/mL, while the optimal concentration for compounds 4 and 9 to promote Rhodiola tibetica seed germination was 0.001 mg/mL. Compound 12 showed optimal seed-germination-promoting activity at a concentration of 0.1 mg/mL. Compared with the positive drug 6-benzyladenine (6-BA), compounds 2, 3, 4, 7, 9, and 12 could extend the seed germination period of Rhodiola tibetica up to the 11th day.
Effects of Seasonal Variation on Nitrogen Use in Brazilian Cerrado Grass Communities
Authors: Keller Victor Camargo , Pereira-Silva Erico Fernando Lopes , Meirelles Sergio Tadeu , Hardt Elisa
Published: May 2024

In savanna ecosystems, the seasonal effects of nitrogen forms and availability, as well as their utilization by plants, influence the abundance and distribution of herbaceous species in grassland communities. This study examines seasonal effects on nitrogen availability and utilization by native grass species in the Cerrado, a savanna ecosystem in Brazil. Ammonium and nitrate levels in soil, nitrate acquisition and transport, and Nitrate Reductase Activity (NRA) in different plant parts during dry and wet periods were assessed. Results indicated higher soil nitrate availability during the wet period, influenced by precipitation, with leaves showing a higher nitrate content compared to roots. There was seasonal modulation in nitrate reduction, with leaves being the primary site during the dry period and roots during the wet period. The studied grass species exhibited heterogeneous responses to seasonal nitrogen availability, potentially affecting community abundance patterns. Findings suggest that edaphoclimatic seasonality plays a crucial role in nitrogen distribution and utilization capacity by grass plants in the Cerrado, contributing to the understanding of these ecosystems’ ecology.
Anatomical Bone Characteristics of the Buccal Step Insertion Site for Mini-Screw Placement in Orthodontic Treatment: A CBCT Study
Authors: Derton Nicola , Bellocchio Angela Mirea , Ciancio Elia , Barbera Serena , Caddia Andrea , Arveda Niki , Nucera Riccardo
Published: May 2024

Background: To analyze the anatomical characteristics of a posterior area in the mandible localized distally to the second molars and extending in the vestibular direction toward the bony step, which we define as “buccal step”, in a patient with different skeletal patterns for mini-screw insertion. Methods: The sample included 85 CBCT (cone beam computed tomography) records selected from the digital archive. Analysis focused on the buccal step area. Sections were obtained in axial view using reference lines, and measurements of cortical and total bone were taken at specific points M0 (starting point, 6 mm apical from CEJc—cementoenamel junction crest), M2 (located 2 mm posterior to M0 in the apical direction), and M4 (positioned 4 mm posterior to M0 in the apical direction) in both directions. Six measurements were recorded for each scan root plane, assessing cortical and total bone depth. Results: The thickness of the bone increases toward the inside of the mouth at all tested sites (M0, M2, M4), which is good for placing mini-screws. Cortical bone thickness decreases toward the inside of the mouth, with no significant differences among the sites except for M0 vs. M4. People with a particular jaw shape (hypo-divergent) have a thicker cortical bone, indicating that facial structure affects bone thickness. Conclusions: The posterior buccal step insertion site has biomechanical advantages and reduces the risk of damaging roots during mini-screw insertions.
A Multiple Scattering-Based Technique for Isotopic Identification in Cosmic Rays
Authors: Dimiccoli Francesco , Follega Francesco Maria
Published: May 2024

Analyzing the isotopic composition of cosmic rays (CRs) provides valuable insights into the galactic environment and helps refine existing propagation models. A particular interest is devoted to secondary-to-primary ratios of light isotopic components of CRs, the measurement of which can provide complementary information with respect to secondary-to-primary ratios like B/C. Given the complexity of the concurrent measurement of velocity and momentum required to differentiate isotopes of the same Z, a task typically accomplished using magnetic spectrometers, existing measurements of these ratios only effectively characterize the low-energy region (below 1 GeV/nucl). This study introduces a novel technique for isotopic distinction in CRs at high energies up to 100 GeV/nucl based on multiple scattering, which, combined with the proposed measurement of velocity, represent an interesting alternative to magnetic spectrometers. The performance of this technique was assessed through a dedicated simulation using the GEANT4 package, with specific emphasis on Z = 1 isotopes.
An Effective Modification Strategy to Build Multifunctional Peptides Based on a Trypsin Inhibitory Peptide of the Kunitz Family
Authors: Wang Ying , Shi Daning , Zou Wanchen , Jiang Yangyang , Wang Tao , Chen Xiaoling , Ma Chengbang , Li Wei , Chen Tianbao , Burrows James F. , Wang Lei , Zhou Mei
Published: May 2024

Peptides with antimicrobial activity or protease inhibitory activity are potential candidates to supplement traditional antibiotics or cancer chemotherapies. However, the potential of many peptides are limited by drawbacks such as cytotoxicity or susceptibility to hydrolysis. Therefore, strategies to modify the structure of promising peptides may represent an effective approach for developing more promising clinical candidates. In this study, the mature peptide OSTI−1949, a Kunitz-type inhibitor from Odorrana schmackeri, and four designed analogues were successfully synthesised. In contrast to the parent peptide, the analogues showed impressive multi-functionality including antimicrobial, anticancer, and trypsin inhibitory activities. In terms of safety, there were no obvious changes observed in the haemolytic activity at the highest tested concentration, and the analogue OSTI−2461 showed an increase in activity against cancer cell lines without cytotoxicity to normal cells (HaCaT). In summary, through structural modification of a natural Kunitz-type peptide, the biological activity of analogues was improved whilst retaining low cytotoxicity. The strategy of helicity enhancement by forming an artificial α-helix and ß-sheet structure provides a promising way to develop original bioactive peptides for clinical therapeutics.
A Two-Way Proposal for the Determination of Bioequivalence for Narrow Therapeutic Index Drugs in the European Union
Authors: Paixao Paulo , Garcia Arieta Alfredo , Silva Nuno , Petric Zvonimir , Bonelli Milton , Morais José Augusto Guimarães , Blake Kevin , Gouveia Luís Filipe
Published: May 2024

In the European Union, bioequivalence (BE) for narrow therapeutic index (NTI) drugs is currently demonstrated when the 90% confidence interval for the ratio of the population geometric means of the test and reference products for AUC, and in some cases for Cmax, falls within the acceptance range of 90.00% to 111.11%. However, meeting this requirement results in an increased difficulty of demonstrating BE and a need for clinical trials with larger subject sample sizes, especially for medium-to-high variability drugs. To address this challenge, a scaled average BE based on the reference product within-subject variability for narrowing the acceptance range of NTI drugs was recently proposed. However, this approach showed increased type I error (T1E), especially close to the cut-off point between the unscaled and scaled portions of the method. Based on simulations, this limitation can be overcome by predefining the protocol the path to be followed: either the fixed 90.00–111.11% acceptance range approach or the previously proposed scaled average BE approach with a slight adjustment of the one-sided significance level α to 0.042 for a 2 × 3 × 3 partial replicate design and without a lower cut-off point. This results in a mixed approach allowing to reduce the sample size whilst not inflating the T1E.
Application of Nanomaterial-Based Sonodynamic Therapy in Tumor Therapy
Authors: Yang Nan , Li Jianmin , Yu Shujie , Xia Guoyu , Li Dingyang , Yuan Longlong , Wang Qingluo , Ding Lijun , Fan Zhongxiong , Li Jinyao
Published: May 2024

Sonodynamic therapy (SDT) has attracted significant attention in recent years as it is an innovative approach to tumor treatment. It involves the utilization of sound waves or ultrasound (US) to activate acoustic sensitizers, enabling targeted drug release for precise tumor treatment. This review aims to provide a comprehensive overview of SDT, encompassing its underlying principles and therapeutic mechanisms, the applications of nanomaterials, and potential synergies with combination therapies. The review begins by introducing the fundamental principle of SDT and delving into the intricate mechanisms through which it facilitates tumor treatment. A detailed analysis is presented, outlining how SDT effectively destroys tumor cells by modulating drug release mechanisms. Subsequently, this review explores the diverse range of nanomaterials utilized in SDT applications and highlights their specific contributions to enhancing treatment outcomes. Furthermore, the potential to combine SDT with other therapeutic modalities such as photothermal therapy (PTT) and chemotherapy is discussed. These combined approaches aim to synergistically improve therapeutic efficacy while mitigating side effects. In conclusion, SDT emerges as a promising frontier in tumor treatment that offers personalized and effective treatment options with the potential to revolutionize patient care. As research progresses, SDT is poised to play a pivotal role in shaping the future landscape of oncology by providing patients with a broader spectrum of efficacious and tailored treatment options.
General Direct Anticancer Effects of Deer Growing Antler Extract in Several Tumour Cell Lines, and Immune System-Mediated Effects in Xenograft Glioblastoma
Authors: Rossetti Alessandra , Chonco Louis , Alegría Nicolas , Zelli Veronica , García Andrés J. , Ramírez-Castillejo Carmen , Tessitore Alessandra , de Cabo Carlos , Landete-Castillejos Tomás , Festuccia Claudio
Published: May 2024

Deer antlers are the fastest growing tissue. Because they are based on proto-oncogenes, to avoid the risk of cancer, antlers evolved strong anticancer mechanisms, and thus their extract (DVA) is effective also against the few human tumours studied so far. We assessed whether DVA is a general anticancer compound by testing the direct effects in cells of different tumours: glioblastoma (GBM; lines U87MG and U251), colorectal (CRC; lines DLD-1, HT-29, SW480, and SW620), breast cancer (BRCA; lines MCF7, SKBR3, and PA00), and leukaemia (THP-1). DVA reduced the viability of tumours but not healthy cells (NHC; lines 293T and HaCaT). Mobility decreased at least for the longest test (72 h). Intraperitoneal/oral 200 mg DVA/kg administration in GBM xenograft mice for 28 d reduced tumour weight by 66.3% and 61.4% respectively, and it also reduced spleen weight (43.8%). In addition, tumours treated with DVA showed symptoms of liquefactive necrosis. Serum cytokines showed DVA up-regulated factors related to tumour fighting and down-regulated those related to inducing immune tolerance to the tumour. DVA shows general anticancer effects in the lines tested and, in GBM mice, also strong indirect effects apparently mediated by the immune system. DVA may contain a future anticancer medicine without secondary effects.
Ligand- and Structure-Based Virtual Screening Identifies New Inhibitors of the Interaction of the SARS-CoV-2 Spike Protein with the ACE2 Host Receptor
Authors: Delgado-Maldonado Timoteo , González-González Alonzo , Moreno-Rodríguez Adriana , Bocanegra-García Virgilio , Martinez-Vazquez Ana Verónica , de Luna-Santillana Erick de Jesús , Pujadas Gerard , Rojas-Verde Guadalupe , Lara-Ramírez Edgar E. , Rivera Gildardo
Published: May 2024

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a fast-spreading viral pathogen and poses a serious threat to human health. New SARS-CoV-2 variants have been arising worldwide; therefore, is necessary to explore more therapeutic options. The interaction of the viral spike (S) protein with the angiotensin-converting enzyme 2 (ACE2) host receptor is an attractive drug target to prevent the infection via the inhibition of virus cell entry. In this study, Ligand- and Structure-Based Virtual Screening (LBVS and SBVS) was performed to propose potential inhibitors capable of blocking the S receptor-binding domain (RBD) and ACE2 interaction. The best five lead compounds were confirmed as inhibitors through ELISA-based enzyme assays. The docking studies and molecular dynamic (MD) simulations of the selected compounds maintained the molecular interaction and stability (RMSD fluctuations less than 5 Å) with key residues of the S protein. The compounds DRI-1, DRI-2, DRI-3, DRI-4, and DRI-5 efficiently block the interaction between the SARS-CoV-2 spike protein and receptor ACE2 (from 69.90 to 99.65% of inhibition) at 50 µM. The most potent inhibitors were DRI-2 (IC50 = 8.8 µM) and DRI-3 (IC50 = 2.1 µM) and have an acceptable profile of cytotoxicity (CC50 > 90 µM). Therefore, these compounds could be good candidates for further SARS-CoV-2 preclinical experiments.
A Comprehensive Review of the Rheological Properties of Powders in Pharmaceuticals
Authors: Brubaker Jack , Moghtadernejad Sara
Published: May 2024

The perpetual significance of the pharmaceutical industry in society necessitates ongoing research efforts to enhance the efficacy of its manufacturing processes. Given that drug product manufacturing typically involves powder processing, a thorough understanding of powder characterization is needed for optimal process performance. Powder rheology is commonly examined in pharmaceutical manufacturing to elucidate the relationship between powder properties and the performance of pharmaceutical processes. This paper provides a brief discussion of recent literature regarding the various powder properties and characterization techniques encompassed in powder rheology. The powder properties are categorized into particle size, particle morphology, friability, electrostatics, permeability, wettability, cohesion, bulk density, and agglomeration sections. A distinct focus is placed on the segment about powder wettability. This review informs readers about the fundamental properties of powders known to influence pharmaceutical processes. It discusses the interrelationships among these properties, powder characterization techniques, and ideal states of powder properties that lead to optimal process performance.
Computational Insights into the Interaction between Neprilysin and α-Bisabolol: Proteolytic Activity against Beta-Amyloid Aggregates in Alzheimer’s Disease
Authors: Martins Jonathan Elias Rodrigues , da Cruz Freire José Ednésio , Vasconcelos-Filho Francisco Sérgio Lopes , da Silva de Almeida Diego , Ceccatto Vânia Marilande , de Sousa Bruno Lopes
Published: May 2024

(1) Background: Alzheimer’s disease (AD) is an irreversible disorder of the central nervous system associated with beta-amyloid protein (Aβ) deposition and accumulation. Current treatments can only act on symptoms and not the etiologic agent. Neprilysin and α-bisabolol have been shown to reduce the aggregation of Aβ, suggesting a potential interaction between both molecules, leading to increased proteolytic activity on Aβ aggregates. (2) Methods: Computational simulations were conducted to explore the interaction between murine neprilysin [NEP(m)] and α-bisabolol and their effects on enzymatic activity. NEP(m) structure was predicted using comparative modeling, and the binding pattern to α-bisabolol and its effects on leu-enkephalin binding were explored through docking calculations and molecular dynamics simulations, respectively. (3) Results: The findings suggest that α-bisabolol stabilizes the Val481-Pro488 segment of NEP2(m), which directly interacts with the peptide substrate, enabling an optimized alignment between the catalytic residue Glu525 and leu-enkephalin. (4) Conclusions: This computational evidence strongly supports the notion that α-bisabolol stabilizes peptide substrates at the NEP2(m) catalytic site, leading to the positive modulation of enzymatic activity.
The Fracture Evolution Mechanism of Tunnels with Different Cross-Sections under Biaxial Loading
Authors: Jia Lexin , Qiu Shili , Cong Yu , Wang Xiaoshan
Published: May 2024

Biaxial compression tests based on an elliptical tunnel were conducted to study the failure characteristics and the meso-crack evolution mechanism of tunnels with different cross-sections constructed in sandstone. The progressive crack propagation process around the elliptical tunnel was investigated using a real-time digital image correlation (DIC) system. Numerical simulations were performed on egg-shaped, U-shaped, and straight-walled arched tunnels based on the mesoscopic parameters of the elliptical tunnel and following the principle of an equal cross-sectional area. The meso-crack evolution and stress conditions of the four types of tunnels were compared. The results show that (1) fractures around an elliptical tunnel were mainly distributed at the end of the long axis and mainly induce slabbing failure, and the failure mode is similar to a V-shaped notch; (2) strain localization is an important characteristic of rock fracturing, which forebodes the initiation, propagation, and coalescence paths of macro-cracks; and (3) the peak loads of tunnels with egg-shaped, U-shaped, and straight-walled arched cross-sections are 98.76%, 97.56%, and 90.57% that of an elliptical cross-section. The elliptical cross-section shows the optimal bearing capacity.
Understanding Plugging Agent Emplacement Depth with Polymer Shear Thinning: Insights from Experiments and Numerical Modeling
Authors: He Shanbin , Xue Chunqi , Du Chang , Mao Yahui , Li Shengnan , Zhong Jianhua , Guo Liwen , Wang Shuoliang
Published: May 2024

Polymer-plugging agents are widely employed in profile control and water-plugging measures, serving as a crucial component for efficient reservoir development. However, quantitatively monitoring the emplacement depth of polymer-plugging agents in low-permeability and high-permeability layers remains a challenging bottleneck. Presently, insufficient attention on shear thinning, a critical rheological property for water shut-off and profile control, has limited our understanding of polymer distribution laws. In this study, polymer shear-thinning experiments are firstly conducted to explore polymer variations with flow rate. The novelty of the research is that varying polymer viscosity is implemented instead of the fixed-fluid viscosity that is conventionally used. The fitted correlation is then integrated into the 2D and 3D heterogeneous numerical models for simulations, and a multivariate nonlinear regression analysis is performed based on the simulation results. The results show that lower polymer emplacement depth ratios corresponded to higher viscosity loss rates under the same flow rate. An increase in the initial permeability ratio corresponds to a decrease in the emplacement ratio, along with a reduction in the fraction of the plugging agent penetrating the low permeability formations. The model was applied to the Kunan Oilfield and demonstrated a polymer reduction of approximately 3000 tons compared to traditional methods. Despite the slightly complex nature of the multivariate nonlinear mathematical model, it presents clear advantages in controlling plugging agent distribution and estimating dosage, laying good theoretical ground for the effective and efficient recovery of subsurface resources.
Predicting Bulk Density for Agglomerated Raspberry Ketone via Integrating Morphological and Size Metrics Using Artificial Neural Networks
Authors: Zhou Xiaomeng , Xuanyuan Shutian , Ye Yang , Sun Ying , Du Haowen , Qi Luguang , Li Chang , Xie Chuang
Published: May 2024

The bulk density of the particles, which is directly related to transportation and storage costs, is an important basic characteristic of products as well as an important parameter in many processing systems. This work quantified the relationship between the tapped bulk density of raspberry ketone with different degrees of agglomeration and morphological metrics (particle shape descriptors and roughness descriptors) and size metrics (size descriptors) and developed an artificial neural network (ANN) prediction model for the tapped bulk density of raspberry ketone. Samples prepared under different conditions were sieved and remixed, the tapped bulk density of the particles was then measured, and the descriptor features of the particles were obtained by combining them with image processing. The dimensions of the variables were decreased by principal component analysis and variance processing. To overcome the hyperparameter estimation of the heuristic-based artificial neural networks, the network model architectures were optimized by a neural architecture search strategy combining two-objective optimization. The results demonstrated that the tapped bulk density of raspberry ketone products is not only related to the descriptors of particle size and shape but also has a non-negligible relationship with particle roughness descriptors. The performance of the optimal ANN model demonstrated that the model can well predict the tapped bulk density of raspberry ketone with different degrees of agglomeration. The ANN model obtained by extracting morphology and size metrics through online image analysis can be used to measure the tapped bulk density in real-time and has the potential to be used for developing model-based online process monitoring.
The Influence of Polyphenolic Compounds on Anaerobic Digestion of Pepper Processing Waste during Biogas and Biomethane Production
Authors: Zupančič Gregor Drago , Lončar Anamarija , Ranilović Jasmina , Šubarić Drago , Panjičko Mario
Published: May 2024

Pepper processing waste has the potential to be used as a substrate in the process of anaerobic digestion, but because of its high polyphenol content, certain limitations are expected. During the determination of the biodegradability of pepper samples, a biogas potential of 687 L/kg DM was observed, as well as a biomethane potential of 401 L/kg DM. While both the testing of biodegradability and the process in the pilot scale progressed, it was observed that total polyphenol content in both cases decreased. Also, as far as individual polyphenols during the process in the pilot scale are concerned, it can be observed that at the end of the process no procyanidin A2, epicatechin, myricetin, and quercetin were detected. The observed concentration of the ferulic acid on the last day of the process was 0.09 µg/g. Finally, it can be concluded that the presence of polyphenols did not significantly affect the biogas potential of pepper waste. Due to its relatively stable biogas production, as far as biogas production on the pilot scale is concerned, it can be concluded that pepper processing waste has the potential to be used as a substrate for biogas production.